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The goal of the work described here was to develop the first neuronavigation-guided transcranial histotripsy (NaviTH) system and associated workflow for transcranial ablation. The NaviTH system consists of a 360-element, 700 kHz transmitter–receiver-capable transcranial histotripsy array, a clinical neuronavigation system and associated equipment for patient-to-array co-registration and therapy planning and targeting software systems. A workflow for NaviTH treatments, including pre-treatment aberration correction, was developed. Targeting errors stemming from target registration errors (TREs) during the patient-to-array co-registration process, as well as focal shifts caused by skull-induced aberrations, were investigated and characterized. The NaviTH system was used in treatments of two <96 h post-mortem human cadavers and in experiments in two excised human skullcaps. The NaviTH was successfully used to create ablations in the cadaver brains as confirmed in post-treatment magnetic resonance imaging A total of three ablations were created in the cadaver brains, and targeting errors of 9, 3.4 and 4.4 mm were observed in corpus callosum, septum and thalamus targets, respectively. Errors were found to be caused primarily by TREs resulting from transducer tracking instrument design flaws and imperfections in the treatment workflow. Transducer tracking instrument design and workflow improvements reduced TREs to <2 mm, and skull-induced focal shifts, following pre-treatment aberration correction, were 0.3 mm. Total targeting errors of the NaviTH system following the noted improvements were 2.5 mm. The feasibility of using the first NaviTH system in a human cadaver model has been determined. Although accuracy still needs to be improved, the proposed system has the potential to allow for transcranial histotripsy therapies without requiring active magnetic resonance treatment guidance. [ABSTRACT FROM AUTHOR]

As the coronavirus disease 2019 (COVID-19) pandemic spread to the United States in 2020, there was an impetus toward postponing or ceasing nonurgent transsphenoidal pituitary surgeries to prevent the spread of the virus. Some centers encouraged transcranial approaches for patients with declining neurologic function. However, no large-scale data exist evaluating the effects that this situation had on national pituitary practice patterns. Pituitary surgeries in the National Inpatient Sample were identified from 2017 to 2020. Surgeries in 2020 were compared with the 3 years previously to determine any differences in demographics, surgical trends/approaches, and perioperative outcomes. In 2020, there was a decline in overall pituitary surgeries (34.2 vs. 36.3%; odds ratio (OR), 0.88; P < 0.001) yet transsphenoidal approaches represented a higher proportion of interventions (69.0 vs. 64.9%; P < 0.001). Neurosurgical complications were higher (51.9 vs. 47.4%; OR, 1.13; P < 0.001) and patients were less likely to be discharged home (86.4 vs. 88.5%; OR, 0.84; P < 0.001). This finding was especially true in April 2020 during the first peak in COVID-19 cases, when transcranial approaches and odds of mortality/complications were highest. In 2020, transsphenoidal surgery remained the preferred approach for pituitary tumor resection despite initial recommendations against the approach to prevent COVID-19 spread. Pituitary surgeries had a higher risk of periprocedural complications despite accounting for preoperative comorbidities, COVID-19 infection status, and surgical approach, suggesting that an overwhelmed hospital system can negatively influence surgical outcomes in noninfected patients. [ABSTRACT FROM AUTHOR]

Transcranial histotripsy has shown promise as a non-invasive neurosurgical tool, as it has the ability to treat a wide range of locations in the brain without overheating the skull. One important effect of histotripsy in the brain is the blood–brain barrier (BBB) opening (BBBO) at the ablation site, but there is a knowledge gap concerning the extent of histotripsy-induced BBBO. Here we describe induction of BBBO by transcranial histotripsy and use of magnetic resonance imaging (MRI) and histology to quantify changes in BBBO at the periphery of the histotripsy ablation zone over time in the healthy mouse brain. An eight-element, 1 MHz histotripsy transducer with a focal distance of 32.5 mm was used to treat the brains of 23 healthy female BL6 mice. T1-gadolinium (T1-Gd) MR images were acquired immediately following histotripsy treatment and during each of the subsequent 4 wk to quantify the size and intensity of BBB leakage. The T1-Gd MRI results revealed that the hyperintense BBBO volume increased over the first week and subsided gradually over the following 3 wk. Histology revealed complete loss of tight junction proteins and blood vessels in the center of the ablation region immediately after histotripsy, partial recovery in the periphery of the ablation zone 1 wk following histotripsy and near-complete recovery of tight junction complex after 4 wk. These results provide the first evidence of transcranial histotripsy-induced BBBO and repair at the periphery of the ablation zone. [ABSTRACT FROM AUTHOR]

Cerebral venous sinus thrombosis (CVST) may impair dynamic cerebral autoregulation (dCA) of the middle cerebral artery (MCA). However, most studies have focused on dCA of the MCA; a few studies are based on the posterior cerebral artery (PCA) during silent reading and neurovascular coupling (NVC). This study explored the effects of CVST on dCA of the MCA and PCA during silent reading and NVC. From January 2021 to August 2022, 60 CVST patients and 30 controls were enrolled in this study. Non-invasive continuous beat-to-beat blood pressure, cerebral blood flow velocity and other associated information on the MCA and PCA during silent reading were collected using a transcranial Doppler. NVC assessment was performed by opening and closing the eyes periodically based on voice prompts, and eye-opening visual stimulation was achieved by silently reading Chinese tourism materials. Visual stimulation signals can selectively activate Brodmann's areas 17, 18, and 19 of the occipital when reading silently with open eyes, prompting them to release neurotransmitters and dilate PCA. dCA was determined by transfer function analysis. In dCA of the PCA during silent reading, the CVST group's very low frequency phase was lower than that of the control group (p = 0.047). In NVC, the difference in the indexes of the cerebrovascular conductance and visually evoked flow response of the CVST group were lower than those of the control group (p = 0.017 and p = 0.019, respectively). Compared with the control group, dCA and NVC of the PCA during silent reading were impaired in CVST patients. [ABSTRACT FROM AUTHOR]

Currently, there is a knowledge gap in our understanding of the magnetic resonance imaging (MRI) characteristics of brain tumors treated with histotripsy to evaluate treatment response as well as treatment-related injuries. Our aim was to bridge this gap by investigating and correlating MRI with histological analysis after histotripsy treatment of mouse brain with and without brain tumors and evaluating the evolution of the histotripsy ablation zone on MRI over time. An eight-element, 1 MHz histotripsy transducer with a focal distance of 32.5 mm was used to treat orthotopic glioma-bearing mice and normal mice. The tumor burden at the time of treatment was ∼5 mm3. T2, T2*, T1 and T1-gadolinium (Gd) MR images and histology of the brain were acquired on days 0, 2 and 7 for tumor-bearing mice and days 0, 2, 7, 14, 21 and 28 post-histotripsy for normal mice. T2 and T2* sequences most accurately correlated with histotripsy treatment zone. The treatment-induced blood products, T1 along with T2, revealed blood product evolution from oxygenated, de-oxygenated blood and methemoglobin to hemosiderin. And T1-Gd revealed the state of the blood–brain barrier arising from the tumor or histotripsy ablation. Histotripsy leads to minor localized bleeding, which resolves within the first 7 d as evident on hematoxylin and eosin staining. By day 14, the ablation zone could be distinguished only by the macrophage-laden hemosiderin, which resides around the ablation zone, rendering the treated zone hypo-intense on all MR sequences. These results provide a library of radiological features on MRI sequences correlated to histology, thus allowing for non-invasive evaluation of histotripsy treatment effects in in vivo experiments. [ABSTRACT FROM AUTHOR]

Single-element low-intensity focused ultrasound (LIFU) is an emerging form of human neuromodulation. Current coupling methods are impractical for clinical bedside use. Here, we evaluate commercially available high-viscosity gel polymer matrices as couplants for human LIFU neuromodulation applications. We first empirically tested the acoustic transmission of three densities at 500 kHz and then subjected the gel with the least acoustic attenuation to further tests of the effect of thickness, frequency, de-gassing and production variability. The highest-density gel had the lowest acoustic attenuation (3.3%) with low lateral (<0.5 mm) and axial (<2 mm) beam distortion. Different thicknesses of the gel up to 10 mm did not appreciably affect results. The gel polymers exhibited frequency-dependent attenuation at 1 and 3 MHz up to 86.6%, as well as significant beam distortion >4 mm. Poor de-gassing methods also increased pressure attenuation at 500 kHz up to 59.6%. Standardized methods of making these gels should be established to reduce variability. Commercially available de-gassed, high-density gel matrices are a low-cost, easily malleable, low-attenuation and distortion medium for the coupling of single-element LIFU transducers for human neuromodulation applications at 500 kHz. [ABSTRACT FROM AUTHOR]

Transcranial focused ultrasound has the potential to noninvasively modulate deep brain circuits and impart sustained, neuroplastic effects. Bring the approach closer to translations by demonstrating sustained modulation of deep brain circuits and choice behavior in task-performing non-human primates. Low-intensity transcranial ultrasound of 30 s in duration was delivered in a controlled manner into deep brain targets (left or right lateral geniculate nucleus; LGN) of non-human primates while the subjects decided whether a left or a right visual target appeared first. While the animals performed the task, we recorded intracranial EEG from occipital screws. The ultrasound was delivered into the deep brain targets daily for a period of more than 6 months. The brief stimulation induced effects on choice behavior that persisted up to 15 minutes and were specific to the sonicated target. Stimulation of the left/right LGN increased the proportion of rightward/leftward choices. These effects were accompanied by an increase in gamma activity over visual cortex. The contralateral effect on choice behavior and the increase in gamma, compared to sham stimulation, suggest that the stimulation excited the target neural circuits. There were no detrimental effects on the animals' discrimination performance over the months-long course of the stimulation. This study demonstrates that brief, 30-s ultrasonic stimulation induces neuroplastic effects specifically in the target deep brain circuits, and that the stimulation can be applied daily without detrimental effects. These findings encourage repeated applications of transcranial ultrasound to malfunctioning deep brain circuits in humans with the goal of providing a durable therapeutic reset. • Transcranial ultrasound induces sustained modulation of deep brain circuits in task-performing non-human primates. • The deep brain stimulation elicits a contralateral bias in visual choice behavior. • The stimulation increases gamma and decreases alpha and beta activity in visual cortex. • The stimulation is applied safely over the course of several months. [ABSTRACT FROM AUTHOR]

Responsive neurostimulation (RNS) is a treatment option for patients with refractory epilepsy when surgical resection is not possible due to overlap of the irritative zone and eloquent cortex. Presurgical evaluations for RNS placement typically rely on invasive methods. This study investigated the potential of transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG) to provide key presurgical information non-invasively. We hypothesized that these non-invasive methods may assist in optimizing RNS placement by providing useful information for seizure localization by MEG and eloquent cortex mapping by TMS. A retrospective chart review identified nine patients who underwent RNS placement (mean age = 20.4 years [ SD = 5.6], two-thirds were female). Characterization of the irritative zone using MEG was successful in eight of nine patients. Non-invasive mapping of relevant eloquent cortex was attempted in all patients. TMS was successful in eight of nine patients, and MEG was successful in two of six patients. Importantly, patients mapped with non-invasive modalities experienced an average seizure reduction of 77 % at their most recent clinic visit, compared to 75 % seizure reduction in those with invasive evaluations, indicating appropriate RNS placement. These data demonstrate that TMS and MEG can provide key information for RNS and may be feasible alternatives to invasive methods for assisting in decision making regarding RNS placement. Non-invasive methods for determining RNS placement have a high rate of success when data from multiple non-invasive modalities converge and can inform more accurate placement of intracranial electrodes prior to RNS placement or mitigate their need. • Non-invasive characterization of the irritative zone using magnetoencephalography (MEG) is possible. • Non-invasive mapping of eloquent cortex is possible using transcranial magnetic stimulation (TMS). • TMS and MEG can provide key information for responsive neurostimulator (RNS) placement. [ABSTRACT FROM AUTHOR]

An increase in the latency of a motor evoked potential might be as significant as a decrease in amplitude to predict a significant and clinically symptomatic neurological injury in spinal surgery for adolescent idiopathic scoliosis. The aim of the study was to investigate the impact of monitoring of latency of motor evoked potentials during spinal surgery for adolescent idiopathic scoliosis by describing intraoperative data. Preoperative recordings of 50 patients undergoing posterior spinal fusion for idiopathic scoliosis were studied. Latencies of appearance of the motor evoked potential curves on the right and left side were recorded for each group of muscles at several key moments during the procedure (basal, before the first implant, before and after corrective maneuvers). Mean latencies were approximately the same in each muscle group on the right and the left side, before and after correction. There was no significant increase in latency during surgery. Overall results showed that the measured latency did not differ significantly between the two age groups (p=0.07). Negative correlation between height and the means of latencies was recorded in the abductor pollicis brevis and abductor digiti minimi (r=0.4; p=0.009), rectus femoris (r=0.4; p=0.01), tibialis anterior (r=0.4; p=0.007), and abductor hallucis (r=0.5; p=0.0004). No significant correlation was found between age and intraoperative parameters. Intraoperative latency could be a reliable intraoperative monitoring criteria with low variability, that might be used to predict postoperative motor deficits in surgery for adolescent idiopathic scoliosis. [ABSTRACT FROM AUTHOR]

• C1(+)-C4(-) or C2(+)–C3(-) stimulation was performed to induce unilateral muscle responses. • This stimulation induced unilateral MEPs with a suprathreshold stimulation in 97% of patients. • This technique specifically activates the motor cortex with localized current distribution. Transcranial electrical stimulation motor evoked potentials (TES-MEP) are widely used to monitor motor function; however, broad current spread and induced body movement are limitations of this technique. We herein report a localized stimulation technique for TES-MEP that induces unilateral MEP responses. The stimulation of C1(+)-C4(-) or C2(+)–C3(-) was performed to induce right- or left-sided muscle contraction, respectively, in 70 patients. Electromyography was recorded by placing electrodes on the bilateral abductor pollicis brevis (APB) and abductor hallucis (AH) muscles. Stimulation conditions were regulated in the range to induce unilateral muscle contractions contralateral to the anodal stimulation. The thresholds and amplitudes of TES-MEP were retrospectively analyzed. The thresholds of APB were lower than those of AH in 47 patients, AH thresholds were lower than those of APB in 6 patients, and both APB and AH started to respond at the same intensity in 15 patients. This technical stimulation induced contralateral limb contractions with a suprathreshold stimulation of 129.4 ± 35.6 mA (mean ± standard deviation) in 68 patients (97%). Amplitudes in the suprathreshold stimulation of APB and AH responses were 727.5 ± 695.7 and 403.3 ± 325.7 μV, respectively. The C1(+)–C4/C2(+)–C3(-) stimulation in TES-MEP enables a localized stimulation to induce unilateral MEP responses. Our stimulation technique enables the stable and safe monitoring of unilateral limbs, and contributes to the reliable monitoring of motor function in neurosurgery. [ABSTRACT FROM AUTHOR]

• Significant venous flow alterations occur post arteriovenous malformation resection (brain) • Trancranial Colour Duplex demonstrates increased venous pulsatility and velocity. • Significantly increased venous flow occurs in pial veins bilaterally. • Increased venous diameter and pulsatility indicates increased venous pressure. • Haemorrhagic complications may be due to distal vasospasm of pial veins: venous hypertension. Brain arteriovenous malformation (bAVM) resection imposes several post-operative clinical challenges including intracranial haemorrhage (ICH). Daily non-invasive monitoring of haemodynamic measurements may be useful in predicting post-operative ICH. This prospective study used transcranial colour duplex (TCCD) and central aortic pressure (CAP) measurements to evaluate 15 bAVM patients pre-operatively and daily ≤ 14 days post-operatively. TCCD measurements of middle cerebral artery and veins included peak systolic (PSV), end diastolic (EDV), and pulsatility indices (PI). Parameters were compared with 7 craniotomy patients (non-bAVM craniotomy/surgical group). Normal reference values included 20 healthy volunteers. Significant middle cerebral vein MCV changes in bAVM patients occurred; Maximal PSV was significantly higher (median 47 cm/s) compared to non-bAVM craniotomy/surgical controls (median 17 cm/s, p = 0.0123); maximal PI was significantly higher (median 0.99, p = 0.005) compared to the non-bAVM craniotomy/surgical controls (median 0.49). In 8 of 15 patients, increased MCV velocity and pulsatility "stabilised" within 14 days post-operatively. Mean number of days for the 8 patients to reach stable state was 5.9 days, (range 0–9 days). To our knowledge, this is the first imaging study demonstrating significant venous changes post bAVM resection. Significant increased venous flow occurs in pial veins bilaterally. Increased pressure of venous flow is evidenced by a significant increase in diameter and pulsatility. Subsequently, haemorrhagic complications may be due distal constriction of the pial veins causing venous hypertension. The cause of the dilated vascular bed is unknown. [ABSTRACT FROM AUTHOR]

Exposure to ultrasound combined with intravenous injection of microbubbles is a technique that can be used to temporarily disrupt the blood-brain barrier. Transcranial monitoring of cavitation can be done with one or more passive cavitation detectors (PCDs). However, the positioning of the PCDs relative to the cavitation site and the attenuation of these signals by the skull are two sources of error in the quantification of cavitation activity. The aim of this study was to evaluate in vitro the amplitude variation of cavitation signals that can be expected for an excised porcine skull model. The variation caused by the relative positioning of the PCD with respect to the cavitation site was quantified. A position-based correction of the signal amplitude was evaluated. Pig skull samples were used to assess variation in signal amplitude caused by bone. The overall coefficient of variation of the signals owing to these measurement biases was estimated at 30.8%. [ABSTRACT FROM AUTHOR]

To quantitatively compare different microsurgical and endoscopic approaches to the middle cranial fossa in a preclinical setting with a novel, computer-based research method. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Epilepsy is a neurological disorder characterized by abnormal neuron discharge, and one-third of epilepsy patients suffer from drug-resistant epilepsy (DRE). The current management for DRE includes epileptogenic lesion resection, disconnection, and neuromodulation. Neuromodulation is achieved through invasive electrical stimulus including deep brain stimulation, vagus nerve stimulation, or responsive neurostimulation (RNS). As an alternative therapy, transcranial focused ultrasound (FUS) can transcranially and non-invasively modulate neuron activity. This study seeks to verify the use of FUS pulsations to suppress spikes in an acute epileptic small-animal model, and to investigate possible biological mechanisms by which FUS pulsations interfere with epileptic neuronal activity. The study used a total of 76 Sprague-Dawley rats. For the epilepsy model, rats were administered pentylenetetrazol (PTZ) to induce acute epileptic-like abnormal neuron discharges, followed by FUS exposure. Various ultrasound parameters were set to test the epilepsy-suppressing effect, while concurrently monitoring and analyzing electroencephalogram (EEG) signals. Animal behavior was monitored and histological examinations were conducted to evaluate the hazard posed by ultrasound exposure and the expression of neuronal activity markers. Western blotting was used to evaluate the correlation between FUS-induced epileptic suppression and the PI3K-mTOR signaling pathway. We observed that FUS pulsations effectively suppressed epileptic activity and observed EEG spectrum oscillations; the spike-suppressing effect depended on the selection of ultrasound parameters and highly correlated with FUS exposure level. Expression level changes of c-Fos and GAD65 were confirmed in the cortex and hippocampus, indicating that FUS pulsations deactivated excitatory cells and activated GABAergic terminals. No tissue damage, inflammatory response, or behavioral abnormalities were observed in rats treated with FUS under these exposure parameters. We also found that the FUS pulsations down-regulated the S6 phosphorylation and decreased pAKT expression. Our results suggest that pulsed FUS exposure effectively suppresses epileptic spikes in an acute epilepsy animal model, and finds that ultrasound pulsation interferes with neuronal activity and affects the PTZ-induced PI3K-Akt-mTOR pathway, which might help explain the mechanism underlying ultrasound-related epileptic spike control. • Focused ultrasound pulsation effectively suppresses epileptic spikes in an acute epilepsy animal model. • FUS induced spike-suppressing effect depends on the selection of ultrasound parameters. • Ultrasound pulsation down-regulates the S6 phosphorylation and decreases pAKT expression. [ABSTRACT FROM AUTHOR]

[Display omitted] • Therapeutic photobiomodulation refers to irradiation of the brain using low-intensity red or near-infrared light. • Recent advances support importance of transcranial photobiomodulation for central nervous system disorders. • Adjusted parameters of photobiomodulation are the key factors in optimizing the treatment effect. Transcranial photobiomodulation refers to irradiation of the brain through the skull using low-intensity red or near-infrared light, which is the most commonly studied method of light energy biotherapy for central nervous system disorders. The absorption of photons by specific chromophores within the cell elevates ATP synthesis, reduces oxidative stress damage, alleviates inflammation or mediates the activation of transcription factors and signaling mediators through secondary mediators, which in turn trigger downstream signaling pathways to cause a series of photobiological effects including upregulation of neurotrophic factors. Multiple mechanisms are simultaneously involved in the pathological process of central nervous system disorders. The pleiotropic treatment of transcranial photobiomodulation towards multiple targets plays a beneficial role in improving hemodynamics, neural repair and improving behaviors in central nervous system disorders such as ischemic stroke, traumatic brain injury, neurodegenerative diseases, epilepsy and depression. This review mainly introduces the mechanism and recent preclinical and clinical advances of transcranial photobiomodulation for central nervous system disorders, which will provide a reference for clinicians to understand and engage in related studies, and calls for more and larger studies to validate and develop a wider application of transcranial photobiomodulation in central nervous system. [ABSTRACT FROM AUTHOR]

• We examine the effect of photobiomodulation on brain activity using fMRI. • Photobiomodulation had no effect on cerebral blood flow or resting state activity. • After finger-tapping, photobiomodulation resulted in reduction in brain activity. • Affected regions were putamen, primary somatosensory and parietal association cortex. • These light-induced changes served to deactivate the so-called default mode network. We explore whether near infrared light can change patterns of resting (task-negative) and/or evoked (task-positive; eg finger-tapping) brain activity in normal, young human subjects using fMRI (functional magnetic resonance imaging). To this end, we used a vielight transcranial device (810 nm) and compared the scans in subjects after active- and sham-light sessions. Our fMRI results showed that, while light had no effect on cerebral blood flow and global resting state brain activity (task-negative), there were clear differences between the active- and sham-light sessions in the patterns of evoked brain activity after finger-tapping (task-positive). The evoked brain regions included the putamen, primary somatosensory and parietal association cortex, and the overall effect of the light was to suppress or reduce their activity. We also found that while light had no effect on the resting functional connectivity of the putamen and primary somatosensory cortex and the rest of the brain, it did have an effect on the functional connectivity of parietal association cortex. In summary, our fMRI findings indicated that transcranially applied light did have a major impact on brain activity in normal subjects, but only when the brain region was itself functionally active, when undertaking a particular task. We suggest that these light-induced changes, particularly those in parietal association cortex, were associated with attention and novelty, and served to deactivate the so-called default mode network. Our results lay the template for our planned fMRI explorations into the effects of light in both Alzheimer's and Parkinson's disease patients. [ABSTRACT FROM AUTHOR]

To evaluate the feasibility of transcranial sonography in patients harboring polymethylmethacrylate cranioplasties (PMMA-CP) and explore whether this material is a valid sonic window to explore intracerebral structures. In 6 patients, we performed transcranial sonography (TCS), using the PMMA-CP as sonic window. To test the reliability of ultrasound images, we collected several quantitative and qualitative measurements of intracranial structures and compared these sonographic images with standard computed tomography (CT) scan images. We found that PMMA-CP is a very good sonic window and allowed us to obtain very good quality echographic images of intracranial structures, as shown by the comparison of measurements with CT scan, which were very reliable. The main drawback was related to the shape (i.e., the curvature) of the cranial flap, which hindered the ultrasound probe from correctly adhering to the scalp. Although limited by the restricted number of cases, this preliminary experience represents the first available data about the serial use of TCS using PMMA-CP as window. These results open the path to the routine use of TCS to longitudinally control patients already harboring PMMA-CP. More, we here discuss its potential role in globally reducing the number of follow-up CT and magnetic resonance imaging scans required in different type of patients and pathologies. [ABSTRACT FROM AUTHOR]

Highlights • Corticospinal excitability to biceps brachii is phase-dependent during arm cycling. • Corticospinal excitability to biceps brachii is task-dependent during arm cycling. • Corticospinal excitability to the biceps and triceps brachii are different. Abstract The purpose of the present study was to examine corticospinal excitability to the biceps and triceps brachii during arm cycling and an intensity-matched tonic contraction using stimulus response curves (SRCs) elicited via transcranial magnetic stimulation (TMS). Corticospinal excitability was assessed using TMS elicited motor-evoked potentials (MEPs) at eight different stimulation intensities (85–190% of MEP threshold). MEPs were recorded during arm cycling at two different positions, mid-elbow flexion (6 o'clock relative to a clock face) and mid-elbow extension (12 o'clock relative to a clock face), in addition to an intensity-matched (12 o'clock) tonic contraction. At the 12 o'clock position, the slope of the SRC was significantly lower during arm cycling than the tonic contraction for the biceps brachii (Cycling: 0.64 ± 0.47, Tonic: 1.02 ± 0.38, P < 0.05) but was not different for the triceps brachii (Cycling: 1.33 ± 0.49, Tonic: 1.48 ± 0.43, P = 0.42). Within arm cycling, the SRC slope was significantly greater at the 6 o'clock position than 12 o'clock position for the biceps brachii (6 o'clock: 1.37 ± 0.24, 12 o'clock: 0.64 ± 0.47, P < 0.05) but was not different for the triceps brachii (6 o'clock: 1.11 ± 0.28, 12 o'clock: 1.33 ± 0.49, P = 0.34). These findings demonstrate that corticospinal excitability to the biceps brachii is task-dependent during the extension phase of arm cycling. Neither position nor task influenced corticospinal excitability to the triceps brachii, providing further support that the motor control of locomotor outputs is muscle-specific. [ABSTRACT FROM AUTHOR]

We describe a new application of acoustoelectric imaging for non-invasive mapping of the location, magnitude and polarity of current generated by a clinical deep brain stimulation (DBS) device. Ultrasound at 1MHz was focused near the DBS device as short current pulses were injected across different DBS leads. A recording electrode detected the high-frequency acoustoelectric interaction signal. Linear scans of the US beam produced time-varying images of the magnitude and polarity of the induced current, enabling precise localization of the DBS leads within 0.70mm, a detection threshold of 1.75mA at 1 MPa and a sensitivity of 0.52 ± 0.07 μV/(mA*MPa). Monopole and dipole configurations in saline were repeated through a human skullcap. Despite 13.8-dB ultrasound attenuation through bone, acoustoelectric imaging was still >10dB above background with a sensitivity of 0.56 ± 0.10 μV/(mA*MPa). This proof-of-concept study indicates that selective mapping of lead currents through a DBS device may be possible using non-invasive acoustoelectric imaging. [ABSTRACT FROM AUTHOR]

• A large planar transducer is used to emit ultrasound through human skull specimens. • Global brain sonication yields skull lens effects and intracranial reflections. • Sonication trajectory influences intracranial ultrasound field distribution. • Ultrasound dose homogeneity is scored across the human skull intracranial space. Contrary to conditioning a Focused Ultrasound (FUS) beam to sonicate a localized region of the human brain, the goal of this investigation was to explore the prospect of distributing homogeneous ultrasound energy over the entire brain space with a large cranium-wide ultrasound beam. Recent ultrasound preclincal studies utilizing large or whole brain stimulation regions create a demand for expanding the treatment envelope of transcranial pulsed-low intensity ultrasound towards Global Brain Sonication (GBS) for potential human investigation. Here, we conduct ultrasound field characterizations when transmitting pulsed ultrasound through human skull specimens using a 1–3 piezocomposite planar transducer operating at 464 kHz with an active single-element surface of 30 × 30 cm. Through computational simulation and hydrophone scanning methodology, ultrasound wave behavior and dose homogeneity in the brain space were evaluated under various trajectories of sonication using the planar transducer. Clinically relevant pulse parameters used for transcranial therapeutic ultrasound applications were used in the experiments. Simulations and empirical testing revealed that dose homogeneity and acoustic intensity over the brain space are influenced by sonication trajectory, skull lens effects, and acoustic wave reflections. The transducer can emit a spatial peak pulse average intensity of 4.03 W/cm2 (0.24 MPa) measured in the free-field at 464 kHz with electrical power of 1 kW. The simulation showed that approximately 99 % of the cranial volume was exposed with <30 % of the maximum external acoustic intensity being transmitted into the skull. The transmission loss across all sonication trajectories is similar to previously reported FUS studies. A marker for GBS dose homogeneity is introduced to score the ultrasound pressure field uniformity in the intracranial space. Results of this study identify the initial challenges of exposing the entire human brain space with ultrasound using a large cranium-wide sonication beam intended for global brain therapeutic modulation. [ABSTRACT FROM AUTHOR]

Functional ultrasound (fUS) imaging by ultrasensitive Doppler detection of blood volume was previously reported to measure adult rat brain activation and functional connectivity with unmatched spatiotemporal sampling (100 μm, 1 ms), but skull-induced attenuation of ultrasonic waves imposed skull surgery or contrast agent use. Also, fUS feasibility remains to be validated in mice, a major pre-clinical model organism. In the study described here, we performed full-depth ultrasensitive Doppler imaging and 3-D Doppler tomography of the entire mouse brain under anesthesia, non-invasively through the intact skull and skin, without contrast agents. Similar results were obtained in anesthetized young rats up to postnatal day 35, thus enabling longitudinal studies on postnatal brain development. Using a newly developed ultralight ultrasonic probe and an optimized ultrasonic sequence, we also performed minimally invasive full-transcranial fUS imaging of brain vasculature and whisker stimulation-induced barrel cortex activation in awake and freely moving mice, validating transcranial fUS for brain imaging, without anesthesia-induced bias, for behavioral studies. [ABSTRACT FROM AUTHOR]

Background: Data and best practice recommendations for transcranial magnetic stimulation (TMS) use in adults are largely available. Although there are fewer data in pediatric populations and no published guidelines, its practice in children continues to grow.Methods: We performed a literature search through PubMed to review all TMS studies from 1985 to 2016 involving children and documented any adverse events. Crude risks were calculated per session.Results: Following data screening we identified 42 single-pulse and/or paired-pulse TMS studies involving 639 healthy children, 482 children with central nervous system disorders, and 84 children with epilepsy. Adverse events occurred at rates of 3.42%, 5.97%, and 4.55% respective to population and number of sessions. We also report 23 repetitive TMS studies involving 230 central nervous system and 24 children with epilepsy with adverse event rates of 3.78% and 0.0%, respectively. We finally identified three theta-burst stimulation studies involving 90 healthy children, 40 children with central nervous system disorder, and no epileptic children, with adverse event rates of 9.78% and 10.11%, respectively. Three seizures were found to have occurred in central nervous system disorder individuals during repetitive TMS, with a risk of 0.14% per session. There was no significant difference in frequency of adverse events by group (P = 0.988) or modality (P = 0.928).Conclusions: Available data suggest that risk from TMS/theta-burst stimulation in children is similar to adults. We recommend that TMS users in this population follow the most recent adult safety guidelines until sufficient data are available for pediatric specific guidelines. We also encourage continued surveillance through surveys and assessments on a session basis. [ABSTRACT FROM AUTHOR]

Background: Cerebral microemboli (ME) are frequently generated during orthopaedic surgery and may impair cerebral integrity. However, the nature of cerebral ME, being either of solid or gaseous origin, is poorly investigated. Our primary aim was to determine both the frequency and nature of cerebral ME in generally anaesthetised patients undergoing major orthopaedic surgery.Methods: Fifty patients (hip/knee/shoulder prosthesis, spine surgery) were enrolled. Cerebral ME and cerebral blood flow velocity (CBFV) were determined in both middle cerebral arteries for 15 min preoperatively and postoperatively, using transcranial Doppler ultrasound. Cerebral tissue oxygen index, determined by near-infrared spectroscopy, was further examined. Statistical analysis was carried out using the Wilcoxon matched-pairs signed-ranks test (median (25 th ; 75 th percentile), P  < 0.05).Results: Overall the frequency of postoperative cerebral ME rose to 600% of preoperative values. Primarily gaseous ME occurred preoperatively and postoperatively [19 (6; 63) vs 116 (24; 373), P  < 0.001], while the number of solid ME was negligibly small [1 (0; 2) vs 2 (0; 6), P  < 0.001]. CBFV and cerebral tissue oxygen index remained unaltered bilaterally before and after surgery.Conclusions: Our findings indicate that cerebral ME considerably increase after major orthopaedic surgery under general anaesthesia. The predominant accumulation of gaseous ME and their preoperative occurrence, suggest that the general anaesthesia and individual patient factors may contribute to the embolic load in addition to orthopaedic surgery.Clinical trial registration: . NCT02340416. [ABSTRACT FROM AUTHOR]

Background/objective: We sought to assess the different patterns of cerebral hemodynamic changes in staged carotid angioplasty and stenting (CAS).Methods: We prospectively recruited a cohort of patients with regular angioplasty or staged angioplasty from October 2013 to August 2015. The hemodynamic changes, including peak systolic, end-diastolic, and mean flow velocities in the ipsilateral middle cerebral artery (MCA) and the contralateral anterior cerebral artery (ACA), were recorded by transcranial Doppler ultrasound.Results: Between October 2013 to August 2015, 25 patients (age range from 48 to 78 years, 96% male) with CAS were recruited, of whom 13 patients received staged angioplasty and 12 patients received regular angioplasty. Patients in the staged angioplasty group showed a higher degree of stenosis in the internal carotid artery. After the procedure, the peak systolic, diastolic, and mean flow velocities in the ipsilateral MCA in the staged angioplasty group were significantly higher than those in the regular angioplasty group (P = .028, .036, and .027, respectively). In the staged angioplasty group, first, the peak systolic, end-diastolic, and mean flow velocities in the contralateral ACA decreased significantly soon after balloon dilation in stage I (P = .042, .033, and .034, respectively). Second, the peak systolic, diastolic, and mean flow velocities in the ipsilateral MCA increased after stent placement in stage II (P = .006, .042, and .003, respectively).Conclusions: Two-stage hemodynamic changes were observed in staged angioplasty. The velocities in the ipsilateral MCA started to increase significantly after the collateral flow diminished. [ABSTRACT FROM AUTHOR]

Dramatic hemodynamic changes occur following resection of brain arteriovenous malformations (AVM). Transcranial Doppler (TCD) records non-invasive velocity and pulsatility parameters. We undertook a systematic review to assess AVM hemodynamics including the time course of changes in velocity and pulsatility in patients undergoing AVM resection. The review employed the Embase and Medline databases. A search strategy was designed. An initial title search for clinical series on AVM and TCD was performed followed by a search for reports on AVM and TCD. A total of 283 publications were selected. Full text analysis produced 54 studies with extractable data regarding AVM, velocity and pulsatility. Two TCD techniques were utilized: conventional “blind” TCD (blind TCD); and transcranial color duplex Doppler (TCCD). Of these, 23 publications reported on blind TCD and seven on TCCD. The presence of high velocity and low pulsatility within AVM feeding arteries preoperatively followed by a postoperative decrease in velocity and subsequent increase in pulsatility of feeding arteries is established. The time sequence of hemodynamic changes following AVM resection using TCD remains uncertain, confounded by variations in methodology and timing of perioperative measurements. Of the two techniques, TCCD reported qualitative aspects including improved differentiation of feeding arteries from draining veins. However, there are a limited number of studies supporting this conclusion. Furthermore, none report reproducible changes with time from treatment. TCCD appears to be a useful technique to analyze the hemodynamic changes occurring following treatment of AVM, however little data is available. This is a field of research that is appropriate to pursue. [ABSTRACT FROM AUTHOR]

Highlights • tDCS is a useful neuromodulation approach to manage obsessive compulsive symptoms in schizophrenia. • Cathodal stimulation at supplementary motor area is a viable and effective tDCS protocol to manage OCD in schizophrenia. • Neuronal circuitry responding to tDCS for OCD in schizophrenia may be similar to that of OCD without schizophrenia. Abstract Management of obsessive compulsive disorder (OCD) remains a challenge, particularly in individuals having co-existing psychotic symptoms. Even in patients with schizophrenia having a fair to good response in psychotic symptoms, these obsessive-compulsive symptoms defy response to antipsychotic and anti-obsessive pharmaco-therapeutic approach to a great extent. Recently developed neuromodulation techniques such as transcranial direct current stimulation (tDCS) can serve a viable and effective approach to manage such cases. The present paper documents the first utilization of tDCS (cathode: supplementary motor area; anode: right occipital cortex) as an add-on approach to pharmacotherapy to manage co-morbid OCD in a case of chronic schizophrenia. [ABSTRACT FROM AUTHOR]

• We proposed the framework of transcranial focused ultrasound (tFUS) stimulation integrating our two previously proposed methods for tFUS transducer configuration optimization and a subject-specific 3D-printed helmet. • To validate this framework, tFUS stimulations were applied to the left dorsolateral prefrontal cortex (DLPFC) while human participants were performing anti-saccade tasks. • The result indicates that the cortical stimulation using our tFUS setup effectively reduces the error rates of anti-saccade tasks, whereas no significant effect was observed on their latencies. • We demonstrated that our tFUS framework can be effectively used in human behavioral study, and our tFUS stimulation targeted to the DLPFC could generate a neuromodulatory effect on AS behavior. As a novel non-invasive human brain stimulation method, transcranial focused ultrasound (tFUS) is receiving growing attention due to its superior spatial specificity and depth penetrability. Since the focal point of tFUS needs to be fixated precisely to the target brain region during stimulation, a critical issue is to identify and maintain the accurate position and orientation of the tFUS transducer relative to the subject's head. This study aims to propose the entire framework of tFUS stimulation integrating the methods previously proposed by the authors for tFUS transducer configuration optimization and a subject-specific 3D-printed helmet, and to validate this complete setup in a human behavioral neuromodulation study. To find the optimal configuration of the tFUS transducer, a numerical method based on subject-specific tFUS beamlines simulation was used. Then, the subject-specific 3D-printed helmet has been applied to effectively secure the transducer at the estimated optimal configuration. To validate this tFUS framework, a common behavioral neuromodulation paradigm was chosen; the effect of the dorsolateral prefrontal cortex (DLPFC) stimulation on anti-saccade (AS) behavior. While human participants (n=2) were performing AS tasks, tFUS stimulations were randomly applied to the left DLPFC right after the fixation target disappeared. The neuromodulation result strongly suggests that the cortical stimulation using the proposed tFUS setup is effective in significantly reducing the error rates of anti-saccades (about -10 %p for S1 and -16 %p for S2), whereas no significant effect was observed on their latencies. These observed behavioral effects are consistent with the previous results based on conventional brain stimulation or lesion studies. The proposed subject-specific tFUS framework has been effectively used in human neuromodulation study. The result suggests that the tFUS stimulation targeted to the DLPFC can generate a neuromodulatory effect on AS behavior. [ABSTRACT FROM AUTHOR]

Background A small proportion of individuals with Tourette syndrome (TS) have a lifelong course of illness that fails to respond to conventional treatments. Open label studies have suggested that low frequency (1-Hz) repetitive transcranial magnetic stimulation (rTMS) targeting the supplementary motor area (SMA) may be effective in reducing tic severity. Objective/Hypothesis To examine the efficacy of rTMS over the SMA for TS in a randomized double-blind sham-controlled trial (RCT). Methods We conducted a two-site RCT-rTMS with 20 adults with severe TS for 3 weeks. Treatment consisted of 15 sessions (1-Hz; 30 min; 1800 pulses per day) of active or sham rTMS at 110% of the motor threshold over the SMA. A subsequent 3 week course of active rTMS treatment was offered. Results Of the 20 patients (16 males; mean age of 33.7 ± 12.2 years), 9 received active and 11 received sham rTMS. After 3 weeks, patients receiving active rTMS showed on average a 17.3% reduction in the YGTSS total tic score compared to a 13.2% reduction in those receiving sham rTMS, resulting in no statistically significant reduction in tic severity ( P = 0.27). An additional 3 week open label active treatment for those patients ( n = 7) initially randomized to active rTMS resulted in a significant overall 29.7% reduction in tic severity compared to baseline ( P = 0.04). Conclusion This RCT did not demonstrate efficacy of 3-week SMA-targeted low frequency rTMS in the treatment of severe adult TS. Further studies using longer or alternative stimulation protocols are warranted. [ABSTRACT FROM AUTHOR]

Transnasal-penetrating intracranial injuries are rare traumatic brain injuries that can cause serious and fatal brain damage and a high mortality rate and necessitate immediate multidisciplinary surgical management. We describe an uncommon case whereby a patient who presented with an accidental penetrating injury of the brain was found to have a wooden transnasal-penetrating intracranial object. A 28-year-old man consulted an ear, nose, and throat (ENT) surgeon after complaints of headache for two days, a history of epistaxis, and vomitus. The right side of the nose had been punctured by wood as a result of falling from a motorcycle. A computed tomography (CT) scan led to diagnosis of a transnasal penetrating intracranial injury. Removal of the transcranial foreign body was carried out jointly by a neurosurgeon and ENT surgeon. Postoperatively, antibiotics were given for 14 days, and the patient was discharged without neurological deficit. Early diagnostic procedures, such as CT scan of the skull to assess trajectory and extent of vascular and brain tissue injury, are required for appropriate surgical planning and post-operative treatment of such patients. Surgery was performed by combined transcranial and transnasal endoscopy to identify the skull base, dura mater defect, and brain tissue damage. Removal of the corpus alienum by transnasal endoscopy yielded a good outcome. Combined transcranial and transnasal endoscopic approach showed better result than transcranial approach only. The wooden foreign body can be completely eliminated transnasally without active bleeding using this approach. The patient was discharged with good outcome. • Transnasal-penetrating intracranial injuries can cause serious and fatal brain damage. • We report a rare case of penetrating injury to the brain due to a wooden transnasal-penetrating intracranial object. • Surgery was performed by combined transcranial and transnasal endoscopy. • That combined approach showed better results than transcranial approach only. [ABSTRACT FROM AUTHOR]

Abstract: Background: Suicide attempts and completed suicides are common, yet there are no proven acute medication or device treatments for treating a suicidal crisis. Repeated daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) for 4–6 weeks is a new FDA-approved treatment for acute depression. Some open-label rTMS studies have found rapid reductions in suicidality. Design: This study tests whether a high dose of rTMS to suicidal inpatients is feasible and safe, and also whether this higher dosing might rapidly improve suicidal thinking. This prospective, 2-site, randomized, active sham-controlled (1:1 randomization) design incorporated 9 sessions of rTMS over 3 days as adjunctive to usual inpatient suicidality treatment. The setting was two inpatient military hospital wards (one VA, the other DOD). Patients: Research staff screened approximately 377 inpatients, yielding 41 adults admitted for suicidal crisis. Because of the funding source, all patients also had either post-traumatic stress disorder, mild traumatic brain injury, or both. TMS methods: Repetitive TMS (rTMS) was delivered to the left prefrontal cortex with a figure-eight solid core coil at 120% motor threshold, 10 Hertz (Hz), 5 second (s) train duration, 10 s intertrain interval for 30 minutes (6000 pulses) 3 times daily for 3 days (total 9 sessions; 54,000 stimuli). Sham rTMS used a similar coil that contained a metal insert blocking the magnetic field and utilized electrodes on the scalp, which delivered a matched somatosensory sensation. Main outcome measure: Primary outcomes were the daily change in severity of suicidal thinking as measured by the Beck Scale of Suicidal Ideation (SSI) administered at baseline and then daily, as well as subjective visual analog scale measures before and after each TMS session. Mixed model repeated measures (MMRM) analysis was performed on modified intent to treat (mITT) and completer populations. Results: This intense schedule of rTMS with suicidal inpatients was feasible and safe. Minimal side effects occurred, none differing by arm, and the 3-day retention rate was 88%. No one died of suicide within the 6 month followup. From the mITT analyses, SSI scores declined rapidly over the 3 days for both groups (sham change −15.3 points, active change −15.4 points), with a trend for more rapid decline on the first day with active rTMS (sham change −6.4 points, active −10.7 points, P = 0.12). This decline was more pronounced in the completers subgroup [sham change −5.9 (95% CI: −10.1, −1.7), active −13 points (95% CI: −18.7, −7.4); P = 0.054]. Subjective ratings of ‘being bothered by thoughts of suicide’ declined non-significantly more with active rTMS than with sham at the end of 9 sessions of treatment in the mITT analysis [sham change −31.9 (95% CI: −41.7, −22.0), active change −42.5 (95% CI: −53.8, −31.2); P = 0.17]. There was a significant decrease in the completers sample [sham change −24.9 (95% CI: −34.4, −15.3), active change −43.8 (95% CI: −57.2, −30.3); P = 0.028]. Conclusions: Delivering high doses of left prefrontal rTMS over three days (54,000 stimuli) to suicidal inpatients is possible and safe, with few side effects and no worsening of suicidal thinking. The suggestions of a rapid anti-suicide effect (day 1 SSI data, Visual Analogue Scale data over the 3 days) need to be tested for replication in a larger sample. Trial registration: ClinicalTrials.gov Identifier: NCT01212848, TMS for suicidal ideation. [Copyright &y& Elsevier]

Abstract: In the early 20th century, the first successful surgical removal of a tuberculum sellae meningioma (TSM) was performed and described by Harvey Cushing. It soon became recognized that TSM pose a formidable challenge for skull base surgeons because of their deep and sensitive location, proximity to critical neurovascular elements, and often dense and fibrous nature. Because of this, over the next several decades controversy transpired regarding their optimal method of resection. Early attempts involved utilization of open transcranial routes. This included classic bilateral and unilateral frontal approaches, followed by pterional or frontotemporal approaches, which have evolved to incorporate skull base modifications, such as the supraorbital, orbitozygomatic, and orbitopterional approaches. Minimally invasive supraorbital keyhole approaches through eyebrow incisions have also been adopted. Over the past 25years, the microsurgical transsphenoidal approach, classically used for pituitary and parasellar tumors, was modified to resect suprasesllar TSM via the extended transsphenoidal approach. More recently, with the evolution of endoscopic techniques, resection of TSM has been achieved using purely endoscopic endonasal transplanum transtuberculum approaches. Although each of these techniques has been successfully described for the treatment of TSM, the question still remains: is it better to access and operate on these lesions via a traditional, transcranial avenue, or are they better treated via endoscopic endonasal techniques? We outline the surgical management of TSM through history, from early transcranial and transsphenoidal approaches to modern extended endoscopic endonasal procedures. We briefly explore the arguments favoring each of the methods and the advancements which have emerged to further optimize surgical resection. [Copyright &y& Elsevier]

Abstract: With stroke currently the second-leading cause of death globally, and 87% of all strokes classified as ischemic, the development of a fast, accessible, cost-effective approach for imaging occlusive stroke could have a significant impact on health care outcomes and costs. Although clinical examination and standard computed tomography alone do not provide adequate information for understanding the complex temporal events that occur during an ischemic stroke, ultrasound imaging is well suited to the task of examining blood flow dynamics in real time and may allow for localization of a clot. A prototype bilateral 3-D ultrasound imaging system using two matrix array probes on either side of the head allows for correction of skull-induced aberration throughout two entire phased array imaging volumes. We investigated the feasibility of applying this custom correction technique in five healthy volunteers with Definity microbubble contrast enhancement. Subjects were scanned simultaneously via both temporal acoustic windows in 3-D color flow mode. The number of color flow voxels above a common threshold increased as a result of aberration correction in five of five subjects, with a mean increase of 33.9%. The percentage of large arteries visualized by 3-D color Doppler imaging increased from 46% without aberration correction to 60% with aberration correction. [Copyright &y& Elsevier]

Highlights: [•] We review all cerebellar non-motor non-invasive stimulation studies. [•] Effects seen in learning, memory, cognition, emotions, perception and timing. [•] Diversity seen in stimulation parameters and targets despite similar tasks. [•] Neuronavigation approaches shown to be beneficial. [•] Improved understanding of physiology of stimulation essential. [Copyright &y& Elsevier]

Abstract: Ultrasound imaging has been proposed as a rapid, portable alternative imaging modality to examine stroke patients in pre-hospital or emergency room settings. However, in performing transcranial ultrasound examinations, 8%–29% of patients in a general population may present with window failure, in which case it is not possible to acquire clinically useful sonographic information through the temporal bone acoustic window. In this work, we describe the technical considerations, design and fabrication of low-frequency (1.2 MHz), large aperture (25.3 mm) sparse matrix array transducers for 3-D imaging in the event of window failure. These transducers are integrated into a system for real-time 3-D bilateral transcranial imaging—the ultrasound brain helmet—and color flow imaging capabilities at 1.2 MHz are directly compared with arrays operating at 1.8 MHz in a flow phantom with attenuation comparable to the in vivo case. Contrast-enhanced imaging allowed visualization of arteries of the Circle of Willis in 5 of 5 subjects and 8 of 10 sides of the head despite probe placement outside of the acoustic window. Results suggest that this type of transducer may allow acquisition of useful images either in individuals with poor windows or outside of the temporal acoustic window in the field. [Copyright &y& Elsevier]

Abstract: The distortion and attenuation of transcranial ultrasound (US) signals are significant problems in US imaging of the brain. Of the variety of proposed solutions, shear-mode transmission through the skull is one of the more recent options and has been shown to reduce distortion of the US beam. This study examined the effects of transcranial shear-mode transmission on the images of a contrast-agent–filled polytetrafluoroethylene tube produced by a 32-element 750 kHz linear phased array transducer through an ex vivo human skull section. Although the tube was successfully imaged using shear-mode transmission with subharmonic imaging in 6 of 9 cases, the tube was visible in only 1 of 9 cases for both the fundamental and the second harmonic frequencies. Some improvement in the location of the axial image was seen at the fundamental frequency using shear mode. No improvement was seen at the other two frequencies, but this may be due to low transducer sensitivity. As well, neither the presence of the skull nor the incident angle changed the distance at which signals from the two tubes could be resolved. With this transducer, these distances were found to be 5 mm laterally and 3 mm axially for the fundamental and second harmonic images, and 10 mm and 5 mm for the subharmonic images. The results show that the subharmonic signal was the most successful of the three examined in penetrating a thick skull but that the success comes at the cost of image resolution. [Copyright &y& Elsevier]

Background: The growing use of transcranial electric and magnetic (EM) brain stimulation in basic research and in clinical applications necessitates a clear understanding of what constitutes the dose of EM stimulation and how it should be reported. Methods: This paper provides fundamental definitions and principles for reporting of dose that encompass any transcranial EM brain stimulation protocol. Results: The biologic effects of EM stimulation are mediated through an electromagnetic field injected (via electric stimulation) or induced (via magnetic stimulation) in the body. Therefore, transcranial EM stimulation dose ought to be defined by all parameters of the stimulation device that affect the electromagnetic field generated in the body, including the stimulation electrode or coil configuration parameters: shape, size, position, and electrical properties, as well as the electrode or coil current (or voltage) waveform parameters: pulse shape, amplitude, width, polarity, and repetition frequency; duration of and interval between bursts or trains of pulses; total number of pulses; and interval between stimulation sessions and total number of sessions. Knowledge of the electromagnetic field generated in the body may not be sufficient but is necessary to understand the biologic effects of EM stimulation. Conclusions: We believe that reporting of EM stimulation dose should be guided by the principle of reproducibility: sufficient information about the stimulation parameters should be provided so that the dose can be replicated. [ABSTRACT FROM AUTHOR]

Summary: Because of the recent hypothesis of involvement of the venous hemodynamics in multiple sclerosis (MS), and because of the pitfalls of these studies, there is the need to achieve a definite conclusion from a large sample of subjects by using a strict and controlled neurosonological protocol. The aim of the advanced protocol, designed for a subgroup of the FISM study, is to analyze several items of the venous hemodynamics in order to obtain more pathophysiological data on venous circulation. Advanced Ultrasound Protocol: This is a multicenter, observational study. From a pool of about 1200 adults with MS, 400 healthy subjects and 400 subjects with other neurodegenerative disorders (2000 subjects in total) will be selected a population able to be examined by the advanced protocol. The examiner will always be blind on the clinical diagnosis, and the exams will be performed according to a standard protocol, whose measurements are mandatory for all participating centers. The advanced protocol is on a voluntary basis and it is optional. It includes, besides the basic one, measurements of blood flow volumes in carotid and vertebral arteries and in jugular and vertebral veins (inflow and outflow), with the definition of the drainage pattern. The ultrasound examination at each clinical site will be followed by a second centralized blinded evaluation. The prevalence of CCSVI in MS will be estimated, with confidence intervals at 95%, and compared with the prevalence in other groups. Moreover, multiple analysis will be done comparing venous hemodynamics in the three different groups. [ABSTRACT FROM AUTHOR]

Summary: Introduction: The ultrasound examination of intracranial venous structures by transcranial color-coded sonography (TCCS) is a validated and standardized application. Similarly some intracranial venous sinuses are known for their relatively low insonation rate, as straight sinus (SRS) and transverse sinus (TS), ranging from 35% to 73%. The relatively high frequency of hypoplasia of TS can partially take account for these data. The aim of this study is to evaluate the feasibility of this approach in a standard TCCS examination, in comparison with magnetic resonance (MR) findings by using the Virtual Navigator system. Patients and methods: The standardized approach to the TS was a contralateral insonation, starting to the SRS plane and angulating downwards the probe. In this way it is possible to insonate the proximal segment of the contralateral TS. We proposed a new approach with an extreme downwards tilting and a slow opposite angulation of the probe for examining the ispilateral TS. Forty consecutive subjects were chosen among patients who underwent standard TCCS examinations at our lab and had a suitable temporal acoustic window, and a recently performed MR venography. The contralateral TS insonation rate was compared with the ipsilateral one. Results and discussion: The insonation rate was 61/80 (76.25%) for the contralateral TS and 75/80 (93.75%) for the ipsilateral approach. Two of 5 not detectable TS were aplasic in MR venography and the others were not identified by a poor acoustic window. Conclusions: The ipsilateral approach could be associated to the contralateral standard study for insonating the TS. [ABSTRACT FROM AUTHOR]

Summary: Introduction: Neuroradiological techniques are known for their high spatial resolution in imaging of intracranial structures, in comparison with neurosonological techniques (TCCS), known for their high temporal resolution. An ideal study of intracranial circulation should combine the high temporal resolution of ultrasound with the high spatial resolution of Magnetic Resonance (MR) Imaging. This imaging fusion system is actually used for the ultrasound liver examination and it is known as Virtual Navigator. Therefore we implemented this system for the examination of the intracranial venous hemodynamics. Patients and methods: Fifteen consecutive subjects (7 men and 8 women, mean age 51.5±8.64 years) were chosen among patients who underwent standard TCCS examinations at our lab and had age >18 years, a suitable temporal acoustic window and a recently performed intracranial MR venography. The axial scanning approach was used from the temporal window and the standard TCCS examination was compared with the Virtual Navigator examination, for the insonation rate of the basal vein of Rosenthal (BVR), Galen vein (GV), Straight sinus (SRS) and Transverse sinus (TS). Results and discussion: The insonation rates of the venous structures are only slightly improved for BVR (from 90% to 96.67%) but are substantially increased for SRS and TS (for this last one from 63.33% to 86.67%) with a statistically significant difference (p <0.05). Conclusions: The Virtual Navigator protocol can help to insonate the intracranial venous system. [ABSTRACT FROM AUTHOR]

Summary: Introduction: The epidemiology and the prognosis of asymptomatic moyamoya arteriopathy is virtually unknown, mainly in white western population, while symptomatic moyamoya arteriopathy is a more known disease, both in children and in adult people. We are presenting a single centre case series of six asymptomatic adult people with a neurosonological (Transcranial Colour Coded Sonography – TCCS) suspicion of this type of cerebral arteriopathy, confirmed by Digital Subtraction Angiography (DSA). Patients and methods: During a time period of three years we collected a series of six patients (5 female and 1 male, mean age 29.16+8.45 years) with a neurosonological suspicion and a neuroradiological diagnostic confirmation of moyamoya type arteriopathy. All patients underwent TCCS, brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) and DSA, besides the differential diagnosis of immunological or infectious etiology. The mean follow-up was 1.8 years. Results and discussion: All patients but one had a bilateral internal carotid artery (ICA) stenosis at terminus and M1 middle cerebral artery (MCA) multiple stenoses. There is only one young patient with an atypical unilateral pathway and narrowing of extracranial ICA with prominent posterior cerebral artery (PCA) compensation. No clinical events occurred during the follow-up and also brain MRI failed to find new ischemic lesions, compared with the baseline examination. Conclusions: Asymptomatic cerebral moyamoya arteriopathy is an infrequent but underestimated condition in young white people. More prognostic informations are needed in order to define the natural course and propose the treatment. [ABSTRACT FROM AUTHOR]

Abstract: The great potential of transcranial Doppler (TCD) as a tool for neuromonitoring is limited by the current parameterization of the signal. This article proposes a set of new parameters that more accurately represents the shape of the waveform and eliminates a number of confounding factors. This set of parameters was tested in 227 patients with ipsilateral carotid artery stenosis and compared with 31 normal subjects recruited at our laboratory. From the TCD waveform, we calculated on a beat-to-beat basis the maximal change in flow velocity at stroke onset (acceleration or acc), the maximal flow velocity during the first 100 ms of systole (sys1) and the maximal flow velocity in the remaining part of systole (sys2). All data were normalized relative to the mean diastolic flow velocity over an interval ranging from 520 till 600 ms after stroke onset (dias@560). For the group with carotid stenosis compared with the normal controls the average ± SD for acc (20.2 ± 9.5 vs. 20.2 ± 6.7; p = 0.98) and sys1 (1.82 ± 0.38 vs. 1.77 ± 0.56; p = 0.35) did not differ significantly. The average ±SD for sys2 (1.94 ± 0.33 vs. 1.50 ± 0.12; p < 0.001), however, was significantly higher in the group with carotid stenosis than in the group of normal subjects. The difference between sys1 and sys2 (“sys1–sys2”) was lower in the patient group than in controls (−0.12 ± 0.16 vs. 0.27 ± 0.22; p < 0.001). For the acc, there was a significantly higher variance in the group with stenosis than without (p < 0.001). Of the old parameters, the beat-to-beat mean (37.0 ± 13.1 vs. 41.3 ± 15.9; p = 0.17) and the pulsatility index (PI; 1.00 ± 0.26 vs. 0.91 ± 0.23; p = 0.06) were not significantly different between groups. Graphed together the acc and “sys1–sys2” parameters allowed a clear demarcation of both groups whereas in a graph of the old parameters mean and PI both groups overlapped considerably. In conclusion, the proposed set of new parameters not only has theoretical and practical benefits but also has excellent discriminative power in a group of carotid patients compared with normal controls. [Copyright &y& Elsevier]

Abstract: We investigated the safety of transcranial-targeting midfrequency (0.1 to 1 MHz) ultrasonic thrombolysis for acute ischemic stroke. We applied a new therapeutic and imaging transducer to healthy Macaca monkey brains via sonication of the ipsilateral middle cerebral artery through an acoustic temporal window. Young adult cynomolgus monkeys (Macaca fascicularis) were assigned to a group without sonication (control), a group maintained for 1 d after sonication (C1) and a group maintained for 7 d after sonication (C7; n = 3 for each). Two elder rhesus monkeys (Macaca mulatta) were ultrasonicated under transvenous injection of the recombinant tissue plasminogen activator alteplase (0.9 mg/kg), and maintained for 7 d (R). An automatic switching circuit alternately operated a therapeutic ultrasound beam (T-beam) generator for thrombolysis (frequency = 490 kHz; intensity = 0.72 W/cm2) and a diagnostic color-flow imaging ultrasound beam (D-beam; frequency = 2.5 MHz; intensity = 0.20 W/cm2). A 15-min protocol, comprising four repeats of a sequence of 120-s T-beam activation followed by 30-s D-beam activation and then 5-min T-beam deactivation together with D-beam activation, was repeated four times over 60 min. After confirmation of neurologic deficits, the brains were removed and investigated histologically and immunohistochemically. Three skull samples were subjected to 494-kHz continuous waveform ultrasound, the transcranial intensity was measured and the mechanical index was calculated. None of the monkeys showed neurologic deficits after ultrasonication. The transskull ultrasound intensity rate was 48 ± 12%. The intracranial mechanical index value was 0.15. The novel system did not cause tissue damage in the primate brain and no cavitation effect was detected intracranially. [Copyright &y& Elsevier]

Abstract: The aim of this study was to assess the feasibility and reproducibility of a simple and nonobtrusive repeated sit-stand maneuver to assess cerebral autoregulation (CA) in healthy old subjects >70 years. In 27 subjects aged 76 (SD 4) years, we continuously measured blood pressure using photoplethysmography and cerebral blood flow velocity in the middle cerebral artery (transcranial Doppler ultrasonography) during 5min of sitting rest and again during repeated sit-stand maneuvers at 10 s (0.05Hz) and 5 s (0.1Hz) intervals. In 11 randomly selected subjects, these measurements were repeated after 3 months. Both maneuvers induced substantial periodic oscillations in pressure and flow. For example, the maneuvers at 0.05Hz increased the power spectral density (magnitude) of blood pressure and cerebral blood flow velocity oscillations with 16.3 (mm Hg)2 and 14.5 (cm/s)2, respectively (p <0.001). These larger oscillations led to an increase in transfer function coherence compared with spontaneous oscillations from 0.46 to 0.60 for 0.05Hz maneuvers and from 0.56 to 0.76 for 0.1Hz maneuvers (p <0.01), allowing for more confident assessment of CA through transfer function phase and gain. This increased coherence was not associated with improved reproducibility however. In conclusion, we were able to investigate CA in old patients using these repeated sit-stand maneuvers, which, compared with spontaneous oscillations, produced a stronger and more clinically relevant hemodynamic challenge for CA. (E-mail: j.claassen@ger.umcn.nl) [Copyright &y& Elsevier]

Abstract: Objective: To examine the relationship between the ratio of injected current to electrode area (I/A) and the current density at a fixed target point in the brain under the electrode during transcranial direct current stimulation (tDCS). Methods: Numerical methods were used to calculate the current density distribution in a standard spherical head model as well as in a homogeneous cylindrical conductor. Results: The calculations using the cylindrical model showed that, for the same I/A ratio, the current density at a fixed depth under the electrode was lower for the smaller of the two electrodes. Using the spherical model, the current density at a fixed target point in the brain under the electrode was found to be a non-linear function of the I/A ratio. For smaller electrodes, more current than predicted by the I/A ratio was required to achieve a predetermined current density in the brain. Conclusions: A non-linear relationship exists between the injected current, the electrode area and the current density at a fixed target point in the brain, which can be described in terms of a montage-specific I–A curve. Significance: I–A curves calculated using realistic head models or obtained experimentally should be used when adjusting the current for different electrode sizes or when comparing the effect of different current–electrode area combinations. [Copyright &y& Elsevier]

Abstract: Statins have been shown in two recent small phase I/II trials to be associated with a marked reduction in clinical and transcranial Doppler (TCD) evidence of vasospasm after aneurysmal subarachnoid haemorrhage (SAH). The purpose of this study was to assess the clinical impact of this treatment in a larger number of patients. Fifty-eight individuals were treated in the year before, and 72 patients treated in the year after, the introduction of a 2week course of 40mg/day pravastatin therapy for SAH. Statins did not result in reduced TCD velocities, clinical or angiographic vasospasm, or improvements in global outcome at the time of hospital discharge. A measurable reduction in the rates of vasospasm was expected, based on the size of the effect of statin therapy in the previous small studies. There remains significant uncertainty as to the role of statins in preventing vasospasm after SAH. [Copyright &y& Elsevier]

• The tympanic membrane is that closest place in the head, to which noninvasive electric stimulation can be applied. • Tympanic membrane electrode is four times more efficient than ear canal electrode and 10 times more than scalp electrodes in terms of electrically evoked auditory responses. • Tympanic membrane electric stimulation is more effective in tinnitus suppression than ear canal and scalp-based electric stimulation. 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 alternative to interventions using invasive electrical stimulation such as cochlear implantation, or other non-invasive transcranial electrical stimulation methods. [ABSTRACT FROM AUTHOR]

Abtract: We describe early stage experiments to test the feasibility of an ultrasound brain helmet to produce multiple simultaneous real-time three-dimensional (3D) scans of the cerebral vasculature from temporal and suboccipital acoustic windows of the skull. The transducer hardware and software of the Volumetrics Medical Imaging (Durham, NC, USA) real-time 3D scanner were modified to support dual 2.5 MHz matrix arrays of 256 transmit elements and 128 receive elements which produce two simultaneous 64° pyramidal scans. The real-time display format consists of two coronal B-mode images merged into a 128° sector, two simultaneous parasagittal images merged into a 128° x 64° C-mode plane and a simultaneous 64° axial image. Real-time 3D color Doppler scans from a skull phantom with latex blood vessel were obtained after contrast agent injection as a proof of concept. The long-term goal is to produce real-time 3D ultrasound images of the cerebral vasculature from a portable unit capable of internet transmission thus enabling interactive 3D imaging, remote diagnosis and earlier therapeutic intervention. We are motivated by the urgency for rapid diagnosis of stroke due to the short time window of effective therapeutic intervention. (E-mail: ssmith@duke.edu) [Copyright &y& Elsevier]

Abstract: Transcranial magnetic stimulation (TMS) is a non-invasive method to investigate motor pathways and to create a map of the somatotopical organization of the motor cortex: ordinary mapping procedures requires a focal brain stimulation over different spots of the scalp and electromyographic (EMG) recording from a muscle. Finding an appropriate and a valid visual representation of collected data is a crucial step in research and clinical field to allow a relatively fast, intra- and inter-patient comparison of motor cortex mapping. Aim of this study was to develop and to validate a method to map cortical representation of an intrinsic hand muscle (abductor digiti minimi, ADM) using a two-dimensional spline interpolation of EMG peak amplitudes obtained with TMS. The interpolated model will result in a graphical colour-scaled representation of the motor cortex for the investigated muscle; fitted model was finally validated by comparing derived parameters with those directly measured to ensure the strength and reliability of the model. Ten healthy volunteers (mean age±S.D.: 35.3±4.7 years, 4 males and 6 females) were enrolled in the study. Transcranial stimulation was performed by placing a figure-of-eight coil over a predefined grid on the scalp of the subject. EMG responses were recorded from the right abductor digiti minimi (ADM): averaged EMG peak amplitudes obtained at each node were then used to perform spline interpolation and to derive other parameters like center of gravity (CoG). Arithmetical mean of all resting motor threshold at the hotspot was 50.6±3.4% of the maximal stimulator output. Average amplitude at the hotspot was 1.72±0.80mV and its coordinates, expressed as median, were x =4.5cm and y =0.0cm. Mean CoG was located at x =4.86±0.57cm and y =0.35±0.10cm. Mean interpolated peak coordinates for ADM were xf =4.86±0.58cm and yf =0.36±0.12cm, while mean fitted peak amplitude was 0.87±0.47mV. Results suggest how it is possible to map the primary motor cortex using two-dimensional spline interpolation of peak-to-peak amplitudes obtained by single pulse TMS delivered on several scalp positions, which will result in a smooth, easy to read, colour-scaled map. However, like other visual representation modalities, the interpolation should become complementary to traditional methods and not a substitute of a precise and accurate cortical motor mapping. [Copyright &y& Elsevier]

Abstract: Contrast-enhanced (CE) transcranial ultrasound (US) and reconstructed 3-D transcranial ultrasound have shown advantages over traditional methods in a variety of cerebrovascular diseases. We present the results from a novel ultrasound technique, namely real-time 3-D contrast-enhanced transcranial ultrasound. Using real-time 3-D (RT3D) ultrasound and microbubble contrast agent, we scanned 17 healthy volunteers via a single temporal window and nine via the suboccipital window and report our detection rates for the major cerebral vessels. In 71% of subjects, both of our observers identified the ipsilateral circle of Willis from the temporal window, and in 59% we imaged the entire circle of Willis. From the suboccipital window, both observers detected the entire vertebrobasilar circulation in 22% of subjects, and in 44%, the basilar artery. After performing phase aberration correction on one subject, we were able to increase the diagnostic value of the scan, detecting a vessel not present in the uncorrected scan. These preliminary results suggest that RT3D CE transcranial US and RT3D CE transcranial US with phase aberration correction have the potential to greatly impact the field of neurosonology. (E-mail: ni3@duke.edu) [Copyright &y& Elsevier]

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