A phase I trial of accelerated intermittent theta burst rTMS for amnestic MCI.

BACKGROUND: Emerging evidence suggests that repetitive transcranial magnetic stimulation (rTMS) enhances cognition in mild cognitive impairment (MCI). Accelerated intermittent theta burst stimulation (iTBS) rTMS protocols are promising as they substantially reduce burden by shortening the treatment course, but the safety, feasibility, and acceptability of iTBS have not been established in MCI. METHODS: 24 older adults with amnestic MCI (aMCI) due to possible Alzheimer's disease enrolled in a phase I trial of open-label accelerated iTBS to the left dorsolateral prefrontal cortex (8 stimulation sessions of 600 pulses of iTBS/day for 3 days). Participants rated common side effects during and after each session and retrospectively (at post-treatment and 4-week follow-up). They completed brain MRI (for safety assessments and electric field modeling), neuropsychiatric evaluations, and neuropsychological testing before and after treatment; a subset of measures was administered at follow-up. RESULTS: Retention was high (95%) and there were no adverse neuroradiological, neuropsychiatric, or neurocognitive effects of treatment. Participants reported high acceptability, minimal side effects, and low desire to quit despite some rating the treatment as tiring. Electric field modeling data suggest that all participants received safe and therapeutic cortical stimulation intensities. We observed a significant, large effect size (d=0.98) improvement in fluid cognition using the NIH Toolbox Cognition Battery from pre-treatment to post-treatment. CONCLUSIONS: Our findings support the safety, feasibility, and acceptability of accelerated iTBS in aMCI. In addition, we provide evidence of target engagement in the form of improved cognition following treatment. These promising results directly inform future trials aimed at optimizing treatment parameters. TRIAL REGISTRATION NUMBER: NCT04503096.

Template MRI scans reliably approximate individual and group-level tES and TMS electric fields induced in motor and prefrontal circuits.

Background: Electric field (E-field) modeling is a valuable method of elucidating the cortical target engagement from transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (tES), but it is typically dependent on individual MRI scans. In this study, we systematically tested whether E-field models in template MNI-152 and Ernie scans can reliably approximate group-level E-fields induced in N = 195 individuals across 5 diagnoses (healthy, alcohol use disorder, tobacco use disorder, anxiety, depression). Methods: We computed 788 E-field models using the CHARM-SimNIBS 4.0.0 pipeline with 4 E-field models per participant (motor and prefrontal targets for TMS and tES). We additionally calculated permutation analyses to determine the point of stability of E-fields to assess whether the 152 brains represented in the MNI-152 template is sufficient. Results: Group-level E-fields did not significantly differ between the individual vs. MNI-152 template and Ernie scans for any stimulation modality or location (p > 0.05). However, TMS-induced E-field magnitudes significantly varied by diagnosis; individuals with generalized anxiety had significantly higher prefrontal and motor E-field magnitudes than healthy controls and those with alcohol use disorder and depression (p < 0.001). The point of stability for group-level E-field magnitudes ranged from 42 (motor tES) to 52 participants (prefrontal TMS). Conclusion: MNI-152 and Ernie models reliably estimate group-average TMS and tES-induced E-fields transdiagnostically. The MNI-152 template includes sufficient scans to control for interindividual anatomical differences (i.e., above the point of stability). Taken together, using the MNI-152 and Ernie brains to approximate group-level E-fields is a valid and reliable approach.

Altered cerebral perfusion in response to chronic mild hypercapnia and head-down tilt Bed rest as an analog for Spaceflight.

PURPOSE: Following prolonged stays on the International Space Station (ISS), some astronauts exhibit visual acuity changes, ophthalmological findings, and mildly elevated intracranial pressures as part of a novel process called spaceflight-associated neuro-ocular syndrome (SANS). To determine the pathophysiology of SANS, NASA conducted a multi-investigator study in which 11 healthy participants underwent head-down tilt bed rest, mimicking microgravity-induced cephalad fluid shifts, combined with elevated ambient CO2 levels similar to those on the ISS (HDT+CO2). As part of that study, we examined the effects of HDT+CO2 on cerebral perfusion. METHODS: Using arterial spin labeling, we compared cerebral perfusion before, during, and after HDT+CO2 in participants who developed SANS (n = 5) with those who did not (n = 6). RESULTS: All participants demonstrated a decrease in perfusion during HDT+CO2 (mean decrease of 25.1% at HDT7 and 16.2% at HDT29); however, the timing and degree of change varied between the groups. At day 7 of HDT+CO2, the SANS group experienced a greater reduction in perfusion than the non-SANS group (p =.05, 95% CI:-0.19 to 16.11, d=.94, large effect). Conversely, by day 29 of HDT+CO2, the SANS group had significantly higher perfusion (approaching their baseline) than the non-SANS group (p = .04, 95% CI:0.33 to 13.07, d=1.01, large effect). CONCLUSION: Compared with baseline and recovery, HDT+CO2 resulted in reduced cerebral perfusion which varied based on SANS status. Further studies are needed to unravel the relative role of HDT vs hypercapnia, to determine if these perfusion changes are clinically relevant, and whether perfusion changes contribute to the development of SANS during spaceflight.

Juvenile xanthogranuloma of the subdural spaces mimicking chronic hematoma with positive FDG uptake on PET: case report.

The authors report an unusual presentation of juvenile xanthogranuloma (JXG), a non-Langerhans cell histiocytosis of infancy and early childhood. This entity typically presents as a cutaneous head or neck nodule but can manifest with more systemic involvement including in the central nervous system. However, currently there is limited information regarding specific imaging features differentiating JXG from other neuropathological entities, with diagnosis typically made only after tissue sampling. The authors reviewed the initial images of a young patient with shunt-treated hydrocephalus and enlarging, chronic, extraaxial processes presumed to reflect subdural collections from overshunting, and they examine the operative discovery of a mass lesion that was pathologically proven to be JXG. Their results incorporate the important associated histological and advanced imaging features, including previously unreported metabolic activity on FDG PET. Ultimately, the case underscores the need to consider JXG in differential diagnoses of pediatric intracranial masses and highlights the potential role of PET in the initial diagnosis and response to treatment.

A Helpful Tool in Diagnosing Stroke Mimics: Arterial Spin Labeled Perfusion Magnetic Resonance Imaging.

BACKGROUND: Prompt and effective management of acute ischemic stroke in the emergency setting requires a high level of suspicion and accurate diagnosis. Conversely, identifying stroke mimics can be challenging, given the similarity of their clinical symptomatology, the necessary rapid assessment and triage, and the overall frenetic pace inherent in the goal of rapid thrombolysis ("time is brain"). CASE REPORT: We describe a case that involves an elderly patient with acute hemiplegia and dysarthria. Given these concerning symptoms, and multiple preexisting cerebrovascular risk factors (including paroxysmal atrial fibrillation), a "stroke alert" was issued. Imaging was negative for infarct and she was ultimately diagnosed with hemiplegic migraine based on her symptoms and impressive findings on a novel magnetic resonance sequence called arterial spin labeled (ASL) perfusion. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Identifying a nonischemic etiology in a presumed stroke patient, while often difficult, can obviate unnecessary treatment, improve patient care, and promote appropriate resource allocation. As imaging and treatment of cerebrovascular disease advances, the optimization of multidisciplinary care should incorporate neuroradiologists informing and availing their clinical colleagues of applications of an ever-expanding imaging armamentarium. This case is an excellent example of both a common challenging stroke mimic and the potential benefits of ASL perfusion imaging in refining and expediting accurate diagnosis. In addition, it serves as a more general introduction to the particular strengths of this noninvasive, noncontrast magnetic resonance technique, which can be employed to assess varied emergent neuropathology.

Spaceflight-Associated Changes in the Opacification of the Paranasal Sinuses and Mastoid Air Cells in Astronauts.

Importance: Head congestion is one of the most common somatic symptoms experienced by astronauts during spaceflight; however, changes in the opacification of the paranasal sinuses or mastoid air cells in astronauts have not been adequately studied. Objectives: To quantify preflight to postflight changes in the opacification of the paranasal sinuses and mastoid air cells in Space Shuttle astronauts and International Space Station (ISS) astronauts and to assess whether there are differences between the 2 groups of astronauts. Design, Setting, and Participants: This cohort study examined preflight and postflight head magnetic resonance images (MRIs) of 35 astronauts who had participated in either a short-duration (≤30 days) Space Shuttle mission or a long-duration (>30 days) ISS mission and had undergone both preflight and postflight MRI. Images were obtained before and after spaceflight. Images were evaluated by 2 neuroradiologists blinded to which mission each astronaut had flown and to which images were preflight or postflight images. Exposure: Spaceflight on the Space Shuttle or the ISS. Main Outcomes and Measures: Measured outcomes included preflight to postflight changes in Lund-Mackay scores for the paranasal sinuses and in scores grading mastoid effusions. Results: Most astronauts in both the Space Shuttle group (n = 17; 15 men; mean [SD] age at launch, 47.7 [3.1] years) and the ISS group (n = 18; 14 men; mean [SD] age at launch, 48.6 [4.7] years) exhibited either no change or a reduction in paranasal sinus opacification as seen on postflight MRI scans (Space Shuttle group: 6 [35.3%] had no sinus opacification before or after spaceflight, 5 [29.4%] had less sinus opacification after spaceflight, 3 [17.6%] had the same amount of sinus opacification before and after spaceflight, and 3 [17.6%] had increased paranasal sinus opacification after spaceflight; ISS group: 8 [44.4%] had no sinus opacification before or after spaceflight, 4 [22.2%] had less sinus opacification after spaceflight, 1 (5.6%) had the same amount of sinus opacification before and after spaceflight, and 5 [27.8%] had scores consistent with increased paranasal sinus opacification after spaceflight). Long-duration spaceflight (ISS group) was associated with an increased risk of mastoid effusion relative to short-duration spaceflight (relative risk, 4.72; 95% CI, 1.2-18.5). Images were obtained a mean (SD) 287.5 (208.6) days (range, 18-627 days) prior to and 6.8 (5.8) days (range, 1-20 days) after spaceflight. Astronauts had undergone either a mean (SD) of 13.6 (1.6) days of spaceflight on the Space Shuttle (17 astronauts) or 164.8 (18.9) days on the ISS (18 astronauts). Conclusions and Relevance: This study found that exposure to spaceflight conditions on the ISS is associated with an increased likelihood for the formation of mastoid effusions. There was no association between exposure to spaceflight conditions and changes in paranasal sinus opacification. The limitations of this study include lack of information concerning medical history and mission-specific operational experience for individual astronauts. Further studies are indicated to determine the cause and composition of the mastoid effusions.

Effects of Spaceflight on Astronaut Brain Structure as Indicated on MRI.

BACKGROUND: There is limited information regarding the effects of spaceflight on the anatomical configuration of the brain and on cerebrospinal fluid (CSF) spaces. METHODS: We used magnetic resonance imaging (MRI) to compare images of 18 astronauts' brains before and after missions of long duration, involving stays on the International Space Station, and of 16 astronauts' brains before and after missions of short duration, involving participation in the Space Shuttle Program. Images were interpreted by readers who were unaware of the flight duration. We also generated paired preflight and postflight MRI cine clips derived from high-resolution, three-dimensional imaging of 12 astronauts after long-duration flights and from 6 astronauts after short-duration flights in order to assess the extent of narrowing of CSF spaces and the displacement of brain structures. We also compared preflight ventricular volumes with postflight ventricular volumes by means of an automated analysis of T1-weighted MRIs. The main prespecified analyses focused on the change in the volume of the central sulcus, the change in the volume of CSF spaces at the vertex, and vertical displacement of the brain. RESULTS: Narrowing of the central sulcus occurred in 17 of 18 astronauts after long-duration flights (mean flight time, 164.8 days) and in 3 of 16 astronauts after short-duration flights (mean flight time, 13.6 days) (P<0.001). Cine clips from a subgroup of astronauts showed an upward shift of the brain after all long-duration flights (12 astronauts) but not after short-duration flights (6 astronauts) and narrowing of CSF spaces at the vertex after all long-duration flights (12 astronauts) and in 1 of 6 astronauts after short-duration flights. Three astronauts in the long-duration group had optic-disk edema, and all 3 had narrowing of the central sulcus. A cine clip was available for 1 of these 3 astronauts, and the cine clip showed upward shift of the brain. CONCLUSIONS: Narrowing of the central sulcus, upward shift of the brain, and narrowing of CSF spaces at the vertex occurred frequently and predominantly in astronauts after long-duration flights. Further investigation, including repeated postflight imaging conducted after some time on Earth, is required to determine the duration and clinical significance of these changes. (Funded by the National Aeronautics and Space Administration.).

Light-induced Hemiplegia, an Atypical Case of Retinal Steal Syndrome.

Atherosclerosis affecting the carotid arteries accounts for up to 20% of ischemic strokes 1. The clinical effects of atherosclerotic occlusive disease vary according to multiple factors, one of which is collateral circulation. In response to a chronic decrease in cerebral perfusion from atherosclerotic occlusion, alternative flow pathways, or collaterals, develop in a variety of patterns. In the setting of carotid occlusion, flow from the Circle of Willis, if complete, often comprises the main cerebral collateral network. In addition, contributions from leptomeningeal and extracranial to intracranial collaterals may develop. In the latter, reversal of flow in the ophthalmic artery can reconstitute to restore supraclinoid internal carotid artery flow. We report a case of the unusual sequela of a collateral flow pattern via the ophthalmic artery that induces a unique retinal steal phenomenon.

Acute Preoperative Infarcts and Poor Cerebrovascular Reserve Are Independent Risk Factors for Severe Ischemic Complications following Direct Extracranial-Intracranial Bypass for Moyamoya Disease.

BACKGROUND AND PURPOSE: Severe ischemic changes are a rare but devastating complication following direct superficial temporal artery to MCA bypass in patients with Moyamoya disease. This study was undertaken to determine whether preoperative MR imaging and/or cerebrovascular reserve assessment by using reference standard stable xenon-enhanced CT could predict such complications. MATERIALS AND METHODS: Among all adult patients undergoing direct bypass at our institution between 2005 and 2010 who received a clinically interpretable xenon-enhanced CT examination, we identified index cases (patients with >15-mL postoperative infarcts) and control cases (patients without postoperative infarcts and without transient or permanent ischemic symptoms). Differences between groups were evaluated by using the Mann-Whitney U test. Univariate and multivariate generalized linear model regression was used to test predictors of postoperative infarct. RESULTS: Six index cases were identified and compared with 25 controls. Infarct size in the index cases was 95 ± 55 mL. Four of 6 index cases (67%), but no control patients, had preoperative acute infarcts. Baseline CBF was similar, but cerebrovascular reserve was significantly lower in the index cases compared with control cases. For example, in the anterior circulation, median cerebrovascular reserve was -0.4% (range, -38.0%-16.6%) in index versus 26.3% (range, -8.2%-60.5%) in control patients (P = .003). Multivariate analysis demonstrated that the presence of a small preoperative infarct (regardless of location) and impaired cerebrovascular reserve were independent, significant predictors of severe postoperative ischemic injury. CONCLUSIONS: Acute infarcts and impaired cerebrovascular reserve on preoperative imaging are independent risk factors for severe ischemic complications following superficial temporal artery to MCA bypass in Moyamoya disease.

Recombinant human bone morphogenetic protein-2 as an adjunct for spine fusion in a pediatric population.

BACKGROUND/AIMS: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is responsible for multiple different signaling processes including positive effects on bone formation and fusion. In 2002, rhBMP-2 was approved for use in anterior lumbar spinal fusion by the Food and Drug Administration. Since that time, rhBMP-2 use for spinal fusion has become widespread. The use of rh-BMP2 for pediatric spinal fusion, however, has not been widely reported. We report the experience of the use of rhBMP-2 for pediatric spinal fusion at the University of Florida. METHODS: Data on patients under the age of 18 years who underwent spinal fusion with rhBMP-2 as an adjunct were retrospectively collected. Of these, 17 met the inclusion criteria and were reviewed. Two patients did not have adequate postoperative imaging. Fifteen patients were included in the final review. RESULTS: All 15 patients showed osseous fusion. Complications included one CSF leak and one wound infection, one misplaced screw requiring revision, and one case of adjacent segment kyphosis requiring extension of the original construct. CONCLUSION: rhBMP-2 is a successful adjunct for fusion in pediatric patients. Many of these patients had congenital defects that historically decrease fusion rates. rhBMP-2 appears safe and has an associated high rate of osseous fusion.