Horky LL, Gerbaudo VH, Zaitsev A, Plesniak W, Hainer J, Govindarajulu U, Kikinis R, Dietrich J. Systemic Chemotherapy Decreases Brain Glucose Metabolism. Ann Clin Transl Neurol. 2014;1 (10) :788-98.Abstract

OBJECTIVE: Cancer patients may experience neurologic adverse effects, such as alterations in neurocognitive function, as a consequence of chemotherapy. The mechanisms underlying such neurotoxic syndromes remain poorly understood. We here describe the temporal and regional effects of systemically administered platinum-based chemotherapy on glucose metabolism in the brain of cancer patients. METHODS: Using sequential FDG-PET/CT imaging prior to and after administration of chemotherapy, we retrospectively characterized the effects of intravenously administered chemotherapy on brain glucose metabolism in a total of 24 brain regions in a homogenous cohort of 10 patients with newly diagnosed non-small-cell lung cancer. RESULTS: Significant alterations of glucose metabolism were found in response to chemotherapy in all gray matter structures, including cortical structures, deep nuclei, hippocampi, and cerebellum. Metabolic changes were also notable in frontotemporal white matter (WM) network systems, including the corpus callosum, subcortical, and periventricular WM tracts. INTERPRETATION: Our data demonstrate a decrease in glucose metabolism in both gray and white matter structures associated with chemotherapy. Among the affected regions are those relevant to the maintenance of brain plasticity and global neurologic function. This study potentially offers novel insights into the spatial and temporal effects of systemic chemotherapy on brain metabolism in cancer patients.

Ren H, Campos-Nanez E, Yaniv Z, Banovac F, Abeledo H, Hata N, Cleary K. Treatment Planning and Image Guidance for Radiofrequency Ablations of Large Tumors. IEEE J Biomed Health Inform. 2014;18 (3) :920-8.Abstract

This article addresses the two key challenges in computer-assisted percutaneous tumor ablation: planning multiple overlapping ablations for large tumors while avoiding critical structures, and executing the prescribed plan. Toward semiautomatic treatment planning for image-guided surgical interventions, we develop a systematic approach to the needle-based ablation placement task, ranging from preoperative planning algorithms to an intraoperative execution platform. The planning system incorporates clinical constraints on ablations and trajectories using a multiple objective optimization formulation, which consists of optimal path selection and ablation coverage optimization based on integer programming. The system implementation is presented and validated in both phantom and animal studies. The presented system can potentially be further extended for other ablation techniques such as cryotherapy.

Lee JW, Norden AD, Ligon KL, Golby AJ, Beroukhim R, Quackenbush J, Wells W, Oelschlager K, Maetzold D, Wen PY. Tumor Associated Seizures in Glioblastomas are Influenced by Survival Gene Expression in a Region-specific Manner: A Gene Expression Imaging Study. Epilepsy Res. 2014;108 (5) :843-52.Abstract

Tumor associated seizures (TAS) are common and cause significant morbidity. Both imaging and gene expression features play significant roles in determining TAS, with strong interactions between them. We describe gene expression imaging tools which allow mapping of brain regions where gene expression has significant influence on TAS, and apply these methods to study 77 patients who underwent surgical evaluation for supratentorial glioblastomas. Tumor size and location were measured from MRI scans. A 9-set gene expression profile predicting long-term survivors was obtained from RNA derived from formalin-fixed paraffin embedded tissue. A total of 32 patients (42%) experienced preoperative TAS. Tumor volume was smaller (31.1 vs. 58.8 cubic cm, p<0.001) and there was a trend toward median survival being higher (48.4 vs. 32.7 months, p=0.055) in patients with TAS. Although the expression of only OLIG2 was significantly lower in patients with TAS in a groupwise analysis, gene expression imaging analysis revealed regions with significantly lower expression of OLIG2 and RTN1 in patients with TAS. Gene expression imaging is a powerful technique that demonstrates that the influence of gene expression on TAS is highly region specific. Regional variability should be evaluated with any genomic or molecular markers of solid brain lesions.

Aryal M, Arvanitis CD, Alexander PM, McDannold N. Ultrasound-Mediated Blood-brain Barrier Disruption for Targeted Drug Delivery in the Central Nervous System. Adv Drug Deliv Rev. 2014;72 :94-109.Abstract

The physiology of the vasculature in the central nervous system (CNS), which includes the blood-brain barrier (BBB) and other factors, complicates the delivery of most drugs to the brain. Different methods have been used to bypass the BBB, but they have limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Focused ultrasound (FUS), when combined with circulating microbubbles, is a noninvasive method to locally and transiently disrupt the BBB at discrete targets. This review provides insight on the current status of this unique drug delivery technique, experience in preclinical models, and potential for clinical translation. If translated to humans, this method would offer a flexible means to target therapeutics to desired points or volumes in the brain, and enable the whole arsenal of drugs in the CNS that are currently prevented by the BBB.

Schmidt EJ, Tse ZTH, Reichlin TR, Michaud GF, Watkins RD, Butts-Pauly K, Kwong RY, Stevenson W, Schweitzer J, Byrd I, et al. Voltage-based Device Tracking in a 1.5 Tesla MRI during Imaging: Initial Validation in Swine Models. Magn Reson Med. 2014;71 (3) :1197-209.Abstract

PURPOSE: Voltage-based device-tracking (VDT) systems are commonly used for tracking invasive devices in electrophysiological cardiac-arrhythmia therapy. During electrophysiological procedures, electro-anatomic mapping workstations provide guidance by integrating VDT location and intracardiac electrocardiogram information with X-ray, computerized tomography, ultrasound, and MR images. MR assists navigation, mapping, and radiofrequency ablation. Multimodality interventions require multiple patient transfers between an MRI and the X-ray/ultrasound electrophysiological suite, increasing the likelihood of patient-motion and image misregistration. An MRI-compatible VDT system may increase efficiency, as there is currently no single method to track devices both inside and outside the MRI scanner. METHODS: An MRI-compatible VDT system was constructed by modifying a commercial system. Hardware was added to reduce MRI gradient-ramp and radiofrequency unblanking pulse interference. VDT patches and cables were modified to reduce heating. Five swine cardiac VDT electro-anatomic mapping interventions were performed, navigating inside and thereafter outside the MRI. RESULTS: Three-catheter VDT interventions were performed at >12 frames per second both inside and outside the MRI scanner with <3 mm error. Catheters were followed on VDT- and MRI-derived maps. Simultaneous VDT and imaging was possible in repetition time >32 ms sequences with <0.5 mm errors, and <5% MRI signal-to-noise ratio (SNR) loss. At shorter repetition times, only intracardiac electrocardiogram was reliable. Radiofrequency heating was <1.5°C. CONCLUSION: An MRI-compatible VDT system is feasible.

Wright J. Surgery: The Eyes of the Operation. Nature. 2013;502 (7473) :S88-9.Abstract


Real-time imaging of a patient's body is guiding surgeons and radiologists past healthy tissue to the diseased cells.


Kapur T, Tempany CM, Jolesz FA. Proceedings of the 6th Image Guided Therapy Workshop. 2013;6 :1-87. 2013 IGT Workshop Proceedings
Shriver S, Knierim KE, O'Shea JP, Glover GH, Golby AJ. Pneumatically driven finger movement: a novel passive functional MR imaging technique for presurgical motor and sensory mapping. AJNR Am J Neuroradiol. 2013;34 (1) :E5-7.Abstract
Two of the most common reasons for failure to obtain adequate preoperative functional data are inadequate task performance and excessive head motion. With an MR imaging-compatible pneumatically driven manipulandum, passive motor tasks elicited reproducible contralateral activation in the M1 and S1 in 10 healthy controls and 6 patients. The SMA was localized in all healthy controls and in 5 of 6 patients. Head motion was reduced in passive tasks compared with active tasks.
Kolesov I, Lee J, Vela P, Tannenbaum A. Stochastic Image Registration with User Constraints. Proc SPIE Int Soc Opt Eng. 2013;8669.Abstract
Constrained registration is an active area of research and is the focus of this work. This note describes a non-rigid image registration framework for incorporating landmark constraints. Points that must remain stationary are selected, the user chooses the spatial extent of the inputs, and an automatic step computes the deformable registration, respecting the constraints. Parametrization of the deformation field is by an additive composition of a similarity transformation and a set of Gaussian radial basis functions. The bases' centers, variances, and weights are determined with a global optimization approach that is introduced. This approach is based on the particle filter for performing constrained optimization; it explores a series of states defining a deformation field that is physically meaningful (i.e., invertible) and prevents chosen points from moving. Results on synthetic two dimensional images are presented.
Seifabadi R, Cho NBJ, Song S-E, Tokuda J, Hata N, Tempany CM, Fichtinger G, Iordachita I. Accuracy Study of a Robotic System for MRI-guided Prostate Needle Placement. Int J Med Robot. 2013;9 (3) :305-16.Abstract

BACKGROUND: Accurate needle placement is the first concern in percutaneous MRI-guided prostate interventions. In this phantom study, different sources contributing to the overall needle placement error of a MRI-guided robot for prostate biopsy have been identified, quantified and minimized to the possible extent. METHODS: The overall needle placement error of the system was evaluated in a prostate phantom. This error was broken into two parts: the error associated with the robotic system (called 'before-insertion error') and the error associated with needle-tissue interaction (called 'due-to-insertion error'). Before-insertion error was measured directly in a soft phantom and different sources contributing into this part were identified and quantified. A calibration methodology was developed to minimize the 4-DOF manipulator's error. The due-to-insertion error was indirectly approximated by comparing the overall error and the before-insertion error. The effect of sterilization on the manipulator's accuracy and repeatability was also studied. RESULTS: The average overall system error in the phantom study was 2.5 mm (STD = 1.1 mm). The average robotic system error in the Super Soft plastic phantom was 1.3 mm (STD = 0.7 mm). Assuming orthogonal error components, the needle-tissue interaction error was found to be approximately 2.13 mm, thus making a larger contribution to the overall error. The average susceptibility artifact shift was 0.2 mm. The manipulator's targeting accuracy was 0.71 mm (STD = 0.21 mm) after robot calibration. The robot's repeatability was 0.13 mm. Sterilization had no noticeable influence on the robot's accuracy and repeatability. CONCLUSIONS: The experimental methodology presented in this paper may help researchers to identify, quantify and minimize different sources contributing into the overall needle placement error of an MRI-guided robotic system for prostate needle placement. In the robotic system analysed here, the overall error of the studied system remained within the acceptable range.

Eberlin LS, Norton I, Orringer D, Dunn IF, Liu X, Ide JL, Jarmusch AK, Ligon KL, Jolesz FA, Golby AJ, et al. Ambient Mass Spectrometry for the Intraoperative Molecular Diagnosis of Human Brain Tumors. Proc Natl Acad Sci U S A. 2013;110 (5) :1611-6.Abstract

The main goal of brain tumor surgery is to maximize tumor resection while preserving brain function. However, existing imaging and surgical techniques do not offer the molecular information needed to delineate tumor boundaries. We have developed a system to rapidly analyze and classify brain tumors based on lipid information acquired by desorption electrospray ionization mass spectrometry (DESI-MS). In this study, a classifier was built to discriminate gliomas and meningiomas based on 36 glioma and 19 meningioma samples. The classifier was tested and results were validated for intraoperative use by analyzing and diagnosing tissue sections from 32 surgical specimens obtained from five research subjects who underwent brain tumor resection. The samples analyzed included oligodendroglioma, astrocytoma, and meningioma tumors of different histological grades and tumor cell concentrations. The molecular diagnosis derived from mass-spectrometry imaging corresponded to histopathology diagnosis with very few exceptions. Our work demonstrates that DESI-MS technology has the potential to identify the histology type of brain tumors. It provides information on glioma grade and, most importantly, may help define tumor margins by measuring the tumor cell concentration in a specimen. Results for stereotactically registered samples were correlated to preoperative MRI through neuronavigation, and visualized over segmented 3D MRI tumor volume reconstruction. Our findings demonstrate the potential of ambient mass spectrometry to guide brain tumor surgery by providing rapid diagnosis, and tumor margin assessment in near-real time.

Galsky MD, Xie W, Nakabayashi M, Ross RW, Fennessy FM, Tempany CM, Choueiri TK, Khine K, Kantoff PW, Taplin M-E, et al. Analysis of the Correlation between Endorectal MRI Response to Neoadjuvant Chemotherapy and Biochemical Recurrence in Patients with High-Risk Localized Prostate Cancer. Prostate Cancer Prostatic Dis. 2013;16 (3) :266-70.Abstract

BACKGROUND: Intermediate end points are desirable to expedite the integration of neoadjuvant systemic therapy into the treatment strategy for high-risk localized prostate cancer. Endorectal magnetic resonance imaging at 1.5 Tesla (1.5T erMRI) response has been utilized as an end point in neoadjuvant trials but has not been correlated with clinical outcomes. METHODS: Data were pooled from two trials exploring neoadjuvant chemotherapy in high-risk localized prostate cancer. Trial 1 explored docetaxel for 6 months and Trial 2 explored docetaxel plus bevacizumab for 4.5 months, both before radical prostatectomy. erMRI was done at baseline and end of chemotherapy. 1.5T erMRI response, based upon T2W sequences, was recorded. Multivariable Cox regression was undertaken to evaluate the association between clinical parameters and biochemical recurrence. RESULTS: There were 53 evaluable patients in the combined analysis: 20 (33%) achieved a PSA response, 16 (27%) achieved an erMRI partial response and 24 (40%) achieved an erMRI minor response. Median follow-up was 4.2 years, and 33 of 53 evaluable (62%) patients developed biochemical recurrence. On multivariable analysis, PSA response did not correlate with biochemical recurrence (hazard ratio=0.58, 95% confidence interval (CI) 0.25-1.33) and paradoxically erMRI response was associated with a significantly shorter time to biochemical recurrence (hazard ratio=2.47, 95% CI 1.00-6.13). CONCLUSIONS: Response by 1.5T erMRI does not correlate with a decreased likelihood of biochemical recurrence in patients with high-risk localized prostate cancer treated with neoadjuvant docetaxel and may be associated with inferior outcomes. These data do not support the use of 1.5T erMRI response as a primary end point in neoadjuvant chemotherapy trials.

Risholm P, Janoos F, Norton I, Golby AJ, Wells III WM. Bayesian Characterization of Uncertainty in Intra-subject Non-rigid Registration. Med Image Anal. 2013;17 (5) :538-55.Abstract

In settings where high-level inferences are made based on registered image data, the registration uncertainty can contain important information. In this article, we propose a Bayesian non-rigid registration framework where conventional dissimilarity and regularization energies can be included in the likelihood and the prior distribution on deformations respectively through the use of Boltzmann's distribution. The posterior distribution is characterized using Markov Chain Monte Carlo (MCMC) methods with the effect of the Boltzmann temperature hyper-parameters marginalized under broad uninformative hyper-prior distributions. The MCMC chain permits estimation of the most likely deformation as well as the associated uncertainty. On synthetic examples, we demonstrate the ability of the method to identify the maximum a posteriori estimate and the associated posterior uncertainty, and demonstrate that the posterior distribution can be non-Gaussian. Additionally, results from registering clinical data acquired during neurosurgery for resection of brain tumor are provided; we compare the method to single transformation results from a deterministic optimizer and introduce methods that summarize the high-dimensional uncertainty. At the site of resection, the registration uncertainty increases and the marginal distribution on deformations is shown to be multi-modal.

Mostayed A, Garlapati RR, Joldes GR, Wittek A, Roy A, Kikinis R, Warfield SK, Miller K. Biomechanical Model as a Registration Tool for Image-guided Neurosurgery: Evaluation Against BSpline Registration. Ann Biomed Eng. 2013;41 (11) :2409-25.Abstract

In this paper we evaluate the accuracy of warping of neuro-images using brain deformation predicted by means of a patient-specific biomechanical model against registration using a BSpline-based free form deformation algorithm. Unlike the BSpline algorithm, biomechanics-based registration does not require an intra-operative MR image which is very expensive and cumbersome to acquire. Only sparse intra-operative data on the brain surface is sufficient to compute deformation for the whole brain. In this contribution the deformation fields obtained from both methods are qualitatively compared and overlaps of Canny edges extracted from the images are examined. We define an edge based Hausdorff distance metric to quantitatively evaluate the accuracy of registration for these two algorithms. The qualitative and quantitative evaluations indicate that our biomechanics-based registration algorithm, despite using much less input data, has at least as high registration accuracy as that of the BSpline algorithm.

Arvanitis CD, Livingstone MS, McDannold N. Combined Ultrasound and MR Imaging to Guide Focused Ultrasound Therapies in the Brain. Phys Med Biol. 2013;58 (14) :4749-61.Abstract

Several emerging therapies with potential for use in the brain, harness effects produced by acoustic cavitation--the interaction between ultrasound and microbubbles either generated during sonication or introduced into the vasculature. Systems developed for transcranial MRI-guided focused ultrasound (MRgFUS) thermal ablation can enable their clinical translation, but methods for real-time monitoring and control are currently lacking. Acoustic emissions produced during sonication can provide information about the location, strength and type of the microbubble oscillations within the ultrasound field, and they can be mapped in real-time using passive imaging approaches. Here, we tested whether such mapping can be achieved transcranially within a clinical brain MRgFUS system. We integrated an ultrasound imaging array into the hemisphere transducer of the MRgFUS device. Passive cavitation maps were obtained during sonications combined with a circulating microbubble agent at 20 targets in the cingulate cortex in three macaques. The maps were compared with MRI-evident tissue effects. The system successfully mapped microbubble activity during both stable and inertial cavitation, which was correlated with MRI-evident transient blood-brain barrier disruption and vascular damage, respectively. The location of this activity was coincident with the resulting tissue changes within the expected resolution limits of the system. While preliminary, these data clearly demonstrate, for the first time, that it is possible to construct maps of stable and inertial cavitation transcranially, in a large animal model, and under clinically relevant conditions. Further, these results suggest that this hybrid ultrasound/MRI approach can provide comprehensive guidance for targeted drug delivery via blood-brain barrier disruption and other emerging ultrasound treatments, facilitating their clinical translation. We anticipate that it will also prove to be an important research tool that will further the development of a broad range of microbubble-enhanced therapies.

Córdova H, San José Estépar R, Rodríguez-D'Jesús A, Martínez-Pallí G, Arguis P, Rodríguez de Miguel C, Navarro-Ripoll R, Perdomo JM, Cuatrecasas M, Llach J, et al. Comparative Study of NOTES Alone versus NOTES Guided by a New Image Registration System for Navigation in the Mediastinum: A Study in a Porcine Model. Gastrointest Endosc. 2013;77 (1) :102-7.Abstract

BACKGROUND: Natural orifice transluminal endoscopic surgery (NOTES) mediastinoscopy (MED) through the esophagus has proved to be feasible in the animal model. However, injury of the adjacent pleura and pneumothorax has been reported as a frequent adverse event when using a blind access. OBJECTIVE: To assess the utility and safety of a CT-based image registration system (IRS) for navigation in the mediastinum. DESIGN: Prospective, randomized, controlled trial in 30 Yorkshire pigs. Thirty-minute MEDs were performed: 15 MEDs were performed with IRS guidance (MED-IRS), and 15 MEDs were performed with a blind access. SETTING: Animal research laboratory. INTERVENTIONS: In both groups, the mediastinum was accessed through a 10-cm submucosal tunnel in the esophageal wall. Timed exploration was performed with identification of 8 mediastinal structures. MAIN OUTCOME MEASUREMENTS: Technical feasibility, adverse events, and the number of mediastinal structures identified. RESULTS: Thirty animals weighing 31.5 ± 3.5 kg were included in this study. MED was not possible in 2 animals in the "MED with blind access" group but was possible in all MEDs performed with IRS. The mean number of identified organs was slightly higher in "with IRS-MED" (6.13 ± 1.3) than with MED with blind access (4.7 ± 2.3; P = .066). Moreover, the right atrium and vena cava were identified in more cases with IRS-MED than in MED with blind access (13 vs 3 and 15 vs 11, P = .000 and P = .03, respectively). There were 3 (23%) adverse events with IRS-MED and 4 (27%) with "MED with blind access" (P = not significant), with pneumothorax being the most frequent (2 and 3, respectively). LIMITATIONS: Nonsurvival animal study. CONCLUSIONS: This study demonstrates that the IRS system appears feasible in natural orifice transluminal endoscopic surgery MED and suggests that IRS guidance might be useful for selected procedures.

Tokuda J, Song S-E, Tuncali K, Tempany CM, Hata N. Configurable Automatic Detection and Registration of Fiducial Frames for Device-to-Image Registration in MRI-guided Prostate Interventions. Med Image Comput Comput Assist Interv. 2013;16 (Pt 3) :355-62.Abstract

We propose a novel automatic fiducial frame detection and registration method for device-to-image registration in MRI-guided prostate interventions. The proposed method does not require any manual selection of markers, and can be applied to a variety of fiducial frames, which consist of multiple cylindrical MR-visible markers placed in different orientations. The key idea is that automatic extraction of linear features using a line filter is more robust than that of bright spots by thresholding; by applying a line set registration algorithm to the detected markers, the frame can be registered to the MRI. The method was capable of registering the fiducial frame to the MRI with an accuracy of 1.00 +/- 0.73 mm and 1.41 +/- 1.06 degrees in a phantom study, and was sufficiently robust to detect the fiducial frame in 98% of images acquired in clinical cases despite the existence of anatomical structures in the field of view.

Huang Y, Vykhodtseva NI, Hynynen K. Creating Brain Lesions with Low-intensity Focused Ultrasound with Microbubbles: A Rat Study at Half a Megahertz. Ultrasound Med Biol. 2013;39 (8) :1420-8.Abstract

Low-intensity focused ultrasound was applied with microbubbles (Definity, Lantheus Medical Imaging, North Billerica, MA, USA; 0.02 mL/kg) to produce brain lesions in 50 rats at 558 kHz. Burst sonications (burst length: 10 ms; pulse repetition frequency: 1 Hz; total exposure: 5 min; acoustic power: 0.47-1.3 W) generated ischemic or hemorrhagic lesions at the focal volume revealed by both magnetic resonance imaging and histology. Shorter burst time (2 ms) or shorter sonication time (1 min) reduced the probability of lesion production. Longer pulses (200 ms, 500 ms and continuous wave) caused significant near-field damage. Using microbubbles with focused ultrasound significantly reduced acoustic power levels and, therefore, avoided skull heating issues and potentially can extend the treatable volume of transcranial focused ultrasound to brain tissues close to the skull.

Song S-E, Tokuda J, Tuncali K, Tempany CM, Zhang E, Hata N. Development and Preliminary Evaluation of a Motorized Needle Guide Template for MRI-guided Targeted Prostate Biopsy. IEEE Trans Biomed Eng. 2013;60 (11) :3019-27.Abstract

To overcome the problems of limited needle insertion accuracy and human error in the use of a conventional needle guide template in magnetic resonance imaging (MRI)-guided prostate intervention, we developed a motorized MRI-compatible needle guide template that resembles a transrectal ultrasound-guided prostate template. The motorized template allows automated, gapless needle guidance in a 3T MRI scanner with minimal changes in the current clinical procedure. To evaluate the impact of the motorized template on MRI, signal-to-noise ratio and distortion were measured under various system configurations. A maximum of 44% signal-to-noise ratio decrease was found when the ultrasonic motors were running, and a maximum of 0.4% image distortion was observed due to the presence of the motorized template. To measure needle insertion accuracy, we performed four sets of five random target needle insertions mimicking four biopsy procedures, which resulted in an average in-plane targeting error of 0.94 mm with a standard deviation of 0.34 mm. The evaluation studies indicated that the presence and operation of the motorized template in the MRI bore create insignificant image degradation, and provide submillimeter targeting accuracy. The automated needle guide that is directly controlled by navigation software eliminates human error so that the safety of the procedure can be improved.

Abd-El-Barr MM, Saleh E, Huang RY, Golby AJ. Effect of Disease and Recovery on Functional Anatomy in Brain Tumor Patients: Insights from Functional MRI and Diffusion Tensor Imaging. Imaging Med. 2013;5 (4) :333-46.Abstract

Patients with brain tumors provide a unique opportunity to understand functional brain plasticity. Using advanced imaging techniques, such as functional MRI and diffusion tensor imaging, we have gained tremendous knowledge of brain tumor behavior, transformation, infiltration and destruction of nearby structures. Using these advanced techniques as an adjunct with more proven techniques, such as direct cortical stimulation, intraoperative navigation and advanced microsurgical techniques, we now are able to better formulate safer resection trajectories, perform larger resections at reduced risk and better counsel patients and their families about possible complications. Brain mapping in patients with brain tumors and other lesions has shown us that the old idea of fixed function of the adult cerebral cortex is not entirely true. Improving care for patients with brain lesions in the future will depend on better understanding of the functional organization and plasticity of the adult brain. Advanced noninvasive brain imaging will undoubtedly play a role in advancing this understanding.