Hoby P. Hetherington - US grants

male; female; mental disorders; nervous system; human subject; nuclear magnetic resonance spectroscopy; biomedical resource;

technology /technique development; male; female; mental disorders; nervous system; human subject; nuclear magnetic resonance spectroscopy; cardiovascular system; biomedical resource; bioengineering /biomedical engineering;

magnetic resonance imaging; biomedical resource; biological products;

Epilepsy is one of the most common neurological disorders, affecting one to two million Americans. For approximately 10% of these individuals, the debilitating effects of the disease can not be controlled by medication. Although surgical intervention is highly effective, accurate lateralization and localization of seizure foci based on metabolic measurements have been developed. These techniques include measures of CMRglucose by FDG PET, high-energy phosphates (PCr and ATP) by 31 NMR and measurements of neuronal dysfunction with 1H NMR measurements of N-acetyl aspartate. Although these methodologies have been quite successful (sensitivity and specificity of 70-95%) in the lateralization of mesial temporal lobe epilepsy, the biological mechanisms underlying these observations remains controversial. The findings of decreased high- energy phosphates along with decreased CMRglucose suggest that energy production is impaired. Furthermore, the finding that NAA reductions are 1) reversible and 2) not solely due to neuronal loss; in conjunction with 3) results in mitochondrial preparations linking NAA synthesis rates, ATP production and inhibition of mitochondrial enzymes suggest that the metabolic defect may be due to impaired mitochondrial function. Therefore, the goal of this project is to investigate the role of impaired mitochondrial function. Therefore, the goal of this project is to investigate the role of impaired mitochondrial function as a primary cause for the observed metabolic alterations in temporal lobe epilepsy. To achieve this goal we will combine in vivo measurements of high energy phosphates, NAA, glutamate and TC cycle rate (NMR) and CMRglucose (PET) from patients with temporal lobe epilepsy with detailed measurements of anapleurosis, neurotransmitter cycling (Project 2), mitochondrial function (Project 3) from the resected tissue and the corresponding functional changes in ion homeostasis (Project 4).

[unreadable] DESCRIPTION (provided by applicant): As the primary inhibitory neurotransmitter in mammalian brain, GABA, its content and its receptor systems are the targets of a number of anti-epileptic drugs. Although Petroff and colleagues have studied the effects of various anti-epileptics on brain GABA levels in the occipital lobe, a site distant from the epileptogenic region, to date little information exists regarding GABA levels in the epileptogenic region of patients with temporal lobe epilepsy. This data has largely shown that brain GABA levels are decreased in patients with poor control in comparison to healthy controls and are responsive to a variety of anti-epileptic medications. Conversely, recent preliminary microdialysis studies have shown that ECF GABA is higher in patients with sclerosis as opposed to those without sclerosis (6). Additionally our preliminary data has shown a similar correlation with ECF GABA inversely correlated with hippocampal NAA levels (i.e higher ECF GABA levels are seen in patients with lower NAA levels. To what extent total GABA in the epileptogenic region is increased or decreased relative to control is unknown. Similarly it is unknown if total GABA levels in the epileptogenic parallel GABA levels distant from the seizure focus. Clearly these questions may have significant impact on our understanding of the factors leading to epileptogenic activity in the seizure focus and also provide measures that may aid in the therapeutic management of epilepsy patients. Therefore the development of robust methods for measuring GABA from the temporal lobe in patients with temporal lobe epilepsy would be of significant benefit. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): With recent advances in magnet technology, ultrahigh field magnets (7T and higher) with bore sizes capable of accommodating the adult human head have become available from a variety of research and clinical vendors. The increased field strength confers the intrinsic advantages of increased SNR and for spectroscopic studies, increased spectral resolution and spectral simplification of J coupled resonances such as glutamate and glutamine. Thus, spectroscopic imaging at 7T should provide an ideal platform for evaluating these compounds. Unfortunately, despite the presence of 7T systems dating from late 1990s, there have been few reports of their use in spectroscopic imaging studies. This limitation is largely due to the intrinsic inefficiencies of generating sufficient B1 strength at high field and the resulting increases more than a factor of 10 in power deposition. Thus, many conventional spectroscopic imaging sequences result in long echo times and can exceed FDA guidelines for tissue heating when applied at 7T. To overcome these limitations we will develop novel methods for spectroscopic imaging at 7T which combine both pulse sequence design, B1 shimming and the development of multi-geometry transceiver arrays. Although contrast enhanced and FLAIR imaging are routinely used for monitoring the response to radiochemotherapy in patients with malignant gliomas, false positives (pseudoprogression) arising from necrosis and inflammation in the absence of tumor progression during the acute and sub-acute periods (first 60 days of treatment) occur in 20-40% of the patients being treated. This severely limits the interpretation of early imaging studies, delaying optimal therapeutic response and decreasing survival times. In addition to the common findings of increased choline, lactate and mobile lipids (which are also found in inflammatory cells), cerebral tumors appear to show elevated concentrations glutamine. This is consistent with the major role which glutamine plays in biosynthetic and anapleurotic activities in proliferating tumor cells. Thus, short TE MRSI measurements of glutamine have the potential to significantly aid the serial evaluation of tumors in response to therapy. Therefore, to evaluate the utility of the methods, we will determine if MRSI measurements of glutamine can resolve progression from pseudoprogression in patients with malignant gliomas being treated with radiochemotherapy. PUBLIC HEALTH RELEVANCE: Although spectroscopic imaging at 7T should provide an ideal platform for measurements of amino acids such as glutamate and glutamine, decreased transmission efficiency, large signal intensity losses and power deposition make use of conventional methods difficult. To overcome these limitations we will develop novel methods for spectroscopic imaging at 7T, which combine both pulse sequence design and new ways of shaping RF fields spatially with multi-element coil arrays, which dramatically decrease power deposition and maintain optimal signal detection. We will use these methods to determine if spectroscopic imaging of glutamine can aid in the monitoring the response of malignant gliomas to radiochemotherapy.

DESCRIPTION (provided by applicant): While challenges of SNR, hardware, and pulse sequence have limited the penetration of MRSI into clinical use, it remains among the most sensitive avenues towards assessing cerebral function and an important motivation for ongoing 7T development. However at any field strength, MRSI has challenges for spectral quality, acceptable acquisition time and spatial coverage. Specifically, while 3T MRSI has reported excellent SNR for NAA in supraventricular locations, there remain acknowledged problems for spectral quality in critical brain regions including the temporal and frontal lobes. 7T MRS has shown the expected doubling in SNR, which with the >2-fold greater spectral resolution effectively gives a total 16x reduction for scan time in comparison to 3T. However, problems at 7T focus on rf coil technology and B0 inhomogeneity. At 300MHz, the dielectric constant of tissue results in marked axial and longitudinal B1 inhomogeneities, simultaneous to a linear increase in required power for equivalent B1 generation. With a goal of developing and implementing MR spectroscopic imaging at 7T, our group has developed a transceiver detector which as used with RF shimming, has shown excellent performance at 7T. In collaboration with Resonance Research Inc., we have also shown that with higher order shim mapping and corrections, outstanding field homogeneity can be achieved over extended brain regions. Thus far this success has been primarily achieved over single slice regions. In this project, we will continue to develop this work for wide brain and multi-slice MRSI at 7T. This will be achieved through Aim 1 that extends the longitudinal coverage of the transceiver and further improves large volume Bo homogeneity, and Aim 2 which develops the pulse sequences (B1 based localization, Hadamard and SENSE encoding with the J-refocused acquisition), our goal being high SNR multi-slice spectroscopic imaging with low SAR (~2W/kg). Because methodologic development ideally occurs with real-world targets, we will test these developments with the challenging problem of neocortical epilepsy (NE). Since many NE patients are clinically complex, their evaluation commonly requires intracranial EEG (icEEG), a neurosurgical procedure where intracranial electrodes are used to localize seizures. For this process, it is clear that as much advanced knowledge on where to place electrodes is needed, so as to not miss the seizure onset zone. Yet even with this complex process, the post-surgical outcome is that ~40-50% of patients continue with significant seizures. With the variable etiologies in NE, there are major challenges for MRSI coverage (seizures can arise from any cortical location), volume resolution (typical size of ictal onset zone), and optimal metabolite pattern (is glutamate better than NAA). These unknowns likely explain why MRSI is not routinely used at 3T, but even in anatomically well defined medial temporal lobe epilepsy, there are spectral quality problems at 3T. In Aim 3, we will test the hypothesis that in regions of seizure onset and propagation (as defined by icEEG) the NAA/Cr and Glu/Cr will be abnormal, thus determining the typical voxel size needed for such identification, and whether NAA or glutamate may be more accurate. To bring this work into greater implementation, Aim 4 will take the parameters identified at 7T into a collaboration with O Gonen PhD, New York Univ., a leader in the development and application of 3T wide brain coverage MRSI. We will compare extended volume coverage MRSI at 3T and 7T in healthy controls and in a limited group of patients, allowing us to define the optimum methods at 3T to achieve identification of ictogenic regions. This project proposes a coordinated development in hardware and pulse sequences for 7T MRSI. We believe that this project's impact is broad, not just for improved neurosurgical management of NE, but also for improved imaging and MRSI at 3 and 7T. As stated, 3T MRSI, while successful for supra- ventricular regions, is inconsistent in the temporal lobes. This will improve with our proposed work in higher order shims and algorithms that optimally correct for and redistribute B0 homogeneity. At 7T, the transceiver work is critical as presently there is no clear solution to the problem of homogeneous and extended rf (~20uT) coverage. Thus while the impact of this project is clearly for 7T MRSI, the proposed work in B1 methods and B0 shimming will be highly relevant for many aspects of high field MR, both 7 and 3T.

DESCRIPTION (provided by applicant): Although 7T systems have been available since the late 1990s, progress for brain imaging at 7T has been slowed by the transmit performance of conventional head coils (i.e. a large transmit only volume coil with a receive only phased array). At 7T large single drive transmit head volume coils suffer from poor homogeneity (40-50%) and low efficiency and limited SNR. The use of receive only phased arrays within these coils significantly enhances SNR and enables parallel reception but does not improve the transmit performance. These limitations can be addressed by the use of transceiver arrays which provide both independent transmission and reception. Transceiver arrays using parallel transmission and/or RF shimming offer improved homogeneity, spatially tailored excitation, gradient independent outer volume suppression and reduced SAR. To date, the number of coils in these transceiver arrays has been limited to the number of independent transmit channels (typically 8) and the small size of these coils required to maintain optimal SNR. To address these limitations we will: i) eliminate the need for equal numbers of transmit and receive channels for the multiple row transceiver arrays by developing new pulse sequence methods which utilize RF multiplexing to drive multi-row transceiver arrays and reduce power deposition; ii) enhance the efficiency of multi-plane MRSI data collection and reduce SAR by developing multi-band acquisition MRSI acquisitions. To evaluate the methods developed we will study veterans with mild traumatic brain injury (mTBI) arising from blast exposure. It has become clear that veterans exposed to mTBI from blast injury display delayed neurological deficits, often without clear imaging correlates. In the absence of objective confirmatory imaging evidence, poor performance on cognitive evaluations can be attributed to poor subject effort, complicating diagnosis, management, rehabilitation and raising questions as to validity of the reported disability. Our recent work has demonstrated that in veterans with blast related mTBI, significant metabolic alterations are seen in the hippocampi which correlate with assessments of effort and cognitive performance. Using the enhanced spatial coverage afforded by the methods developed we will evaluate the hypothesis that in veterans exposed to blast related mTBI, the presence and severity of cognitive and neurologic deficits are correlated with metabolic abnormalities/impairments in the functionally linked brain regions.

Although the Trio systems have served as the primary high-end research system for Siemens 3T MRI users for the past decade, the system is no longer state of the art. In addition to limitations with regards to numbers of receivers, gradient performance and SNR, the reconstruction computers and computational pipeline were designed prior to the development of multi-band methods and are prone to failure, which results in data loss. To address these limitations the Prisma line, was developed as part of the Human Connectome project. The Prisma line features a new gradient system capable of twice the amplitude and twice the slew rate. This is critical for: 1) minimizing readout times for high resolution EPI based imaging (fMRI and DTI) to reduce spatial distortion; 2) minimizing TE for DTI studies, to maximize SNR. The Prisma system also features new receiver technologies; 3) moving the initial mixing stage to the RF coil along with 4) high density signal encoding (two receive channels in one) improving both intrinsic SNR and enabling higher channel count coils. While the gradient speed improvements enable higher resolution fMRI and DTI measures of connectivity, the receiver improvements are critical to return the SNR exchanged for higher resolution imaging. Finally, the Prisma system offers (5) 64-channel capability and head coils. The higher channel count enables higher multi-band factors to be used that are necessary to minimize acquisition times to improve statistical power for fMRI and resting state acquisitions. In summary, the Prisma system was designed as part of the Human Connectome project to advance the state of the art for fMRI and DTI imaging of the brain. As such, it has set the standard for human imaging work going forwards. The Magnetic Resonance Research Center (MRRC) is located on the 8th floor of Presbyterian Hospital on the Medical Campus for the University of Pittsburgh with more than 12000sq of space. Currently the MRRC acquires MRI data for more than 50 different active projects from more than 40 investigators in 10 different departments at the University of Pittsburgh and collaborating institutions. The vast majority of these projects, greater than 80%, are focused on neuroimaging, with the vast majority of those utilizing task based fMRI, resting state fMRI, diffusion tensor imaging and tractography to evaluate the relationship between brain structure, function and behavior across a variety of patient groups. Many of these studies are carried out with the Department of Psychiatry, which is internationally recognized for its excellence in both academic and clinical medicine, ranking 1st in NIH funding (2015 report), with the Medical School as a whole ranking 9th in NIH funding. Thus the Prisma system with its roots in the Connectome project was designed to carryout the very work that our center is focused on and supports.

Magnetic Resonance Spectroscopic Imaging (MRSI) has proven to provide unique information for the diagnosis and management of brain tumors, epilepsy, multiple sclerosis and traumatic brain injury. Despite the obvious advantage of imaging approaches over single volume measurements, clinically, most MRS studies are still performed as single voxel studies. The reluctance to include MRSI in clinical evaluations arises primarily from four factors: 1) increased acquisition times; 2) limitations in spectral quality when data is acquired over larger brain regions; 3) limitations in SNR and 4) challenges in sampling the cortical periphery. To overcome these limitations we will develop a fast MRSI method (5-10min.) which uses: 1) two dimensional rosette encoding trajectories to rapidly sample the brain in two dimensions while minimizing gradient demands and improve spectral quality; 2) Hadamard encoding in the third dimension to minimize localization artifacts and provide excellent slice profiles for smaller numbers of partitions (4-8) covering the most relevant brain region; 3) a high degree shim insert to maximize magnetic field homogeneity and improve spectral quality and 4) dynamic spatially selective dephasing to maximize SNR and sample the cortical periphery. Consistent with what is the most widely accepted MRS clinical application currently, we will evaluate the methods in patients with high-grade brain tumors receiving immunotherapy. Although immunotherapy is a highly promising new therapeutic approach for brain tumors, treatment effects can mimic tumor progression on conventional MRI, compromising our ability to effectively monitor and manage these patients. MRSI offers an alternative means to monitor progression, based on tumor metabolism and physiology as opposed to relaxation properties of tissue water (conventional MRI). Thus we believe that MRSI may provide additive values and significantly aid in the management of these patients. This work will be performed at 3T and 7T.