Andrew Frew

Elevated Glutamatergic Compounds in Pregenual Anterior Cingulate in Pediatric Autism Spectrum Disorder Demonstrated by 1H MRS and 1H MRSI

Recent research in autism spectrum disorder (ASD) has aroused interest in anterior cingulate cortex and in the neurometabolite glutamate. We report two studies of pregenual anterior cingulate cortex (pACC) in pediatric ASD. First, we acquired in vivo single-voxel proton magnetic resonance spectroscopy (1H MRS) in 8 children with ASD and 10 typically developing controls who were well matched for age, but with fewer males and higher IQ. In the ASD group in midline pACC, we found mean 17.7% elevation of glutamate + glutamine (Glx) (p<0.05) and 21.2% (p<0.001) decrement in creatine + phosphocreatine (Cr). We then performed a larger (26 subjects with ASD, 16 controls) follow-up study in samples now matched for age, gender, and IQ using proton magnetic resonance spectroscopic imaging (1H MRSI). Higher spatial resolution enabled bilateral pACC acquisition. Significant effects were restricted to right pACC where Glx (9.5%, p<0.05), Cr (6.7%, p<0.05), and N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (10.2%, p<0.01) in the ASD sample were elevated above control. These two independent studies suggest hyperglutamatergia and other neurometabolic abnormalities in pACC in ASD, with possible right-lateralization. The hyperglutamatergic state may reflect an imbalance of excitation over inhibition in the brain as proposed in recent neurodevelopmental models of ASD.

White matter connectivity of human hypothalamus.

The macroscopic extrinsic white matter connectivity and the internal structure of the hypothalamus are still incompletely defined in humans. We investigated whether in-vivo diffusion tensor imaging tractography provides evidence of systematization according to hypothalamic compartmentalization. Six defined hypothalamic macroscopic compartments, preoptic, supraoptic, anteroventral, anterodorsal, lateral and posterior, were probed, within the right and left hemispheres of 14 subjects. Important new insights into the macroscopic structure of hypothalamus and white matter connections were found; the preoptic, anteroventral, lateral and posterior compartments are strongly connected to the cortex. The anteroventral connects particularly to the prefrontal cortex while the preoptic compartment connects mainly to the deep anterior brain. The anterodorsal connects mainly to the medial thalamus and the midline gray matter. There is a rightward frontal trend of hemispheric connectivity for the preoptic, anteroventral and lateral compartments. These findings may aid new neuromodulation applications and understanding in brain connectomics.

Cortical Atrophy in Experimental Autoimmune Encephalomyelitis: In Vivo Imaging

There are strong correlations between cortical atrophy observed by MRI and clinical disability and disease duration in multiple sclerosis (MS). The objective of this study was to evaluate the progression of cortical atrophy over time in vivo in experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model for MS. Volumetric changes in brains of EAE mice and matched healthy controls were quantified by collecting high-resolution T2-weighted magnetic resonance images in vivo and labeling anatomical structures on the images. In vivo scanning permitted us to evaluate brain structure volumes in individual animals over time and we observed that though brain atrophy progressed differently in each individual animal, all mice with EAE demonstrated significant atrophy in whole brain, cerebral cortex, and whole cerebellum compared to normal controls. Furthermore, we found a strong correlation between cerebellar atrophy and cumulative disease score in mice with EAE. Ex vivo MRI showed a significant decrease in brain and cerebellar volume and a trend that did not reach significance in cerebral cortex volume in mice with EAE compared to controls. Cross modality correlations revealed a significant association between neuronal loss on neuropathology and in vivo atrophy of the cerebral cortex by neuroimaging. These results demonstrate that longitudinal in vivo imaging is more sensitive to changes that occur in neurodegenerative disease models than cross-sectional ex vivo imaging. This is the first report of progressive cortical atrophy in vivo in a mouse model of MS.

Diffusion tensor imaging and colored fractional anisotropy mapping of the ventralis intermedius nucleus of the thalamus.

BACKGROUND The ventralis intermedius (VIM) nucleus of the thalamus is the primary surgical target for treatment of tremor. Most centers rely on indirect targeting based on atlas-defined coordinates rather than patient-specific anatomy, making intraoperative physiological mapping critical. Detailed identification of this target based on patient-specific anatomic features can help optimize the surgical treatment of tremor. OBJECTIVE To study colored fractional anisotropic images and diffusion tensor imaging (DTI) tractography to identify characteristic magnetic resonance appearances of the VIM nucleus. METHODS Four patients undergoing stereotactic surgery for essential tremor (ET) were retrospectively studied with analysis of magnetic resonance imaging-based colored fractional anisotropy (FA) images and fiber tractography. All were scanned with a 1.5-T magnetic resonance imaging unit, and all sequences were obtained before frame placement. Because the goal of this study was to identify the DTI characteristics of physiologically defined VIM nucleus, we selected and studied patients who had undergone DTI and had efficacious tremor control with intraoperative microlesioning effect and tremor reduction with less than 2.0-V stimulation. RESULTS Analysis of color FA maps, which graphically illustrate fiber directionality, revealed consistent anatomic patterns. The region of the VIM nucleus can be seen as an intermediate region where there is a characteristic transition of color. Presumptive VIM nucleus interconnectivity with sensorimotor cortex and cerebellum was identified via the internal capsule and the superior cerebellar peduncle, respectively. FA maps could also be used to distinguish segments of gray matter, white matter, and gray-white matter boundaries. CONCLUSION Analysis of DTI and FA maps on widely available 1.5-T magnetic resonance imaging yields clear identification of various structures key to neurosurgical targeting. Prospective evaluation of integrating DTI into neurosurgical planning may be warranted. ABBREVIATIONS DBS: deep brain stimulation DTI: diffusion tensor imaging FA: fractional anisotropy PILC: posterior limb of the internal capsule VIM: ventralis intermedius

The role of modern imaging modalities on deep brain stimulation targeting for mental illness

INTRODUCTION The reversible nature of deep brain stimulation (DBS) brought renewed interest on surgery to medically intractable mental illnesses. The explosion of anatomical and functional imaging has allowed the development of new potential targets and the understanding of historical targets. METHODS Fifteen patients undergoing stereotactic surgery for movement disorders, at UCLAs interventional MRI operating-room, were studied with fiber tracking. Stereotactic targets and fiber tracking were determined on MRIs using the Schaltenbrand-Wahren atlas for definition in the iPlan software. Cingulate, subcaudate, BA25/CgWM, amygdala, posterior hypothalamus, orbitofrontal cortex, nucleus accumbens, anterior limb of the internal capsule and dorsomedial thalamus were studied. DTI parameters used ranged from 10 to 20mm for voxel size in the x/y/z planes, fiber length was kept constant at 36 mm, and fractional anisotropy (FA) threshold varied from 0.20 to 0.25. RESULTS Reliable interconnectivity of targets were determined with DTI and related to PET imaging. Mental illness targets were observed with functional and fiber tract maps. This confirmation yields reliability to DTI imaging in order to determine novel targets and enhance the understanding of areas not well understood. CONCLUSIONS Currently available imaging techniques, the reversibility of DBS to modulate targets promises to bring a brighter future for surgery of mental illness.

Mapping therapeutic response in a patient with malignant glioma.

Short-interval scanning of patients offers a detailed understanding of the natural progression of tumor tissue, as revealed through imaging markers such as contrast enhancement and edema, prior to therapy. Following treatment, short-interval scanning can also provide evidence of attenuation of growth rates. We present a longitudinal imaging study of a patient with glioblastoma multiforme (GBM) scanned 15 times in 104 days on a 3 T MR scanner. Images were analyzed independently by two automated algorithms capable of creating detailed maps of tumor changes as well as volumetric analysis. The algorithms, a nearest-neighbor-based tissue segmentation and a surface-modeling algorithm, tracked the patients response to temozolomide, showing an attenuation of growth. The need for surrogate imaging end-points, of which growth rates are an example, is discussed. Further, the strengths of these algorithms, the insight gained by short-interval scanning, and the need for a better understanding of imaging markers are also described.

Contrast agent dose effects in cerebral dynamic susceptibility contrast magnetic resonance perfusion imaging

To study the contrast agent dose sensitivity of hemodynamic parameters derived from brain dynamic susceptibility contrast MRI (DSC‐MRI).

A Systematic Analysis of the Reliability of Diffusion Tensor Imaging Tractography for Facial Nerve Imaging in Patients with Vestibular Schwannoma

Surgeons need to visualize the facial nerve reliably in relation to the vestibular schwannoma (VS) in surgical planning. Diffusion tensor imaging (DTI) tractography has enabled unprecedented in vivo preoperative visualization. We collected data to measure the accuracy of DTI for an accurate location of the nerve in preoperative VS resection planning. A PubMed search for relevant studies was conducted. Inclusion criteria were gross total resection of VS, preoperative DTI identification of the facial nerve, and intraoperative cranial nerve localization by the surgeon. Exclusion criteria were tumors other than VS and unsuccessful preoperative location of the cranial nerve. Accuracy rate was calculated by comparing the intraoperative and preoperative locations detailed by DTI. The query identified 38 cases of VS that fit our inclusion criteria. Overall, 89% had surgical findings that agreed with the DTI location of the facial nerve. Of these cases, 32 patients had a postoperative House-Brackmann grade I or II. Our findings suggest that DTI is a reliable method for facial nerve imaging. Implementation of this technique may help decrease facial nerve injury during surgery. Limitations and further studies are needed to better understand what factors correlate with successful location of the facial nerve and DTI in patients with VS.

Quantification of pulsatile cerebrospinal fluid flow within the prepontine cistern.

BACKGROUND Phase-contrast MRI (PC-MRI) has previously been used for the quantification of CSF and blood flow throughout the body. We propose a new method of semi-automated segmentation for the prepontine cistern based on anatomical and pulsatility information. METHODS Scans were conducted on 48 patients (69.83 ± 14.28 years) ranging in age from 32 to 88 years along with an additional 11 controls (51.91 ± 21.13 years) ranging in age from 22 to 72 years. The segmentation algorithm developed consists of four stages: anatomical, flow quantification for the aqueduct and prepontine cistern, and blood vessel detection. RESULTS Complete results are presented in Table 1, the 37 preoperative patients and controls had a prepontine cistern stroke volume of 464.32 ± 202.30 and 447.38 ± 75.49 respectively. CONCLUSION Reliable quantification of volumetric CSF flow in complex cisternal spaces is possible using a methodology combining known anatomical features with the pulsatile nature of CSF flow.

Sex-Specific Life Course Changes in the Neuro-Metabolic Phenotype of Glut3 Null Heterozygous Mice: Ketogenic Diet Ameliorates Electroencephalographic Seizures and Improves Sociability

We tested the hypothesis that exposure of glut3+/- mice to a ketogenic diet ameliorates autism-like features, which include aberrant behavior and electrographic seizures. We first investigated the life course sex-specific changes in basal plasma-cerebrospinal fluid (CSF)-brain metabolic profile, brain glucose transport/uptake, glucose and monocarboxylate transporter proteins, and adenosine triphosphate (ATP) in the presence or absence of systemic insulin administration. Glut3+/- male but not female mice (5 months of age) displayed reduced CSF glucose/lactate concentrations with no change in brain Glut1, Mct2, glucose uptake or ATP. Exogenous insulin-induced hypoglycemia increased brain glucose uptake in glut3+/- males alone. Higher plasma-CSF ketones (β-hydroxybutyrate) and lower brain Glut3 in females vs males proved protective in the former while enhancing vulnerability in the latter. As a consequence, increased synaptic proteins (neuroligin4 and SAPAP1) with spontaneous excitatory postsynaptic activity subsequently reduced hippocampal glucose content and increased brain amyloid β1-40 deposition in an age-dependent manner in glut3+/- males but not females (4 to 24 months of age). We then explored the protective effect of a ketogenic diet on ultrasonic vocalization, sociability, spatial learning and memory, and electroencephalogram seizures in male mice (7 days to 6 to 8 months of age) alone. A ketogenic diet partially restored sociability without affecting perturbed vocalization, spatial learning and memory, and reduced seizure events. We conclude that (1) sex-specific and age-dependent perturbations underlie the phenotype of glut3+/- mice, and (2) a ketogenic diet ameliorates seizures caused by increased cortical excitation and improves sociability, but fails to rescue vocalization and cognitive deficits in glut3+/- male mice.