Faculty Bibliography

Increased tryptophan metabolism via the kynurenine pathway is a major mechanism of tumor immuno-resistance. α-[(11)C]Methyl-L: -tryptophan (AMT) is a positron emission tomography (PET) tracer for tryptophan catabolism, and increased AMT uptake has been demonstrated in brain tumors. In this study we evaluated the use of AMT PET for detection of low-grade gliomas and glioneuronal tumors, and determined if kinetic parameters of AMT uptake can differentiate among tumor types. AMT PET images were obtained in 23 patients with newly diagnosed low-grade brain tumors (WHO grade II gliomas and WHO grade I dysembryoplastic neuroepithelial tumors [DNETs]). Kinetic variables, including the unidirectional uptake rate (K-complex) and volume of distribution (VD; which characterizes tracer transport), were measured using a graphical approach from tumor dynamic PET and blood-input data, and metabolic rates ([Formula: see text]) were also calculated. These values as well as tumor/cortex ratios were compared across tumor types. AMT PET showed increased tumor/cortex K-complex (n = 16) and/or VD ratios (n = 15) in 21/23 patients (91%), including 11/13 tumors with no gadolinium enhancement on MRI. No increases in AMT were seen in an oligodendroglioma and a DNET. Astrocytomas and oligoastrocytomas showed higher [Formula: see text] tumor/cortex ratios (1.66 ± 0.46) than oligodendrogliomas (0.96 ± 0.21; P = 0.001) and DNETs (0.75 ± 0.39; P < 0.001). These results demonstrate that AMT PET identifies most low-grade gliomas and DNETs by high uptake, even if these tumors are not contrast-enhancing on MRI. Kinetic analysis of AMT uptake shows significantly higher tumor/cortex tryptophan metabolic ratios in astrocytomas and oligoastrocytomas in comparison with oligodendrogliomas and DNETs.

Angelman syndrome is a genetic disorder characterized by pervasive developmental disability with failure to develop speech. We examined the basis for severe language delay in patients with Angelman syndrome by diffusion tensor imaging. Magnetic resonance imaging/diffusion tensor imaging was performed in 7 children with genetically confirmed Angelman syndrome (age 70 ± 26 months, 5 boys) and 4 age-matched control children to investigate the microstructural integrity of arcuate fasciculus and other major association tracts. Six of 7 children with Angelman syndrome had unidentifiable left arcuate fasciculus, while all control children had identifiable arcuate fasciculus. The right arcuate fasciculus was absent in 6 of 7 children with Angelman syndrome and 1 of 4 control children. Diffusion tensor imaging color mapping suggested aberrant morphology of the arcuate fasciculus region. Other association tracts, including uncinate fasciculus, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, and corticospinal tract, were identifiable but manifested decreased fractional anisotropy in children with Angelman syndrome. Increased apparent diffusion coefficient was seen in all tracts except uncinate fasciculus when compared to control children. Patients with Angelman syndrome have global impairment of white matter integrity in association tracts, particularly the arcuate fasciculus, which reveals severe morphologic changes. This finding could be the result of a potential problem with axon guidance during brain development, possibly due to loss of UBE3A gene expression.

Ten members of a 3-generation pedigree with 7 showing Tourette syndrome/chronic tic phenotype (TS-CTD) were evaluated with whole exome sequencing. We identified 3 novel, nonsynonymous single nucleotide variants in the MRPL3, DNAJC13, and OFCC1 genes that segregated with chronic tic phenotype. These variants were not present in 100 control subjects or in dbSNP/1000 Genomes databases. A novel variant in the 5' untranslated region of the OFCC1 gene was found in 2 TS-CTD patients from a different pedigree. Further studies will clarify the importance of variants in MRPL3, DNAJC13, and OFCC1 genes in TS.

Standard magnetic resonance imaging can diagnose congenital bilateral perisylvian polymicrogyria, but is limited in explaining the heterogeneous clinical spectrum of the related congenital bilateral perisylvian syndrome, characterized by pseudobulbar dysfunction, developmental delay, and epilepsy. We analyzed arcuate fasciculi using diffusion tensor imaging, a major language tract in the perisylvian region interconnecting the Broca and Wernicke areas, and at high risk of becoming developmentally affected in this condition. Six patients with congenital bilateral perisylvian syndrome underwent diffusion tensor imaging and were evaluated. The arcuate fasciculus was manually isolated, using tractography. The tract was identified in three patients who had developed speech, and whose values for various diffusion parameters were similar to those in age-matched controls (patients/controls means: fractional anisotropy, 0.50/0.52; apparent diffusion coefficient, 0.0022/0.0022 mm(2)/second; P = ns for both). However, in three patients with severe impairment and no speech development, the arcuate fasciculus could not be identified by fiber-tracking. In this small series, the absence of arcuate fasciculi on diffusion tensor imaging correlated with a more severe phenotype, which cannot be appreciated via structural magnetic resonance imaging alone.

BACKGROUND:The powerful emotion inducing properties of music are well-known, yet music may convey differing emotional responses depending on environmental factors. We hypothesized that neural mechanisms involved in listening to music may differ when presented together with visual stimuli that conveyed the same emotion as the music when compared to visual stimuli with incongruent emotional content. METHODS:We designed this study to determine the effect of auditory (happy and sad instrumental music) and visual stimuli (happy and sad faces) congruent or incongruent for emotional content on audiovisual processing using fMRI blood oxygenation level-dependent (BOLD) signal contrast. The experiment was conducted in the context of a conventional block-design experiment. A block consisted of three emotional ON periods, music alone (happy or sad music), face alone (happy or sad faces), and music combined with faces where the music excerpt was played while presenting either congruent emotional faces or incongruent emotional faces. RESULTS:We found activity in the superior temporal gyrus (STG) and fusiform gyrus (FG) to be differentially modulated by music and faces depending on the congruence of emotional content. There was a greater BOLD response in STG when the emotion signaled by the music and faces was congruent. Furthermore, the magnitude of these changes differed for happy congruence and sad congruence, i.e., the activation of STG when happy music was presented with happy faces was greater than the activation seen when sad music was presented with sad faces. In contrast, incongruent stimuli diminished the BOLD response in STG and elicited greater signal change in bilateral FG. Behavioral testing supplemented these findings by showing that subject ratings of emotion in faces were influenced by emotion in music. When presented with happy music, happy faces were rated as more happy (p=0.051) and sad faces were rated as less sad (p=0.030). When presented with sad music, happy faces were rated as less happy (p=0.008) and sad faces were rated as sadder (p=0.002). INTERPRETATION/CONCLUSIONS:Happy-sad congruence across modalities may enhance activity in auditory regions while incongruence appears to impact the perception of visual affect, leading to increased activation in face processing regions such as the FG. We suggest that greater understanding of the neural bases of happy-sad congruence across modalities can shed light on basic mechanisms of affective perception and experience and may lead to novel insights in the study of emotion regulation and therapeutic use of music.

We present findings of (11)C-[R]-PK11195 positron emission tomography in a child with X-linked adrenoleukodystrophy. (11)C-[R]-PK11195 is a radioligand with a high and specific affinity for peripheral benzodiazepine receptors, expressed by activated microglia in cases of neuroinflammation, and therefore it is applicable to the in vivo detection of neuroinflammation with positron emission tomography. (11)C-[R]-PK11195 positron emission tomography demonstrated increased tracer binding in the occipital, parietal, and posterior temporal white matter, in the genu of the corpus callosum, the bilateral posterior thalami, most of the posterior limb of the internal capsule, the bilateral cerebral peduncles, and the brainstem, indicating underlying neuroinflammation. The rest of the brain, including the cerebral cortices and cerebellum, exhibited minimal (11)C-[R]-PK11195 binding. Our findings indicate significant neuroinflammation associated with white matter destruction in X-linked adrenoleukodystrophy, which can be visualized in vivo with an (11)C-[R]-PK11195 positron emission tomography scan. (11)C-[R]-PK11195 positron emission tomography may also help evaluate the inflammatory burden and follow-up of the disease evolution. This technique may be particularly useful for evaluating treatment response, which is not easy with other imaging modalities, after white matter is significantly and extensively damaged.

BACKGROUND AND PURPOSE/OBJECTIVE:One of the neurologic substrates of poor language in children with DD is the abnormal development of perisylvian language networks. We sought to determine whether this manifests as aberrant regional changes in diffusivity or geometry of the left AF. MATERIALS AND METHODS/METHODS:We performed DTI studies in 16 young (age, 55.4 ± 18.95 months) patients with DD and 11 age- and sex-matched TD children (age, 60.09 ± 21.27 months). All children were right-handed. To detect the malformation of left AF structure in native or standard space, we proposed new methodology consisting of 2 complementary approaches, principal fiber orientation quantification in color-coded anisotropic maps and tract-based morphometry analysis. RESULTS:Patients with DD did not show the typical pattern of age-related maturity of the AP and ML pathways passing through the left AF (R(2) of the AP pathway: DD versus TD = 0.002 versus 0.4542; R(2) of the ML pathway: DD versus TD = 0.002 versus 0.4154). In addition, the patients with DD showed significantly reduced FA in the temporal portion of the AF (mean FA of DD versus TD = 0.37 ± 0.11 versus 0.48 ± 0.06, P < .001), and the AF showed higher curvatures in the parietotemporal junction, resulting in sharper bends to the Wernicke area (mean curvature of DD versus TD = 0.12 ± 0.03 versus 0.06 ± 0.02, P < .001). CONCLUSIONS:The proposed methods successfully revealed regional abnormalities in the axonal integrity of the left AF in the patients with DD. These abnormalities support the notion that the perisylvian language network is malformed in children with DD.

PURPOSE/OBJECTIVE:We assessed 636 epileptic spasms seen in 11 children (median 44 spasms per child) and determined the spatial and temporal characteristics of ictal high-frequency oscillations (HFOs) in relation to the onset of spasms. METHODS:Electrocorticography (ECoG) signals were sampled from 104-148 cortical sites per child, and the dynamic changes of ictal HFOs were animated on each individual's three-dimensional (3D) magnetic resonance (MR) image surface. KEY FINDINGS/RESULTS:Visual assessment of ictal ECoG recordings revealed that each spasm event was characterized by augmentation of HFOs. Time-frequency analysis demonstrated that ictal augmentation of HFOs at 80-200 Hz was most prominent and generally preceded those at 210-300 Hz and at 70 Hz and slower. Recruitment of HFOs in the rolandic cortex preceded the clinical onset objectively visualized as electromyographic deflection. The presence or absence of ictal motor symptoms was related more to the amplitude of HFOs in the Rolandic cortex than in the seizure-onset zone. In a substantial proportion of epileptic spasms, seizure termination began at the seizure-onset zone and propagated to the surrounding areas; we referred to this observation as the "ictal doughnut phenomenon." Univariate analysis suggested that complete resection of the sites showing the earliest augmentation of ictal HFOs was associated with a good surgical outcome. SIGNIFICANCE/CONCLUSIONS:Recruitment of HFOs at 80-200 Hz in the rolandic area may play a role in determining seizure semiology in epileptic spasms. Our study using macroelectrodes demonstrated that ictal HFOs at 80-200 Hz preceded those at 210-300 Hz.

White matter (WM) loss is associated with cognitive impairment in Sturge-Weber syndrome (SWS). In this study, we evaluated if cognitive and fine motor abnormalities are associated with impaired microstructural integrity in specific WM regions in SWS. Fifteen children with unilateral SWS (age: 3-12.4 y) and 11 controls (age: 6-12.8 y) underwent diffusion tensor imaging. Tract-based spatial statistics was used for objective comparisons of WM fractional anisotropy (FA) and mean diffusivity (MD) between the two groups. In the SWS group, WM FA and MD values were correlated with intelligence quotient (IQ) and fine motor scores, with age as a co-variate. Bilateral, multilobar WM areas showed decreased FA, whereas significant MD increases were confined to small ipsilateral posterior regions in SWS children. IQ in the SWS group (range: 47-128) was positively correlated with FA in the ipsilateral prefrontal WM and inversely associated with MD in the ipsilateral posterior parietal WM. A negative correlation between fine motor function and MD was found in ipsilateral frontal WM encompassing motor pathways. Microstructural WM abnormalities occur not only ipsilateral but also contralateral to the angioma in unilateral SWS. Nevertheless, cognitive and fine motor functions are related to diffusion abnormalities in specific ipsilateral, mostly frontal, WM regions.