Faculty Bibliography

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.

Previous studies of epileptic spasms reported that ictal events were associated with high-frequency oscillations (HFOs) or delta waves involving widespread regions. We determined whether ictal HFOs at 80-200 Hz were coupled with a phase of slow-wave, whether ictal slow-waves were diffusely or locally synchronous signals, and whether the mode of coupling between HFOs and slow-wave phases differed between ictal and interictal states. We studied 11 children who underwent extraoperative electrocorticography (ECoG) recording. The phases and amplitudes of slow-waves were measured at the peak of ictal and interictal HFOs in the seizure-onset sites. Ictal HFOs were locked tightly to the phase of slow-wave at ≤1 Hz. Ictal slow-waves propagated from the seizure-onset site to other regions. In contrast, interictal HFOs in the seizure-onset site were loosely locked to the phase of slow-wave at ≤1 Hz but tightly to that of ≥3-Hz. Ictal slow-waves coupled with HFOs can be explained as near-field and locally synchronized potentials generated by the neocortex rather than far-field potentials generated by subcortical structures. Ictal slow-waves in epileptic spasms may be generated by a mechanism different from what generates interictal HFOs-slow-wave complexes.

Of several molecular probes used in PET, only α-[(11)C]-methyl-L-tryptophan (AMT) is able to pinpoint the epileptic focus itself in the interictal state, by revealing a focus of increased AMT uptake, even when an MRI or glucose metabolism PET demonstrates normal findings. AMT PET appears to be particularly useful in patients with tuberous sclerosis complex and in patients with cortical developmental malformations. Although the sensitivity of AMT PET in finding the epileptic focus is about 70%, its specificity is almost 100%, indicating that if AMT PET identifies an area of increased uptake, it likely represents the epileptic focus which needs to be resected for better surgical outcome. In nontuberous sclerosis complex patients with cortical dysplasia, increased AMT uptake is usually associated with cortical dysplasia type IIB and a very good surgical outcome. Previously, no imaging modality has been able to predict the exact pathology subtype or differentiate between epileptogenic and nonepileptogenic lesions interictally. The neuropathological similarities between tubers and type IIB cortical dysplasia suggest a common mechanism of epilepsy, for which AMT PET is a biomarker. Due to the limited access to AMT PET, as presently it is labeled with (11)C, which has a half-life of only 20 min and therefore has to be synthesized on site using a cyclotron, most of the AMT experience has originated primarily from only two centers. Therefore, there is a need for more clinical studies from other centers and this can be greatly facilitated if AMT can be labeled with (18)F, a PET radionuclide widely available with a half-life of 110 min.

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.

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.

Serial 2-deoxy-2[(18)F]fluoro-D-glucose positron emission tomography was performed in identical twins with Niemann-Pick disease type C. Two such scans, performed at ages 4 and 6 years, revealed a characteristic, unique pattern of brain metabolic abnormality. Whereas the first scans indicated mild, diffuse cortical hypometabolism, most pronounced in the medial frontal cortex, the repeated scans in both twins revealed a unique pattern consisting of severe hypometabolism of the frontal cortex bilaterally, particularly involving medial and inferior frontal regions, and hypometabolism in the bilateral parietal and temporal cortex. In the parietal cortex, lateral and medial aspects were most severely affected, with some sparing of the intermediate parietal region. This progression of brain hypometabolism between two positron emission tomography studies was associated with clinical and neurologic deterioration. This distinctive brain metabolic pattern, which we have observed in no other condition, may constitute a "biomarker" to assess neurologic progression and possible treatment responses in children with Niemann-Pick disease type C, because magnetic resonance imaging findings are either normal at earlier stages or demonstrate only nonspecific changes.

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.

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.