Search PubMed⌕ Search

Biomedical subjects

Donald Wong

Publications and source records attributed to Donald Wong.

At least 19 recordsLinked to original sources
PubMed2006

Activation of the left planum temporale in pitch processing is shaped by language experience.

Implicit, abstract knowledge acquired through language experience can alter cortical processing of complex auditory signals. To isolate prelexical processing of linguistic tones (i.e., pitch variations that convey part of word meaning), a novel design was used in which hybrid stimuli were created by superimposing Thai tones onto Chinese syllables (tonal chimeras) and Chinese tones onto the same syllables (Chinese words). Native speakers of tone languages (Chinese, Thai) underwent fMRI scans as they judged tones from both stimulus sets. In a comparison of native vs. non-native tones, overlapping activity was identified in the left planum temporale (PT). In this area a double dissociation between language experience and neural representation of pitch occurred such that stronger activity was elicited in response to native as compared to non-native tones. This finding suggests that cortical processing of pitch information can be shaped by language experience and, moreover, that lateralized PT activation can be driven by top-down cognitive processing.

Acoustic Stimulation↗
PubMed2005

Neural circuitry underlying sentence-level linguistic prosody.

This study investigates the neural substrates underlying the perception of two sentence-level prosodic phenomena in Mandarin Chinese: contrastive stress (initial vs. final emphasis position) and intonation (declarative vs. interrogative modality). In an fMRI experiment, Chinese and English listeners were asked to selectively attend to either stress or intonation in paired 3-word sentences, and make speeded-response discrimination judgments. Between-group comparisons revealed that the Chinese group exhibited significantly greater activity in the left supramarginal gyrus and posterior middle temporal gyrus relative to the English group for both tasks. These same two regions showed a leftward asymmetry in the stress task for the Chinese group only. For both language groups, rightward asymmetries were observed in the middle portion of the middle frontal gyrus across tasks. All task effects involved greater activity for the stress task as compared to intonation. A left-sided task effect was observed in the posterior middle temporal gyrus for the Chinese group only. Both language groups exhibited a task effect bilaterally in the intraparietal sulcus. These findings support the emerging view that speech prosody perception involves a dynamic interplay among widely distributed regions not only within a single hemisphere but also between the two hemispheres. This model of speech prosody processing emphasizes the role of right hemisphere regions for complex-sound analysis, whereas task-dependent regions in the left hemisphere predominate when language processing is required.

Adult↗
PubMed2005

Nitric oxide reduces T lymphocyte adhesion to human brain microvessel endothelial cells via a cGMP-dependent pathway.

The entry of lymphocytes into the brain is normally limited by the blood-brain barrier, however, during inflammation prominent lymphocytic infiltration occurs. In this study, we investigated the effects of nitric oxide (NO) on the adhesion of T cells to cultured human brain microvessel endothelial cells. T cell adhesion to unstimulated or tumor necrosis factor-alpha (TNF-alpha)-treated cells was quantified by counting the number of lymphocytes bound to the monolayer by light microscopy. TNF-alpha increased T cell adhesion in a time-dependent manner. Incubation of monolayers with NO donors decreased adhesion. This effect was blocked by a guanylyl cyclase inhibitor and mimicked by a cGMP agonist, and was thus dependent on the generation of cGMP. NO did not modulate adhesion molecule expression in the endothelial cells, suggesting an action on the T cells. Pre-treatment of T cells with NO or a cGMP agonist decreased binding to recombinant endothelial adhesion molecules. These findings suggest that NO can modulate the adhesion of T cells to human brain microvessel endothelial cells via a cGMP-dependent mechanism, and may thus regulate lymphocyte traffic during central nervous system inflammation.

Brain↗
PubMed2005

The CXCR4 agonist peptide, CTCE-0021, rapidly mobilizes polymorphonuclear neutrophils and hematopoietic progenitor cells into peripheral blood and synergizes with granulocyte colony-stimulating factor.

OBJECTIVE: Mobilization of hematopoietic stem and progenitor cells (HSPC) by stromal cell-derived factor-1 (SDF-1) has been described; however, sustained adenoviral delivery or N-terminal modification was required for effect and could not be demonstrated with native protein. The aim of this study was to further investigate the SDF-1alpha/CXCR4 axis in HSPC mobilization using CTCE-0021, a cyclized CXCR4 agonist peptide, with comparable bioactivity and improved stability relative to SDF-1alpha. METHODS: Peripheral blood cells and hematopoietic progenitor cells (HPC) were quantitated in mice administered single or multiple doses of CTCE-0021 or SDF-1alpha, or mobilized by granulocyte colony-stimulating factor (G-CSF) in combination with CTCE-0021. Proteases, cytokines, and receptors implicated in HSPC mobilization were evaluated to determine mechanism of action. RESULTS: CTCE-0021 dose-dependently elevated blood neutrophils polymorphonuclear neutrophil [PMN] within 5 minutes that peaked after 1 hour and persisted for 24 hours. PMN mobilization could be maintained by daily dosing. CTCE-0021 mobilized colony-forming unit granulocyte macrophage (CFU-GM), burst-forming unit erythroid (BFU-E), and CFU-granulocyte-erythrocyte-monocyte-megakaryocyte (CFU-GEMM) that peaked within 1 hour after administration, and synergistically enhanced both PMN and HSPC mobilization when combined with G-CSF. Mobilization induced by CTCE-0021 was associated with rapid downregulation of CXCR4 expression on HPC. No appreciable changes in proteases implicated in HPC mobilization were observed. Significantly elevated plasma SDF-1 was detected in mobilized mice, which likely represents CTCE-0021. CONCLUSION: These studies indicate that CTCE-0021 is an efficient and rapid mobilizer of PMN and HPC when used alone and shows synergistic activity when used in combination with G-CSF. The mobilizing effect of this peptide appears to be mediated by downregulation of the CXCR4 receptor on HPC and altered chemokine gradient.

Animals↗
PubMed2004

Neural network for encoding immediate memory in phonological processing.

The aim of this fMRI study was to identify neuroanatomical substrates of immediate memory underlying phonological processing. To distinguish encoding of immediate memory from rehearsal, participants were required to match tones from the first and last positions of a three-syllable list to their following probes in an immediate-recognition paradigm. The first position task included intervening distractors between the target and probe. Increased activations were found in the left inferior frontal gyrus, right lateral cerebellum, and medial frontal gyrus for the target tone in first position. This network mediates articulatory encoding in immediate-response, and articulatory rehearsal in delayed-response paradigms. These findings support a working memory model in which rehearsal is optional, while encoding is an obligatory component of the phonological loop.

Adult↗
PubMed2004

Nitric oxide regulates interactions of PMN with human brain microvessel endothelial cells.

The hypothesis that the NO/cGMP pathway modulates PMN adhesion to human brain microvessel endothelial cells (HBMEC) was examined. Human PMN were incubated with resting or TNF-alpha-treated endothelial monolayers, and adhesion was quantified by light microscopy. TNF-alpha upregulated PMN adhesion in a time-dependent manner. Treatment of HBMEC with the NO donors SNP and DETA NONOate for 4 or 24 h decreased PMN adhesion. This was completely reversed by the guanylyl cyclase inhibitor ODQ, while addition of a cGMP agonist (8-Br-cGMP) decreased PMN adhesion. NO donors did not affect the levels of E-selectin or ICAM-1 in HBMEC. However, pre-treatment of PMN with NO donors or 8-Br-cGMP decreased their adhesion to recombinant E-selectin and ICAM-1, suggesting an effect of NO on PMN. These findings indicate that NO modulates PMN-HBMEC interactions through cGMP and decreases the binding of PMN to the adhesion molecules E-selectin and ICAM-1.

Blotting, Western↗
PubMed2004

Increased plasma levels of stromal-derived factor-1 (SDF-1/CXCL12) enhance human thrombopoiesis and mobilize human colony-forming cells (CFC) in NOD/SCID mice.

OBJECTIVE: Stromal-derived factor-1 (SDF-1/CXCL12) is chemotactic for lympho/hematopoietic stem cells. We have previously shown that increasing peripheral blood (PB) levels of SDF-1 with adenovectors expressing human SDF-1 complementary DNA (ad-SDF-1) leads to hematopoietic stem cell mobilization as well as migration of megakaryocytes and thrombocytosis in mice. Herein, we studied the in vivo effects of ad-SDF-1 and of an analogue peptide of SDF-1 (CTCE-0214) on human hematopoiesis in a xenotransplant model. MATERIALS AND METHODS: Sublethally irradiated (300 cGY) NOD/SCID mice transplanted with human cord blood mononuclear cells (CB MNC) were injected with ad-SDF-1 (10(9) plaque forming units, i.v., x 1) or CTCE-0214 (10 mg/kg/dose, i.v. q 24 hours x 7). Effects on megakaryocytopoiesis (CD41+ cells and platelets) as well as stem cell mobilization were monitored. RESULTS: CB MNC in NOD/SCID mice are able to differentiate into CD41+ cells and platelets, peaking at week 9 at a mean of 3.7 x 10(3)/microL. i.v. injection of ad-SDF-1 increased human CD41+ cells by day 4 in PB and was followed by an increase in human platelet production by day 5, with return to baseline by day 30. Human colony-forming cells (CFC) were mobilized from bone marrow to spleen (by day 6-13) and to PB (by day 13). Human CD34+ and CD33+ cells were mobilized by this treatment as well. A novel SDF-1 peptide agonist (CTCE-0214) also mobilized human CFC and enhanced human thrombopoiesis. CONCLUSION: SDF-1 and its analogue may be of clinical value in stimulating platelet recovery after chemo/radiation treatment as well as in stem cell mobilization.

Adenoviridae↗
PubMed2004

Small peptide analogs to stromal derived factor-1 enhance chemotactic migration of human and mouse hematopoietic cells.

Stromal cell-derived factor 1 (SDF-1) is a chemokine that binds to the CXCR4 receptor. Its functions include acting as a chemotactic factor for hematopoietic stem and progenitor cells. We recently reported the synthesis of a small cyclized peptide analog (31 amino acids) of the terminal regions of SDF-1 that had biological function comparable to the native molecule (67 amino acids). In the present study, we investigated the effects of SDF-1 analogs (CTCE0021 and CTCE0214) in the chemotactic migration of peripheral blood hematopoietic cells (lineage-negative and CD34(+) cells). Enhanced chemotaxis of normal and G-CSF-mobilized hematopoietic cells was observed with both SDF-1 analogs in a dose-dependent manner. The increases were statistically significant (p < or = 0.016 by one-way ANOVA) at analog concentrations of 50 to 100 microg/mL. Colony-forming progenitor cells were not affected by exposure to the analogs up to 100 microg/mL. When different doses of the SDF-1 analog CTCE0214 were administered to mice, significant increases in circulating hematopoietic cells (identified by flow cytometry as lineage(low/-), Sca-1(+), and c-kit(+)) were observed after a single injection of 75 microg per animal. The effect was apparent at 4 hours and became significant at 24 hours. These results suggest that SDF-1 analogs can be considered for mobilization of hematopoietic stem cells.

Amino Acid Sequence↗
PubMed2004

Cytokines, nitric oxide, and cGMP modulate the permeability of an in vitro model of the human blood-brain barrier.

The endothelial cells (EC) of the microvasculature in the brain form the anatomical basis of the blood-brain barrier (BBB). In the present study, the effects of agents that modify the permeability of a well-established in vitro model of the human BBB were studied. The monolayers formed by confluent human brain microvessel endothelial cell (HBMEC) cultures are impermeable to the macromolecule tracer horseradish peroxidase (HRP) and have high electrical resistance. Exposure of HBMEC to various cytokines including TNF-alpha, IL-1beta, interferon gamma (IFN-gamma), or lipopolysaccharide (LPS) decreased transendothelial electrical resistance (TEER) mainly by increasing the permeability of the tight junctions. Primary cultures of HBMEC express endothelial nitric oxide synthase (eNOS) and produce low levels of NO. Treatment with the NO donors sodium nitroprusside (SNP) and DETA NONOate or the cGMP agonist 8-Br-cGMP significantly increased monolayer resistance. Conversely, inhibition of soluble guanylyl cyclase with ODQ rapidly decreased the resistance, and pretreatment of HBMEC with Rp-8-CPT-cGMPS, an inhibitor of cGMP-dependent protein kinase, partially prevented the 8-Br-cGMP-induced increase in resistance. Furthermore, NO donors and 8-Br-cGMP could also reverse the increased permeability of the monolayers induced by IL-1beta, IFN-gamma, and LPS. These results indicate that NO can decrease the permeability of the human BBB through a mechanism at least partly dependent on cGMP production and cGMP-dependent protein kinase activation.

Blood-Brain Barrier↗
PubMed2004

Hemispheric roles in the perception of speech prosody.

Speech prosody is processed in neither a single region nor a specific hemisphere, but engages multiple areas comprising a large-scale spatially distributed network in both hemispheres. It remains to be elucidated whether hemispheric lateralization is based on higher-level prosodic representations or lower-level encoding of acoustic cues, or both. A cross-language (Chinese; English) fMRI study was conducted to examine brain activity elicited by selective attention to Chinese intonation (I) and tone (T) presented in three-syllable (I3, T3) and one-syllable (I1, T1) utterance pairs in a speeded response, discrimination paradigm. The Chinese group exhibited greater activity than the English in a left inferior parietal region across tasks (I1, I3, T1, T3). Only the Chinese group exhibited a leftward asymmetry in inferior parietal and posterior superior temporal (I1, I3, T1, T3), anterior temporal (I1, I3, T1, T3), and frontopolar (I1, I3) regions. Both language groups shared a rightward asymmetry in the mid portions of the superior temporal sulcus and middle frontal gyrus irrespective of prosodic unit or temporal interval. Hemispheric laterality effects enable us to distinguish brain activity associated with higher-order prosodic representations in the Chinese group from that associated with lower-level acoustic/auditory processes that are shared among listeners regardless of language experience. Lateralization is influenced by language experience that shapes the internal prosodic representation of an external auditory signal. We propose that speech prosody perception is mediated primarily by the RH, but is left-lateralized to task-dependent regions when language processing is required beyond the auditory analysis of the complex sound.

Adult↗
PubMed2003

Selective attention to lexical tones recruits left dorsal frontoparietal network.

Phonological processing activates a posterior superior region of inferior prefrontal cortex, but questions still remain about the relationship between phonology and this particular region. In this fMRI experiment, subjects were asked to match an intrasyllabic unit (Chinese tones) in an experimental condition vs. whole syllables in a control condition. The only difference between conditions is mediated by focus of attention, either to a subpart (i.e. tone) of the syllable or to the whole syllable itself. Phonetic extraction of Chinese tones reveals a dorsal frontoparietal network in the LH that engages selective attention and internal guidance, two mediational components that are not restricted to phonological processing.

Acoustic Stimulation↗
PubMed2003

A cross-linguistic fMRI study of perception of intonation and emotion in Chinese.

Conflicting data from neurobehavioral studies of the perception of intonation (linguistic) and emotion (affective) in spoken language highlight the need to further examine how functional attributes of prosodic stimuli are related to hemispheric differences in processing capacity. Because of similarities in their acoustic profiles, intonation and emotion permit us to assess to what extent hemispheric lateralization of speech prosody depends on functional instead of acoustical properties. To examine how the brain processes linguistic and affective prosody, an fMRI study was conducted using Chinese, a tone language in which both intonation and emotion may be signaled prosodically, in addition to lexical tones. Ten Chinese and 10 English subjects were asked to perform discrimination judgments of intonation (I: statement, question) and emotion (E: happy, angry, sad) presented in semantically neutral Chinese sentences. A baseline task required passive listening to the same speech stimuli (S). In direct between-group comparisons, the Chinese group showed left-sided frontoparietal activation for both intonation (I vs. S) and emotion (E vs. S) relative to baseline. When comparing intonation relative to emotion (I vs. E), the Chinese group demonstrated prefrontal activation bilaterally; parietal activation in the left hemisphere only. The reverse comparison (E vs. I), on the other hand, revealed that activation occurred in anterior and posterior prefrontal regions of the right hemisphere only. These findings show that some aspects of perceptual processing of emotion are dissociable from intonation, and, moreover, that they are mediated by the right hemisphere.

Adult↗
PubMed2003

Neural correlates of segmental and tonal information in speech perception.

The Chinese language provides an optimal window for investigating both segmental and suprasegmental units. The aim of this cross-linguistic fMRI study is to elucidate neural mechanisms involved in extraction of Chinese consonants, rhymes, and tones from syllable pairs that are distinguished by only one phonetic feature (minimal) vs. those that are distinguished by two or more phonetic features (non-minimal). Triplets of Chinese monosyllables were constructed for three tasks comparing consonants, rhymes, and tones. Each triplet consisted of two target syllables with an intervening distracter. Ten Chinese and English subjects were asked to selectively attend to targeted sub-syllabic components and make same-different judgments. Direct between-group comparisons in both minimal and non-minimal pairs reveal increased activation for the Chinese group in predominantly left-sided frontal, parietal, and temporal regions. Within-group comparisons of non-minimal and minimal pairs show that frontal and parietal activity varies for each sub-syllabic component. In the frontal lobe, the Chinese group shows bilateral activation of the anterior middle frontal gyrus (MFG) for rhymes and tones only. Within-group comparisons of consonants, rhymes, and tones show that rhymes induce greater activation in the left posterior MFG for the Chinese group when compared to consonants and tones in non-minimal pairs. These findings collectively support the notion of a widely distributed cortical network underlying different aspects of phonological processing. This neural network is sensitive to the phonological structure of a listener's native language. Hum. Brain Mapping 20:185-200, 2003.

Adult↗
PubMed2003

Temporal integration of speech prosody is shaped by language experience: an fMRI study.

Differences in hemispheric functions underlying speech perception may be related to the size of temporal integration windows over which prosodic features (e.g., pitch) span in the speech signal. Chinese tone and intonation, both signaled by variations in pitch contours, span over shorter (local) and longer (global) temporal domains, respectively. This cross-linguistic (Chinese and English) study uses functional magnetic resonance imaging to show that pitch contours associated with tones are processed in the left hemisphere by Chinese listeners only, whereas pitch contours associated with intonation are processed predominantly in the right hemisphere. These findings argue against the view that all aspects of speech prosody are lateralized to the right hemisphere, and promote the idea that varying-sized temporal integration windows reflect a neurobiological adaptation to meet the 'prosodic needs' of a particular language.

Adult↗
PubMed2003

Ultrastructural evidence of early endothelial damage in coronary arteries of rat cardiac allografts.

BACKGROUND: Events that occur early after transplantation, particularly immune recognition of allo-endothelium, initiate transplant vascular disease (TVD). Previous work suggests an important compromise of endothelial integrity as the allo-immune milieu evolves, although mechanisms by which integrity is altered remain unclear. Increased vascular permeability caused by endothelial damage may allow inflammatory cells, lipoproteins, other proteins, and plasma fluid to enter the sub-endothelial space, thereby contributing to the initiation of atherosclerosis. In this study, we examined endothelial integrity in coronary arteries and the proximal aorta after cardiac transplantation in rats. METHODS: We used Lewis-to-Lewis and Lewis-to-F344 rat heterotopic cardiac transplant models. We studied the effects of cyclosporine (5mg/kg/day) therapy compared with saline-treated controls. En face silver nitrate staining was performed to demonstrate endothelial cell borders and gaps. We used scanning electron microscopy to extend silver nitrate findings and to further define the presence and nature of endothelial disruptions. We used transmission electron microscopy to further characterize immune cell identity and interaction with endothelium. RESULTS: Syngrafts and cyclosporine-treated allografts showed normal-looking endothelium similar to that observed in arteries from native hearts. However, saline-treated allografts displayed progressive endothelial destruction, including large intercellular gaps, missing cells, and areas of bare extracellular matrix. Exfoliated surfaces were covered by platelets at various stages of adhesion, activation, and spreading. Similarly, we observed numerous leukocytes as either adherent to the endothelial lining or transmigrating into the sub-endothelial space. Cessation of cyclosporine therapy was associated with the development of similar abnormalities. CONCLUSIONS: Our findings indicate that, especially when immunosuppression is insufficient, early endothelial damage may promote vascular permeability and thereby initiate TVD.

Animals↗
PubMed2002

A cross-linguistic FMRI study of spectral and temporal cues underlying phonological processing.

It remains a matter of controversy precisely what kind of neural mechanisms underlie functional asymmetries in speech processing. Whereas some studies support speech-specific circuits, others suggest that lateralization is dictated by relative computational demands of complex auditory signals in the spectral or time domains. To examine how the brain processes linguistically relevant spectral and temporal information, a functional magnetic resonance imaging study was conducted using Thai speech, in which spectral processing associated with lexical tones and temporal processing associated with vowel length can be differentiated. Ten Thai and 10 Chinese subjects were asked to perform discrimination judgments of pitch and timing patterns presented in the same auditory stimuli under two different conditions: speech (Thai) and nonspeech (hums). In the speech condition, tasks required judging Thai tones (T) and vowel length (VL); in the nonspeech condition, homologous pitch contours (P) and duration patterns (D). A remaining task required listening passively to nonspeech hums (L). Only the Thai group showed activation in the left inferior prefrontal cortex in speech minus nonspeech contrasts for spectral (T vs. P) and temporal (VL vs. D) cues. Thai and Chinese groups, however, exhibited similar fronto-parietal activation patterns in nonspeech hums minus passive listening contrasts for spectral (P vs. L) and temporal (D vs. L) cues. It appears that lower level specialization for acoustic cues in the spectral and temporal domains cannot be generalized to abstract higher order levels of phonological processing. Regardless of the neural mechanisms underlying low-level auditory processing, our findings clearly indicate that hemispheric specialization is sensitive to language-specific factors.

Adult↗
PubMed2002

Neural circuitry underlying perception of duration depends on language experience.

Thai, a language which exhibits a phonemic opposition in vowel length, allows us to compare temporal patterns in linguistic and nonlinguistic contexts. Functional MRI data were collected from Thai and English subjects in a speeded-response, selective attention paradigm as they performed same/different judgments of vowel duration and consonants (Thai speech) and hum duration (nonspeech). Activation occurred predominantly in left inferior prefrontal cortex in both speech tasks for the Thai group, but only in the consonant task for the English group. The Thai group exhibited activation in the left mid superior temporal gyrus in both speech tasks; the English group in the posterior superior temporal gyrus bilaterally. In the hum duration task, peak activation was observed bilaterally in prefrontal cortex for both groups. These crosslinguistic data demonstrate that encoding of complex auditory signals is influenced by their functional role in a particular language.

Adult↗