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1.
Mol Pharm ; 15(6): 2384-2390, 2018 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-29757653

RESUMO

AGS62P1 is an antibody drug conjugate (ADC) composed of a human IgG1κ monoclonal antibody against FLT3 (FMS-like tyrosine kinase 3) with a p-acetyl phenylalanine (pAF) residue inserted at position 124 of each heavy chain linked to the proprietary microtubule disrupting agent AGL-0182-30 via an alkoxyamine linker that forms an oxime upon conjugation to the antibody. AGS62P1 is currently in Phase I human clinical trials for acute myelogenous leukemia (AML). The identified primary metabolite of an oxime-linked ADC is presented for the first time. AGS62P1 metabolism was assessed in xenograft tumor-bearing mice and rats treated with the ADC using liquid chromatography and mass spectrometry-based methods described herein. In this study, we identified the metabolite of AGS62P1 as pAF-AGL-0185-30, which contains a fragment resulting from the catabolism of the antibody component of the ADC and hydrolysis of the terminal amide portion of the linker-payload. We demonstrated that the metabolite of AGS62P1 is tolerated in rats above 1.5 mg/kg and above 0.334 mg/kg in cynomolgus monkeys when given as a single dose. Furthermore, we established in vitro that pAF-AGL-0185-30 does not significantly inhibit hERG or cytochrome P450 family enzymes (CYPs).


Assuntos
Antineoplásicos/metabolismo , Imunoconjugados/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Linhagem Celular Tumoral , Canal de Potássio ERG1/metabolismo , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/química , Leucemia Mieloide Aguda/patologia , Macaca fascicularis , Camundongos , Camundongos SCID , Oximas/química , Ratos , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Bioconjug Chem ; 28(2): 371-381, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28060485

RESUMO

Antibody drug conjugates offer a targeted cancer treatment for the delivery of potent cytotoxic drugs. Derivatives of the natural product dolastatin 10 containing pyridines and other basic amines were examined with the objective of determining if a more hydrophilic auristatin derivative would be potent enough for use as part of an ADC. This may be advantageous if a less hydrophobic drug makes a better ADC. A pyridine derivative, monomethyl auristatin PYE, showed the greatest potency when tested in vivo. While only a modest tumor growth inhibition was observed when the HCC1954 human breast cancer xenografts were treated with"non-cleavable" linker ADCs, tumor regression was seen when treated with an enzymatically degradable "cleavable" linker ADC when conjugated to trastuzumab. Based on these studies, monomethyl auristatin PYE shows promise for use as an ADC payload.


Assuntos
Aminobenzoatos/química , Interações Hidrofóbicas e Hidrofílicas , Imunoconjugados/química , Oligopeptídeos/química , Amidas/química , Animais , Linhagem Celular Tumoral , Humanos , Imunoconjugados/farmacologia , Camundongos , Multimerização Proteica/efeitos dos fármacos , Estrutura Quaternária de Proteína , Tubulina (Proteína)/química , Ensaios Antitumorais Modelo de Xenoenxerto
3.
J Evid Based Dent Pract ; 14 Suppl: 209-21.e1, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24929606

RESUMO

UNLABELLED: The changing health care environment and societal imperatives indicate the need for transformative change within the dental hygiene profession to serve the emerging needs of the public. The American Dental Hygienists' Association is leading the way toward meaningful change. BACKGROUND AND PURPOSE: The American Dental Hygienists' Association (ADHA) has as its vision the integration of dental hygienists into the health care delivery system as essential primary care providers to expand access to oral health care. This article provides data on current dental hygiene education programs and those in development. Also included is a discussion regarding how the dental hygiene profession can better serve the health and wellness needs of society by transforming the way graduates are prepared for the future. METHOD: ADHA's dental hygiene survey center data, policies and a futuristic analysis plus a review of the professional literature describe the current state of dental hygiene education and the profession. A discussion of societal, health care and educational trends that creates the imperative for transformation of the dental hygiene profession is provided. CONCLUSIONS: Ultimately, the purpose of advancing education in dental hygiene is to achieve better oral and overall health for more people. The profession's responsibility to the public includes evaluating its own ability to provide care and taking the steps necessary to ensure its maximum effectiveness. ADHA is leading this process for dental hygienists in diverse ways. It is imperative that the dental hygiene profession understands and embraces the changing health care environment. Through open dialog and the sharing of evidence the professional path will be determined along with forward movement for the benefit of society and the dental hygiene profession.


Assuntos
Higienistas Dentários/educação , Acreditação , Currículo , Assistência Odontológica , Higienistas Dentários/legislação & jurisprudência , Pesquisa em Odontologia , Educação de Pós-Graduação , Escolaridade , Docentes , Acessibilidade aos Serviços de Saúde , Humanos , Equipe de Assistência ao Paciente , Preceptoria , Prática Profissional , Desenvolvimento de Programas , Responsabilidade Social
4.
Brain Cogn ; 68(1): 1-8, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18586370

RESUMO

Facial expression and direction of gaze are two important sources of social information, and what message each conveys may ultimately depend on how the respective information interacts in the eye of the perceiver. Direct gaze signals an interaction with the observer but averted gaze amounts to "pointing with the eyes", and in combination with a fearful facial expression may signal the presence of environmental danger. We used fMRI to examine how gaze direction influences brain processing of facial expression of fear. The combination of fearful faces and averted gazes activated areas related to gaze shifting (STS, IPS) and fear-processing (amygdala, hypothalamus, pallidum). Additional modulation of activation was observed in motion detection areas, in premotor areas and in the somatosensory cortex, bilaterally. Our results indicate that the direction of gaze prompts a process whereby the brain combines the meaning of the facial expression with the information provided by gaze direction, and in the process computes the behavioral implications for the observer.


Assuntos
Encéfalo/fisiologia , Expressão Facial , Medo/fisiologia , Fixação Ocular , Reconhecimento Visual de Modelos/fisiologia , Adulto , Tonsila do Cerebelo/fisiologia , Análise de Variância , Córtex Cerebral/fisiologia , Dominância Cerebral/fisiologia , Feminino , Humanos , Hipotálamo/fisiologia , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Estimulação Luminosa/métodos , Percepção Social , Córtex Somatossensorial/fisiologia , Percepção Visual/fisiologia , Adulto Jovem
5.
Cancer Res ; 78(8): 2115-2126, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29382707

RESUMO

AGS-16C3F is an antibody-drug conjugate (ADC) against ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) containing the mcMMAF linker-payload currently in development for treatment of metastatic renal cell carcinoma. AGS-16C3F and other ADCs have been reported to cause ocular toxicity in patients by unknown mechanisms. To investigate this toxicity, we developed an in vitro assay using human corneal epithelial cells (HCEC) and show that HCECs internalized AGS-16C3F and other ADCs by macropinocytosis, causing inhibition of cell proliferation. We observed the same mechanism for target-independent internalization of AGS-16C3F in fibroblasts and human umbilical vein endothelial cells (HUVEC). Macropinocytosis-mediated intake of macromolecules is facilitated by the presence of positive charges or hydrophobic residues on the surface of the macromolecule. Modification of AGS-16C3F, either by attachment of poly-glutamate peptides, mutation of residue K16 to D on AGS-16C3F [AGS-16C3F(K16D)], or decreasing the overall hydrophobicity via attachment of polyethylene glycol moieties, significantly reduced cytotoxicity against HCECs and other primary cells. Rabbits treated with AGS-16C3F showed significant ocular toxicity, whereas those treated with AGS-16C3F(K16D) presented with less severe and delayed toxicities. Both molecules displayed similar antitumor activity in a mouse xenograft model. These findings establish a mechanism of action for target-independent toxicities of AGS-16C3F and ADCs in general, and provide methods to ameliorate these toxicities.Significance: These findings reveal a mechanism for nonreceptor-mediated toxicities of antibody drug conjugates and potential solutions to alleviate these toxicities. Cancer Res; 78(8); 2115-26. ©2018 AACR.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Epitélio Corneano/efeitos dos fármacos , Imunoconjugados/toxicidade , Pinocitose/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana , Humanos , Macaca fascicularis , Masculino , Modelos Animais , Coelhos , Homologia de Sequência de Aminoácidos
6.
Neuroreport ; 18(4): 301-5, 2007 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-17435592

RESUMO

Migraine has been traditionally considered a nonprogressive, paroxysmal disorder with no brain abnormalities between attacks. We used diffusion tensor imaging to examine interictal diffusion properties of the brains of migraineurs with aura, migraineurs without aura and matched healthy controls. Areas of lower fractional anisotropy were present in migraineurs along the thalamocortical tract. In addition, migraineurs with aura had lower fractional anisotropy in the ventral trigeminothalamic tract, and migraineurs without aura had lower fractional anisotropy in the ventrolateral periaqueductal grey matter. Our results indicate the presence of permanent interictal changes in migraineurs, pointing to an effect of migraine on the trigeminal somatosensory and modulatory pain systems.


Assuntos
Vias Aferentes/patologia , Transtornos de Enxaqueca/patologia , Substância Cinzenta Periaquedutal/patologia , Córtex Somatossensorial/patologia , Núcleos do Trigêmeo/patologia , Adulto , Anisotropia , Estudos de Casos e Controles , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Humanos , Masculino , Transtornos de Enxaqueca/fisiopatologia
7.
Mol Cancer Ther ; 16(9): 1877-1886, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28655784

RESUMO

Thrombocytopenia is a common adverse event in cancer patients treated with antibody-drug conjugates (ADC), including AGS-16C3F, an ADC targeting ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase-3) and trastuzumab emtansine (T-DM1). This study aims to elucidate the mechanism of action of ADC-induced thrombocytopenia. ENPP3 expression in platelets and megakaryocytes (MK) was investigated and shown to be negative. The direct effect of AGS-16C3F on platelets was evaluated using platelet rich plasma following the expression of platelet activation markers. Effects of AGS-16C3F, T-DM1, and control ADCs on maturing megakaryocytes were evaluated in an in vitro system in which human hematopoietic stem cells (HSC) were differentiated into MKs. AGS-16C3F, like T-DM1, did not affect platelets directly, but inhibited MK differentiation by the activity of Cys-mcMMAF, its active metabolite. FcγRIIA did not appear to play an important role in ADC cytotoxicity to differentiating MKs. AGS-16C3F, cytotoxic to MKs, did not bind to FcγRIIA on MKs. Blocking the interaction of T-DM1 with FcγRIIA did not prevent the inhibition of MK differentiation and IgG1-mcMMAF was not as cytotoxic to MKs despite binding to FcγRIIA. Several lines of evidence suggest that internalization of AGS-16C3F into MKs is mediated by macropinocytosis. Macropinocytosis activity of differentiating HSCs correlated with cell sensitivity to AGS-16C3F. AGS-16C3F was colocalized with a macropinocytosis marker, dextran-Texas Red in differentiating MKs. Ethyl isopropyl amiloride (EIPA), a macropinocytosis inhibitor, blocked internalization of dextran-Texas Red and AGS-16C3F. These data support the notion that inhibition of MK differentiation via macropinocytosis-mediated internalization plays a role in ADC-induced thrombocytopenia. Mol Cancer Ther; 16(9); 1877-86. ©2017 AACRSee related article by Zhao et al., p. 1866.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Imunoconjugados/farmacologia , Megacariócitos/citologia , Megacariócitos/efeitos dos fármacos , Pinocitose , Antineoplásicos Imunológicos/efeitos adversos , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Imunoconjugados/efeitos adversos , Megacariócitos/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Transporte Proteico , Receptores de IgG/metabolismo , Trombocitopenia/sangue , Trombocitopenia/induzido quimicamente
8.
PLoS Med ; 3(10): e402, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17048979

RESUMO

BACKGROUND: Patients suffering from migraine with aura (MWA) and migraine without aura (MWoA) show abnormalities in visual motion perception during and between attacks. Whether this represents the consequences of structural changes in motion-processing networks in migraineurs is unknown. Moreover, the diagnosis of migraine relies on patient's history, and finding differences in the brain of migraineurs might help to contribute to basic research aimed at better understanding the pathophysiology of migraine. METHODS AND FINDINGS: To investigate a common potential anatomical basis for these disturbances, we used high-resolution cortical thickness measurement and diffusion tensor imaging (DTI) to examine the motion-processing network in 24 migraine patients (12 with MWA and 12 MWoA) and 15 age-matched healthy controls (HCs). We found increased cortical thickness of motion-processing visual areas MT+ and V3A in migraineurs compared to HCs. Cortical thickness increases were accompanied by abnormalities of the subjacent white matter. In addition, DTI revealed that migraineurs have alterations in superior colliculus and the lateral geniculate nucleus, which are also involved in visual processing. CONCLUSIONS: A structural abnormality in the network of motion-processing areas could account for, or be the result of, the cortical hyperexcitability observed in migraineurs. The finding in patients with both MWA and MWoA of thickness abnormalities in area V3A, previously described as a source in spreading changes involved in visual aura, raises the question as to whether a "silent" cortical spreading depression develops as well in MWoA. In addition, these experimental data may provide clinicians and researchers with a noninvasively acquirable migraine biomarker.


Assuntos
Encéfalo/patologia , Imagem de Difusão por Ressonância Magnética , Enxaqueca com Aura/fisiopatologia , Enxaqueca sem Aura/fisiopatologia , Percepção de Movimento , Rede Nervosa/patologia , Percepção Visual , Adulto , Encéfalo/fisiopatologia , Córtex Cerebral/patologia , Feminino , Corpos Geniculados/patologia , Humanos , Masculino , Enxaqueca com Aura/diagnóstico , Enxaqueca sem Aura/diagnóstico , Rede Nervosa/fisiopatologia , Colículos Superiores/patologia
9.
Mol Imaging Biol ; 18(5): 768-75, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27122234

RESUMO

PURPOSE: Nectin-4 is selectively overexpressed in a variety of cancers and is currently under clinical investigation as a therapeutic target. A monoclonal antibody against nectin-4 (AGS-22M6) was evaluated as an Immuno-positron emission tomography (ImmunoPET) reagent. Its ability to assay nectin-4 expression as well as detect nectin-4 positive tumors in the liver and bone was evaluated using mouse models. PROCEDURES: The biodistribution of [(89)Zr]AGS-22M6 was evaluated in mice bearing tumors with varying levels of nectin-4 expression. An isogenic breast cancer tumor line was used to model metastatic liver and bone disease in mice. The biodistribution of [(18)F]AGS-22M6 in cynomolgus monkeys was evaluated. RESULTS: A positive correlation was demonstrated between tumor nectin-4 expression and [(89)Zr]AGS-22M6 uptake. Tumors in the liver and bone were detected and differentiated based on nectin-4 expression. [(18)F]AGS-22M6 showed limited uptake in cynomolgus monkey tissues. CONCLUSIONS: [(89)Zr]AGS-22M6 is a promising ImmunoPET reagent that can assay nectin-4 expression in both primary and metastatic lesions.


Assuntos
Anticorpos Monoclonais/imunologia , Moléculas de Adesão Celular/imunologia , Tomografia por Emissão de Pósitrons/métodos , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Neoplasias Ósseas/secundário , Linhagem Celular Tumoral , Humanos , Imuno-Histoquímica , Indicadores e Reagentes , Neoplasias Hepáticas/secundário , Macaca fascicularis , Camundongos , Nectinas , Distribuição Tecidual , Zircônio/química
10.
Mol Cancer Ther ; 15(6): 1301-10, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26944921

RESUMO

SLITRK6 is a member of the SLITRK family of neuronal transmembrane proteins that was discovered as a bladder tumor antigen using suppressive subtractive hybridization. Extensive immunohistochemistry showed SLITRK6 to be expressed in multiple epithelial tumors, including bladder, lung, and breast cancer as well as in glioblastoma. To explore the possibility of using SLITRK6 as a target for an antibody-drug conjugate (ADC), we generated a panel of fully human mAbs specific for SLITRK6. ADCs showed potent in vitro and in vivo cytotoxic activity after conjugation to Monomethyl Auristatin E or Monomethyl Auristatin F. The most potent ADC, ASG-15ME, was selected as the development candidate and given the product name AGS15E. ASG-15ME is currently in phase I clinical trials for the treatment of metastatic urothelial cancer. This is the first report that SLITRK6 is a novel antigen in bladder cancer and also the first report of the development of ASG-15ME for the treatment of metastatic bladder cancer. Mol Cancer Ther; 15(6); 1301-10. ©2016 AACR.


Assuntos
Anticorpos Monoclonais/química , Imunoconjugados/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Proteínas de Membrana/antagonistas & inibidores , Oligopeptídeos/química , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoconjugados/química , Imunoconjugados/farmacologia , Neoplasias Renais/metabolismo , Camundongos , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacologia , Regulação para Cima , Urotélio/metabolismo , Urotélio/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
PLoS One ; 6(8): e23340, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21912594

RESUMO

The discrimination of thatcherized faces from typical faces was explored in two simultaneous alternative forced choice tasks. Reaction times (RTs) and errors were measured in a behavioural task. Brain activation was measured in an equivalent fMRI task. In both tasks, participants were tested with upright and inverted faces. Participants were also tested on churches in the behavioural task. The behavioural task confirmed the face specificity of the illusion (by comparing inversion effects for faces against churches) but also demonstrated that the discrimination was primarily, although not exclusively, driven by attending to eyes. The fMRI task showed that, relative to inverted faces, upright grotesque faces are discriminated via activation of a network of emotion/social evaluation processing areas. On the other hand, discrimination of inverted thatcherized faces was associated with increased activation of brain areas that are typically involved in perceptual processing of faces.


Assuntos
Discriminação Psicológica/fisiologia , Face , Ilusões/fisiologia , Adulto , Comportamento/fisiologia , Encéfalo/fisiologia , Sinais (Psicologia) , Feminino , Neuroimagem Funcional , Humanos , Masculino , Estimulação Luminosa , Percepção Visual/fisiologia
12.
Soc Cogn Affect Neurosci ; 4(1): 70-8, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19151375

RESUMO

Although there is evidence of emotion perception deficits in autism spectrum disorder (ASD), research on this topic has been mostly confined to perception of emotions in faces. Using behavioral measures and 3T functional magnetic resonance imaging (fMRI), we examined whether such deficits extend to the perception of bodily expressed emotions. We found that individuals with ASD, in contrast to neurotypical (NT) individuals, did not exhibit a differential pattern of brain activation to bodies expressing fear as compared with emotionally neutral bodies. ASD and NT individuals showed similar patterns of activation in response to bodies engaged in emotionally neutral actions, with the exception of decreased activation in the inferior frontal cortex and the anterior insula in ASD. We discuss these findings in relation to possible abnormalities in a network of cortical and subcortical mechanisms involved in social orienting and emotion contagion. Our data suggest that emotion perception deficits in ASD may be due to compromised processing of the emotional component of observed actions.


Assuntos
Transtorno Autístico/psicologia , Emoções Manifestas/fisiologia , Medo/psicologia , Cinésica , Adulto , Tonsila do Cerebelo/fisiologia , Córtex Cerebral/fisiologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Rede Nervosa/fisiologia , Desempenho Psicomotor/fisiologia , Reconhecimento Psicológico , Percepção Social
13.
Hum Brain Mapp ; 28(5): 441-9, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17133386

RESUMO

ASD involves a fundamental impairment in processing social-communicative information from faces. Several recent studies have challenged earlier findings that individuals with autism spectrum disorder (ASD) have no activation of the fusiform gyrus (fusiform face area, FFA) when viewing faces. In this study, we examined activation to faces in the broader network of face-processing modules that comprise what is known as the social brain. Using 3T functional resonance imaging, we measured BOLD signal changes in 10 ASD subjects and 7 healthy controls passively viewing nonemotional faces. We replicated our original findings of significant activation of face identity-processing areas (FFA and inferior occipital gyrus, IOG) in ASD. However, in addition, we identified hypoactivation in a more widely distributed network of brain areas involved in face processing [including the right amygdala, inferior frontal cortex (IFC), superior temporal sulcus (STS), and face-related somatosensory and premotor cortex]. In ASD, we found functional correlations between a subgroup of areas in the social brain that belong to the mirror neuron system (IFC, STS) and other face-processing areas. The severity of the social symptoms measured by the Autism Diagnostic Observation Schedule was correlated with the right IFC cortical thickness and with functional activation in that area. When viewing faces, adults with ASD show atypical patterns of activation in regions forming the broader face-processing network and social brain, outside the core FFA and IOG regions. These patterns suggest that areas belonging to the mirror neuron system are involved in the face-processing disturbances in ASD.


Assuntos
Transtorno Autístico/patologia , Transtorno Autístico/fisiopatologia , Encéfalo/fisiopatologia , Face , Relações Interpessoais , Reconhecimento Visual de Modelos/fisiologia , Adulto , Encéfalo/irrigação sanguínea , Mapeamento Encefálico , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Estimulação Luminosa/métodos , Vias Visuais/irrigação sanguínea , Vias Visuais/fisiopatologia
14.
Neurology ; 69(21): 1990-5, 2007 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-18025393

RESUMO

OBJECTIVE: To examine morphologic changes in the somatosensory cortex (SSC) of patients with migraine. METHODS: Cortical thickness of the SSC of patients with migraine was measured in vivo and compared with age- and sex-matched healthy subjects. The cohort was composed of 24 patients with migraine, subdivided into 12 patients who had migraine with aura, 12 patients who had migraine without aura, and 12 controls. Group and individual analyses were performed in the SSC and shown as average maps of significant changes in cortical thickness. RESULTS: Migraineurs had on average thicker SSCs than the control group. The most significant thickness changes were noticed in the caudal SSC, where the trigeminal area, including head and face, is somatotopically represented. CONCLUSIONS: Our findings indicate the presence of interictal structural changes in the somatosensory cortex (SSC) of migraineurs. The SSC plays a crucial role in the noxious and nonnoxious somatosensory processing. Thickening in the SSC is in line with diffusional abnormalities observed in the subcortical trigeminal somatosensory pathway of the same migraine cohort in a previous study. Repetitive migraine attacks may lead to, or be the result of, neuroplastic changes in cortical and subcortical structures of the trigeminal somatosensory system.


Assuntos
Imagem Ecoplanar/métodos , Transtornos de Enxaqueca/patologia , Córtex Somatossensorial/patologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
15.
Cereb Cortex ; 16(9): 1276-82, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16306324

RESUMO

Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with impaired social and emotional skills, the anatomical substrate of which is still unknown. In this study, we compared a group of 14 high-functioning ASD adults with a group of controls matched for sex, age, intelligence quotient, and handedness. We used an automated technique of analysis that accurately measures the thickness of the cerebral cortex and generates cross-subject statistics in a coordinate system based on cortical anatomy. We found local decreases of gray matter in the ASD group in areas belonging to the mirror neuron system (MNS), argued to be the basis of empathic behavior. Cortical thinning of the MNS was correlated with ASD symptom severity. Cortical thinning was also observed in areas involved in emotion recognition and social cognition. These findings suggest that the social and emotional deficits characteristic of autism may reflect abnormal thinning of the MNS and the broader network of cortical areas subserving social cognition.


Assuntos
Transtorno Autístico/patologia , Córtex Cerebral/patologia , Cognição , Empatia , Relações Interpessoais , Rede Nervosa/patologia , Vias Neurais/patologia , Neurônios/patologia , Percepção Social , Adulto , Humanos , Masculino
16.
Proc Natl Acad Sci U S A ; 101(47): 16701-6, 2004 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-15546983

RESUMO

Darwin regarded emotions as predispositions to act adaptively, thereby suggesting that characteristic body movements are associated with each emotional state. To this date, investigations of emotional cognition have predominantly concentrated on processes associated with viewing facial expressions. However, expressive body movements may be just as important for understanding the neurobiology of emotional behavior. Here, we used functional MRI to clarify how the brain recognizes happiness or fear expressed by a whole body. Our results indicate that observing fearful body expressions produces increased activity in brain areas narrowly associated with emotional processes and that this emotion-related activity occurs together with activation of areas linked with representation of action and movement. The mechanism of fear contagion hereby suggested may automatically prepare the brain for action.


Assuntos
Medo/fisiologia , Medo/psicologia , Adulto , Encéfalo/fisiologia , Emoções/fisiologia , Feminino , Felicidade , Humanos , Imageamento por Ressonância Magnética , Masculino , Movimento
17.
Neuroimage ; 22(3): 1141-50, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15219586

RESUMO

Prior imaging studies have failed to show activation of the fusiform gyrus in response to emotionally neutral faces in individuals with autism spectrum disorder (ASD) [Critchley et al., Brain 124 (2001) 2059; Schultz et al., Arch. Gen. Psychiatry 57 (2000) 331]. However, individuals with ASD do not typically exhibit the striking behavioral deficits that might be expected to result from fusiform gyrus damage, such as those seen in prosopagnosia, and their deficits appear to extend well beyond face identification to include a wide range of impairments in social perceptual processing. In this study, our goal was to further assess the question of whether individuals with ASD have abnormal fusiform gyrus activation to faces. We used high-field (3 T) functional magnetic resonance imaging to study face perception in 11 adult individuals with autism spectrum disorder (ASD) and 10 normal controls. We used face stimuli, object stimuli, and sensory control stimuli (Fourier scrambled versions of the face and object stimuli) containing a fixation point in the center to ensure that participants were looking at and attending to the images as they were presented. We found that individuals with ASD activated the fusiform face area and other brain areas normally involved in face processing when they viewed faces as compared to non-face stimuli. These data indicate that the face-processing deficits encountered in ASD are not due to a simple dysfunction of the fusiform area, but to more complex anomalies in the distributed network of brain areas involved in social perception and cognition.


Assuntos
Transtorno Autístico/fisiopatologia , Face , Imageamento por Ressonância Magnética , Lobo Occipital/fisiopatologia , Lobo Temporal/fisiopatologia , Percepção Visual , Adulto , Mapeamento Encefálico , Estudos de Casos e Controles , Fixação Ocular , Humanos , Masculino , Pessoa de Meia-Idade
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