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1.
Hum Brain Mapp ; 42(18): 5911-5926, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34547147

RESUMO

Quadrantanopia caused by inadvertent severing of Meyer's Loop of the optic radiation is a well-recognised complication of temporal lobectomy for conditions such as epilepsy. Dissection studies indicate that the anterior extent of Meyer's Loop varies considerably between individuals. Quantifying this for individual patients is thus an important step to improve the safety profile of temporal lobectomies. Previous attempts to delineate Meyer's Loop using diffusion MRI tractography have had difficulty estimating its full anterior extent, required manual ROI placement, and/or relied on advanced diffusion sequences that cannot be acquired routinely in most clinics. Here we present CONSULT: a pipeline that can delineate the optic radiation from raw DICOM data in a completely automated way via a combination of robust pre-processing, segmentation, and alignment stages, plus simple improvements that bolster the efficiency and reliability of standard tractography. We tested CONSULT on 696 scans of predominantly healthy participants (539 unique brains), including both advanced acquisitions and simpler acquisitions that could be acquired in clinically acceptable timeframes. Delineations completed without error in 99.4% of the scans. The distance between Meyer's Loop and the temporal pole closely matched both averages and ranges reported in dissection studies for all tested sequences. Median scan-rescan error of this distance was 1 mm. When tested on two participants with considerable pathology, delineations were successful and realistic. Through this, we demonstrate not only how to identify Meyer's Loop with clinically feasible sequences, but also that this can be achieved without fundamental changes to tractography algorithms or complex post-processing methods.


Assuntos
Imagem de Tensor de Difusão/métodos , Interpretação de Imagem Assistida por Computador/métodos , Vias Visuais/anatomia & histologia , Vias Visuais/diagnóstico por imagem , Adulto , Lobectomia Temporal Anterior/métodos , Feminino , Humanos , Masculino , Cuidados Pré-Operatórios/métodos , Adulto Jovem
2.
Neuroimage ; 211: 116646, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32084566

RESUMO

Diffusion MRI tractography is commonly used to delineate white matter tracts. These delineations can be used for planning neurosurgery or for identifying regions of interest from which microstructural measurements can be taken. Probabilistic tractography produces different delineations each time it is run, potentially leading to microstructural measurements or anatomical delineations that are not reproducible. Generating a sufficiently large number of streamlines is required to avoid this scenario, but what constitutes "sufficient" is difficult to assess and so streamline counts are typically chosen in an arbitrary or qualitative manner. This work explores several factors influencing tractography reliability and details two methods for estimating this reliability. The first method automatically estimates the number of streamlines required to achieve reliable microstructural measurements, whilst the second estimates the number of streamlines required to achieve a reliable binarised trackmap than can be used clinically. Using these methods, we calculated the number of streamlines required to achieve a range of quantitative reproducibility criteria for three anatomical tracts in 40 Human Connectome Project datasets. Actual reproducibility was checked by repeatedly generating the tractograms with the calculated numbers of streamlines. We found that the required number of streamlines varied strongly by anatomical tract, image resolution, number of diffusion directions, the degree of reliability desired, the microstructural measurement of interest, and/or the specifics on how the tractogram was converted to a binary volume. The proposed methods consistently predicted streamline counts that achieved the target reproducibility. Implementations are made available to enable the scientific community to more-easily achieve reproducible tractography.


Assuntos
Imagem de Tensor de Difusão/normas , Processamento de Imagem Assistida por Computador/normas , Substância Branca/anatomia & histologia , Adulto , Conjuntos de Dados como Assunto , Imagem de Tensor de Difusão/métodos , Humanos , Processamento de Imagem Assistida por Computador/métodos , Estudos Prospectivos , Reprodutibilidade dos Testes , Substância Branca/diagnóstico por imagem
3.
BMC Pediatr ; 20(1): 9, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31910803

RESUMO

BACKGROUND: Cerebral palsy (CP) is frequently associated with specific cognitive impairments, such as executive dysfunction which are related to participation and quality of life (QOL). The proposed study will examine whether a computerized executive function (EF) training programme could provide superior benefits for executive functioning, participation, QOL and brain plasticity, as compared to usual care. METHODS: A single-blind randomized controlled trial (RCT) design will be performed. Thirty children with CP aged 8 to 12 years will participate in a home-based computerized multi-modal executive training programme (12 weeks, 5 days a week, 30 min a day training, total dose = 30 h). Thirty children with CP matched by age, sex, motor and intelligence quotient (IQ) will compose the waitlist group. Cognitive, behavioural, emotional, participation and QOL measures will be obtained at three time points: before, immediately after and 9 months after completing the training. Additionally, structural and functional (resting state) magnetic resonance images (MRI) will be obtained in a subsample of 15 children from each group. Outcomes between groups will be compared following standard principles for RCTs. DISCUSSION: The study will test whether the cognitive training programme exerts a positive effect not only on neuropsychological and daily functioning of children with CP but also on other measures such as participation and QOL. We will also use brain MRI to test brain functional and structural changes after the intervention. If this on-line and home-based training programme proves effective, it could be a cost-effective intervention with short- and long-term effects on EF, participation or QOL in CP. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04025749. Registered 19 July 2019. Retrospectively registered.


Assuntos
Paralisia Cerebral , Disfunção Cognitiva , Encéfalo , Criança , Função Executiva , Humanos , Imageamento por Ressonância Magnética , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
4.
BMC Pediatr ; 18(1): 252, 2018 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-30064388

RESUMO

BACKGROUND: Of children with hemiplegic cerebral palsy, 75% have impaired somatosensory function, which contributes to learned non-use of the affected upper limb. Currently, motor learning approaches are used to improve upper-limb motor skills in these children, but few studies have examined the effect of any intervention to ameliorate somatosensory impairments. Recently, Sense© training was piloted with a paediatric sample, seven children with hemiplegic cerebral palsy, demonstrating statistically and clinically significant change in limb position sense, goal performance and bimanual hand-use. This paper describes a protocol for a Randomised Controlled Trial of Sense© for Kids training, hypothesising that its receipt will improve somatosensory discrimination ability more than placebo (dose-matched Goal Directed Therapy via Home Program). Secondary hypotheses include that it will alter brain activation in somatosensory processing regions, white-matter characteristics of the thalamocortical tracts and improve bimanual function, activity and participation more than Goal Directed Training via Home Program. METHODS AND DESIGN: This is a single blind, randomised matched-pair, placebo-controlled trial. Participants will be aged 6-15 years with a confirmed description of hemiplegic cerebral palsy and somatosensory discrimination impairment, as measured by the sense©_assess Kids. Participants will be randomly allocated to receive 3h a week for 6 weeks of either Sense© for Kids or Goal Directed Therapy via Home Program. Children will be matched on age and severity of somatosensory discrimination impairment. The primary outcome will be somatosensory discrimination ability, measured by sense©_assess Kids score. Secondary outcomes will include degree of brain activation in response to a somatosensory task measured by functional MRI, changes in the white matter of the thalamocortical tract measured by diffusion MRI, bimanual motor function, activity and participation. DISCUSSION: This study will assess the efficacy of an intervention to increase somatosensory discrimination ability in children with cerebral palsy. It will explore clinically important questions about the efficacy of intervening in somatosensation impairment to improve bimanual motor function, compared with focusing on motor impairment directly, and whether focusing on motor impairment alone can affect somatosensory ability. TRIAL REGISTRATION: This trial is registered with the Australian New Zealand Clinical Trials Registry, registration number: ACTRN12618000348257. World Health Organisation universal trial number: U1111-1210-1726.


Assuntos
Paralisia Cerebral/reabilitação , Hemiplegia/reabilitação , Hipestesia/terapia , Tato , Adolescente , Paralisia Cerebral/complicações , Paralisia Cerebral/fisiopatologia , Criança , Hemiplegia/fisiopatologia , Humanos , Hipestesia/etiologia , Imageamento por Ressonância Magnética , Projetos de Pesquisa , Método Simples-Cego
5.
Hum Brain Mapp ; 38(9): 4302-4312, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28677154

RESUMO

We have reported reliable changes in behavior, brain structure, and function in 24 healthy right-handed adults who practiced a finger-thumb opposition sequence task with their left hand for 10 min daily, over 4 weeks. Here, we extend these findings by using diffusion MRI to investigate white-matter changes in the corticospinal tract, basal-ganglia, and connections of the dorsolateral prefrontal cortex. Twenty-three participant datasets were available with pre-training and post-training scans. Task performance improved in all participants (mean: 52.8%, SD: 20.0%; group P < 0.01 FWE) and widespread microstructural changes were detected across the motor system of the "trained" hemisphere. Specifically, region-of-interest-based analyses of diffusion MRI (n = 22) revealed significantly increased fractional anisotropy (FA) in the right caudate nucleus (4.9%; P < 0.05 FWE), and decreased mean diffusivity in the left nucleus accumbens (-1.3%; P < 0.05 FWE). Diffusion MRI tractography (n = 22), seeded by sensorimotor cortex fMRI activation, also revealed increased FA in the right corticospinal tract (mean 3.28%; P < 0.05 FWE) predominantly reflecting decreased radial diffusivity. These changes were consistent throughout the entire length of the tract. The left corticospinal tract did not show any changes. FA also increased in white matter connections between the right middle frontal gyrus and both right caudate nucleus (17/22 participants; P < 0.05 FWE) and right supplementary motor area (18/22 participants; P < 0.05 FWE). Equivalent changes in FA were not seen in the left (non-trained) hemisphere. In combination with our functional and structural findings, this study provides detailed, multifocal evidence for widespread neuroplastic changes in the human brain resulting from motor training. Hum Brain Mapp 38:4302-4312, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Aprendizagem/fisiologia , Imageamento por Ressonância Magnética , Destreza Motora/fisiologia , Plasticidade Neuronal/fisiologia , Adolescente , Adulto , Mapeamento Encefálico/métodos , Feminino , Lateralidade Funcional , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Tratos Piramidais/diagnóstico por imagem , Tratos Piramidais/fisiologia , Substância Branca/diagnóstico por imagem , Substância Branca/fisiologia , Adulto Jovem
6.
Hum Brain Mapp ; 38(9): 4773-4787, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28677224

RESUMO

Although different aspects of neuroplasticity can be quantified with behavioral probes, brain stimulation, and brain imaging assessments, no study to date has combined all these approaches into one comprehensive assessment of brain plasticity. Here, 24 healthy right-handed participants practiced a sequence of finger-thumb opposition movements for 10 min each day with their left hand. After 4 weeks, performance for the practiced sequence improved significantly (P < 0.05 FWE) relative to a matched control sequence, with both the left (mean increase: 53.0% practiced, 6.5% control) and right (21.0%; 15.8%) hands. Training also induced significant (cluster p-FWE < 0.001) reductions in functional MRI activation for execution of the trained sequence, relative to the control sequence. These changes were observed as clusters in the premotor and supplementary motor cortices (right hemisphere, 301 voxel cluster; left hemisphere 700 voxel cluster), and sensorimotor cortices and superior parietal lobules (right hemisphere 864 voxel cluster; left hemisphere, 1947 voxel cluster). Transcranial magnetic stimulation over the right ("trained") primary motor cortex yielded a 58.6% mean increase in a measure of motor evoked potential amplitude, as recorded at the left abductor pollicis brevis muscle. Cortical thickness analyses based on structural MRI suggested changes in the right precentral gyrus, right post central gyrus, right dorsolateral prefrontal cortex, and potentially the right supplementary motor area. Such findings are consistent with LTP-like neuroplastic changes in areas that were already responsible for finger sequence execution, rather than improved recruitment of previously nonutilized tissue. Hum Brain Mapp 38:4773-4787, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Mãos/fisiologia , Destreza Motora/fisiologia , Plasticidade Neuronal/fisiologia , Prática Psicológica , Adolescente , Adulto , Mapeamento Encefálico , Circulação Cerebrovascular/fisiologia , Potencial Evocado Motor/fisiologia , Feminino , Lateralidade Funcional , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Músculo Esquelético/fisiologia , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiologia , Tamanho do Órgão , Oxigênio/sangue , Estimulação Magnética Transcraniana , Adulto Jovem
7.
Neural Plast ; 2016: 2643491, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26839711

RESUMO

Direct measurement of recovery from brain injury is an important goal in neurorehabilitation, and requires reliable, objective, and interpretable measures of changes in brain function, referred to generally as "neuroplasticity." One popular imaging modality for measuring neuroplasticity is task-based functional magnetic resonance imaging (t-fMRI). In the field of neurorehabilitation, however, assessing neuroplasticity using t-fMRI presents a significant challenge. This commentary reviews t-fMRI changes commonly reported in patients with cerebral palsy or acquired brain injuries, with a focus on studies of motor rehabilitation, and discusses complexities surrounding their interpretations. Specifically, we discuss the difficulties in interpreting t-fMRI changes in terms of their underlying causes, that is, differentiating whether they reflect genuine reorganisation, neurological restoration, compensation, use of preexisting redundancies, changes in strategy, or maladaptive processes. Furthermore, we discuss the impact of heterogeneous disease states and essential t-fMRI processing steps on the interpretability of activation patterns. To better understand therapy-induced neuroplastic changes, we suggest that researchers utilising t-fMRI consider concurrently acquiring information from an additional modality, to quantify, for example, haemodynamic differences or microstructural changes. We outline a variety of such supplementary measures for investigating brain reorganisation and discuss situations in which they may prove beneficial to the interpretation of t-fMRI data.


Assuntos
Lesões Encefálicas/reabilitação , Imageamento por Ressonância Magnética/métodos , Imagem Multimodal , Plasticidade Neuronal/fisiologia , Recuperação de Função Fisiológica/fisiologia , Lesões Encefálicas/fisiopatologia , Mapeamento Encefálico/métodos , Humanos
8.
Ann Clin Transl Neurol ; 11(10): 2609-2622, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39257055

RESUMO

OBJECTIVES: Neuroimaging studies of dyskinetic cerebral palsy (CP) are scarce and the neuropathological underpinnings are not fully understood. We delineated the corticospinal tract (CST) and cortico-striatal-thalamocortical (CSTC) pathways with probabilistic tractography to assess their (1) integrity and (2) association with motor functioning in people with dyskinetic CP. METHODS: Diffusion weighted magnetic resonance images were obtained for 33 individuals with dyskinetic CP and 33 controls. Fractional anisotropy (FA) and mean diffusivity (MD) for the CST and the CSTC pathways were compared between groups. Correlation analyses were performed between tensor metric values and motor function scores of participants with dyskinetic CP as assessed by the Gross Motor Function Classification System (GMFCS), the Bimanual Fine Motor Function (BFMF), and the Manual Ability Classification System (MACS). RESULTS: White matter integrity in both the CST and the CSTC pathways was reduced in people with dyskinetic CP. The GMFCS, MACS and, less commonly, the BFMF were associated with FA and, particularly, MD in most portions of these pathways. INTERPRETATION: The present study advances our understanding of the involvement of white matter microstructure in sensorimotor pathways and its relationship with motor impairment in people with dyskinetic CP. Our results are consistent with well-described relationships between upper limb function and white matter integrity in the CST and CSTC pathways in other forms of CP. This knowledge may ultimately help prognosis and therapeutic programmes.


Assuntos
Paralisia Cerebral , Imagem de Tensor de Difusão , Tratos Piramidais , Substância Branca , Humanos , Paralisia Cerebral/fisiopatologia , Paralisia Cerebral/diagnóstico por imagem , Paralisia Cerebral/patologia , Masculino , Feminino , Tratos Piramidais/diagnóstico por imagem , Tratos Piramidais/fisiopatologia , Tratos Piramidais/patologia , Adolescente , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Substância Branca/fisiopatologia , Adulto Jovem , Criança , Adulto , Córtex Sensório-Motor/fisiopatologia , Córtex Sensório-Motor/diagnóstico por imagem , Córtex Sensório-Motor/patologia , Imagem de Difusão por Ressonância Magnética , Atividade Motora/fisiologia
9.
bioRxiv ; 2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-39091832

RESUMO

Background: Deep brain stimulation (DBS) of the anterior limb of the internal capsule (ALIC) is an emerging treatment for severe, refractory obsessive-compulsive disorder (OCD). The therapeutic effects of DBS are hypothesized to be mediated by direct modulation of a distributed cortico-striato-thalmo-cortical network underlying OCD symptoms. However, the exact underlying mechanism by which DBS exerts its therapeutic effects still remains unclear. Method: In five participants receiving DBS for severe, refractory OCD (3 responders, 2 non-responders), we conducted a DBS On/Off cycling paradigm during the acquisition of functional MRI to determine the network effects of stimulation across a variety of bipolar configurations. We also performed tractography using diffusion-weighted imaging (DWI) to relate the functional impact of DBS to the underlying structural connectivity between active stimulation contacts and functional brain networks. Results: We found that therapeutic DBS had a distributed effect, suppressing BOLD activity within regions such as the orbitofrontal cortex, dorsomedial prefrontal cortex, and subthalamic nuclei compared to non-therapeutic configurations. Many of the regions suppressed by therapeutic DBS were components of the default mode network (DMN). Moreover, the estimated stimulation field from the therapeutic configurations exhibited significant structural connectivity to core nodes of the DMN. Conclusions: Therapeutic DBS for OCD suppresses BOLD activity within a distributed set of regions within the DMN relative to non-therapeutic configurations. We propose that these effects may be mediated by interruption of communication through structural white matter connections surrounding the DBS active contacts.

10.
PLoS One ; 17(2): e0247343, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35180211

RESUMO

Magnetic Resonance Imaging (MRI) motion artefacts frequently complicate structural and diffusion MRI analyses. While diffusion imaging is easily 'scrubbed' of motion affected volumes, the same is not true for T1w or T2w 'structural' images. Structural images are critical to most diffusion-imaging pipelines thus their corruption can lead to disproportionate data loss. To enable diffusion-image processing when structural images are missing or have been corrupted, we propose a means by which synthetic structural images can be generated from diffusion MRI. This technique combines multi-tissue constrained spherical deconvolution, which is central to many existing diffusion analyses, with the Bloch equations that allow simulation of MRI intensities for given scanner parameters and magnetic resonance (MR) tissue properties. We applied this technique to 32 scans, including those acquired on different scanners, with different protocols and with pathology present. The resulting synthetic T1w and T2w images were visually convincing and exhibited similar tissue contrast to acquired structural images. These were also of sufficient quality to drive a Freesurfer-based tractographic analysis. In this analysis, probabilistic tractography connecting the thalamus to the primary sensorimotor cortex was delineated with Freesurfer, using either real or synthetic structural images. Tractography for real and synthetic conditions was largely identical in terms of both voxels encountered (Dice 0.88-0.95) and mean fractional anisotropy (intrasubject absolute difference 0.00-0.02). We provide executables for the proposed technique in the hope that these may aid the community in analysing datasets where structural image corruption is common, such as studies of children or cognitively impaired persons.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Líquido Cefalorraquidiano/diagnóstico por imagem , Imagem de Tensor de Difusão/métodos , Epilepsia/diagnóstico por imagem , Glioma/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Anisotropia , Artefatos , Estudos de Casos e Controles , Simulação por Computador , Conectoma/métodos , Voluntários Saudáveis , Humanos , Processamento de Imagem Assistida por Computador/métodos
11.
Cancers (Basel) ; 13(18)2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34572747

RESUMO

Immunotherapy has transformed the treatment landscape of melanoma; however, despite improvements in patient outcomes, monotherapy can often lead to resistance and tumour escape. Therefore, there is a need for new therapies, combination strategies and biomarker-guided decision making to increase the subset of patients most likely to benefit from treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors act by synthetic lethality to target tumour cells with homologous recombination deficiencies such as BRCA mutations. However, the application of PARP inhibitors could be extended to a broad range of BRCA-negative cancers with high rates of DNA damage repair pathway mutations, such as melanoma. Additionally, PARP inhibition has the potential to augment the therapeutic effect of immunotherapy through multi-faceted immune-priming capabilities. In this review, we detail the immunological role of PARP and rationale for combining PARP and immune checkpoint inhibitors, with a particular focus on a subset of melanoma with homologous recombination defects that may benefit most from this targeted approach. We summarise the biology supporting this combined regimen and discuss preclinical results as well as ongoing clinical trials in melanoma which may impact future treatment.

12.
Neurooncol Adv ; 2(1): vdaa030, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32642689

RESUMO

BACKGROUND: High-grade glioma (HGG) remains a recalcitrant clinical problem despite many decades of research. A major challenge in improving prognosis is the inability of current therapeutic strategies to address a clinically significant burden of infiltrating tumor cells that extend beyond the margins of the primary tumor mass. Such cells cannot be surgically excised nor efficiently targeted by radiation therapy. Therapeutic targeting of this tumor cell population is significantly hampered by the presence of an intact blood-brain barrier (BBB). In this study, we performed a preclinical investigation of the efficiency of MR-guided Focused Ultrasound (FUS) to temporarily disrupt the BBB to allow selective delivery of a tumor-targeting antibody to infiltrating tumor. METHODS: Structural MRI, dynamic-contrast enhancement MRI, and histology were used to fully characterize the MR-enhancing properties of a patient-derived xenograft (PDX) orthotopic mouse model of HGG and to develop a reproducible, robust model of nonenhancing HGG. PET-CT imaging techniques were then used to evaluate the efficacy of FUS to increase 89Zr-radiolabeled antibody concentration in nonenhancing HGG regions and adjacent non-targeted tumor tissue. RESULTS: The PDX mouse model of HGG has a significant tumor burden lying behind an intact BBB. Increased antibody uptake in nonenhancing tumor regions is directly proportional to the FUS-targeted volume. FUS locally increased antibody uptake in FUS-targeted regions of the tumor with an intact BBB, while leaving untargeted regions unaffected. CONCLUSIONS: FUS exposure successfully allowed temporary BBB disruption, localized to specifically targeted, nonenhancing, infiltrating tumor regions and delivery of a systemically administered antibody was significantly increased.

13.
Theranostics ; 10(14): 6361-6371, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32483457

RESUMO

The clinical translation of new nanoparticle-based therapies for high-grade glioma (HGG) remains extremely poor. This has partly been due to the lack of suitable preclinical mouse models capable of replicating the complex characteristics of recurrent HGG (rHGG), namely the heterogeneous structural and functional characteristics of the blood-brain barrier (BBB). The goal of this study is to compare the characteristics of the tumor BBB of rHGG with two different mouse models of HGG, the ubiquitously used U87 cell line xenograft model and a patient-derived cell line WK1 xenograft model, in order to assess their suitability for nanomedicine research. Method: Structural MRI was used to assess the extent of BBB opening in mouse models with a fully developed tumor, and dynamic contrast enhanced MRI was used to obtain values of BBB permeability in contrast enhancing tumor. H&E and immunofluorescence staining were used to validate results obtained from the in vivo imaging studies. Results: The extent of BBB disruption and permeability in the contrast enhancing tumor was significantly higher in the U87 model than in rHGG. These values in the WK1 model are similar to those of rHGG. The U87 model is not infiltrative, has an entirely abnormal and leaky vasculature and it is not of glial origin. The WK1 model infiltrates into the non-neoplastic brain parenchyma, it has both regions with intact BBB and regions with leaky BBB and remains of glial origin. Conclusion: The WK1 mouse model more accurately reproduces the extent of BBB disruption, the level of BBB permeability and the histopathological characteristics found in rHGG patients than the U87 mouse model, and is therefore a more clinically relevant model for preclinical evaluations of emerging nanoparticle-based therapies for HGG.


Assuntos
Barreira Hematoencefálica/fisiopatologia , Glioma/patologia , Nanomedicina/métodos , Nanopartículas/administração & dosagem , Animais , Barreira Hematoencefálica/química , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Permeabilidade Capilar , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Glioma/tratamento farmacológico , Glioma/metabolismo , Humanos , Imageamento por Ressonância Magnética/métodos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Nanopartículas/química , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Psychopharmacology (Berl) ; 198(1): 37-49, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18427784

RESUMO

RATIONALE: We have previously demonstrated that subchronic (five daily administrations of 2.6 mg/kg PCP) and chronic intermittent administration of 2.6 mg/kg PCP to rats produces hypofrontality and other neurochemical changes akin to schizophrenia pathology (Cochran et al., Neuropsychopharmacology, 28:265-275, 2003). OBJECTIVES: We sought to determine whether behavioral alterations related to discrete aspects of schizophrenia are also induced by these PCP treatment regimes. MATERIALS AND METHODS: Following administration of vehicle or PCP according to the protocols described above, rats were assessed for attentional set shifting ability, prepulse inhibition (PPI), or social interaction and the locomotor response to a challenge dose of amphetamine. RESULTS: Ability to shift attentional set was impaired 72 h after the last PCP administration following the subchronic and chronic intermittent treatment regimes. PPI was disrupted after each acute administration of PCP in animals under the subchronic treatment regime. However, PPI deficits were not sustained 72 h after the last of five daily administrations. In subchronic and chronic PCP treated animals, no change was found in social interaction behavior, and there was little change in baseline or amphetamine-stimulated locomotor activity, employed as an indicator of dopaminergic hyperfunction. CONCLUSIONS: The temporally distinct behavioral effects of these PCP treatment regimes suggest that PPI deficits relate directly to acute NMDA receptor antagonism, whereas the more enduring set shifting deficits relate to the longer term consequences of NMDA receptor blockade. Therefore, these subchronic and chronic PCP treatment regimes produce hypofrontality (Cochran et al., Neuropsychopharmacology, 28:265-275, 2003) and associated prefrontal cortex-dependent deficits in behavioral flexibility which mirror core deficits in schizophrenia.


Assuntos
Atenção/efeitos dos fármacos , Alucinógenos/farmacologia , Fenciclidina/farmacologia , Reflexo de Sobressalto/efeitos dos fármacos , Anfetamina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/fisiopatologia , Discriminação Psicológica/efeitos dos fármacos , Dopamina/fisiologia , Lobo Frontal/fisiologia , Hipercinese/induzido quimicamente , Hipercinese/psicologia , Masculino , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Neostriado/fisiologia , Ratos , Ratos Long-Evans , Psicologia do Esquizofrênico , Comportamento Social
15.
Neuroimage Clin ; 19: 892-900, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30013928

RESUMO

Purpose: To characterise brain lesions in dyskinetic cerebral palsy (DCP) using the semi-quantitative scale for structural MRI (sqMRI) and to investigate their relationship with motor, communication and cognitive function. Materials and methods: Thirty-nine participants (19 females, median age 21y) with DCP were assessed in terms of motor function, communication and a variety of cognitive domains. Whole-head magnetic resonance imaging (MRI) was performed including T1-MPRAGE, T2 turbo spin echo (axial plane), and fluid attenuated inversion recovery images (FLAIR). A child neurologist visually assessed images for brain lesions and scored these using the sqMRI. Ordinal, Poisson and binomial negative regression models identified which brain lesions accounted for clinical outcomes. Results: Brain lesions were most frequently located in the ventral posterior lateral thalamus and the frontal lobe. Gross (B = 0.180, p < .001; B = 0.658, p < .001) and fine (B = 0.136, p = .003; B = 0.540, p < .001) motor function were associated with global sqMRI score and parietal involvement. Communication functioning was associated with putamen involvement (B = 0.747, p < .028). Intellectual functioning was associated with global sqMRI score and posterior thalamus involvement (B = -0.018, p < .001; B = -0.192, p < .001). Selective attention was associated with global sqMRI score (B = -0.035, p < .001), parietal (B = -0.063, p = .023), and corpus callosum involvement (B = -0.448, p < .001). Visuospatial and visuoperceptive abilities were associated with global sqMRI score (B = -0.078, p = .007) and medial dorsal thalamus involvement (B = -0.139, p < .012), respectively. Conclusions: Key clinical outcomes in DCP are associated with specific observable brain lesions as indexed by a simple lesion scoring system that relies only on standard clinical MRI.


Assuntos
Encéfalo/diagnóstico por imagem , Paralisia Cerebral/diagnóstico por imagem , Cognição/fisiologia , Comunicação , Atividade Motora/fisiologia , Adolescente , Adulto , Encéfalo/fisiopatologia , Paralisia Cerebral/fisiopatologia , Criança , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto Jovem
16.
Int J Dev Neurosci ; 58: 17-25, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28130065

RESUMO

Researchers in the field of child neurology are increasingly looking to supplement clinical trials of motor rehabilitation with neuroimaging in order to better understand the relationship between behavioural training, brain changes, and clinical improvements. Randomised controlled trials are typically accompanied by sample size calculations to detect clinical improvements but, despite the large cost of neuroimaging, not equivalent calculations for concurrently acquired imaging neuroimaging measures of changes in response to intervention. To aid in this regard, a power analysis was conducted for two measures of brain changes that may be indexed in a trial of rehabilitative therapy for cerebral palsy: cortical thickness of the impaired primary sensorimotor cortex, and fractional anisotropy of the impaired, delineated corticospinal tract. Power for measuring fractional anisotropy was assessed for both region-of-interest-seeded and fMRI-seeded diffusion tractography. Taking into account practical limitations, as well as data loss due to behavioural and image-processing issues, estimated required participant numbers were 101, 128 and 59 for cortical thickness, region-of-interest-based tractography, and fMRI-seeded tractography, respectively. These numbers are not adjusted for study attrition. Although these participant numbers may be out of reach of many trials, several options are available to improve statistical power, including careful preparation of participants for scanning using mock simulators, careful consideration of image processing options, and enrolment of as homogeneous a cohort as possible. This work suggests that smaller and moderate sized studies give genuine consideration to harmonising scanning protocols between groups to allow the pooling of data.


Assuntos
Córtex Cerebral/fisiopatologia , Paralisia Cerebral , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Plasticidade Neuronal/fisiologia , Adolescente , Anisotropia , Mapeamento Encefálico , Paralisia Cerebral/diagnóstico por imagem , Paralisia Cerebral/patologia , Paralisia Cerebral/reabilitação , Criança , Imagem de Tensor de Difusão , Feminino , Humanos , Masculino , Probabilidade
17.
Neuroimage Clin ; 15: 789-800, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28702354

RESUMO

BACKGROUND: Dyskinetic cerebral palsy (CP) is one of the most disabling motor types of CP and has been classically associated with injury to the basal ganglia and thalamus. Although cognitive dysfunction is common in CP, there is a paucity of published quantitative analyses investigating the relationship between white matter (WM) microstructure and cognition in this CP type. AIMS: This study aims (1) to compare brain WM microstructure between people with dyskinetic CP and healthy controls, (2) to identify brain regions where WM microstructure is related to intelligence and (3) to identify brain regions where WM microstructure is related to executive function in people with dyskinetic CP and (4) to identify brain regions where the correlations are different between controls and people with CP in IQ and executive functions. PATIENTS AND METHODS: Thirty-three participants with dyskinetic CP (mean ± SD age: 24.42 ± 12.61, 15 female) were age and sex matched with 33 controls. Participants underwent a comprehensive neuropsychological battery to assess intelligence quotient (IQ) and four executive function domains (attentional control, cognitive flexibility, goal setting and information processing). Diffusion weighted MRI scans were acquired at 3T. Voxel-based whole brain groupwise analyses were used to compare fractional anisotropy (FA) and of the CP group to the matched controls using a general lineal model. Further general linear models were used to identify regions where white matter FA correlated with IQ and each of the executive function domains. RESULTS: White matter FA was significantly reduced in the CP group in all cerebral lobes, predominantly in regions connected with the parietal and to a lesser extent the temporal lobes. There was no significant correlation between IQ or any of the four executive function domains and WM microstructure in the control group. In participants with CP, lower IQ was associated with lower FA in all cerebral lobes, predominantly in locations that also showed reduced FA compared to controls. Attentional control, goal setting and information processing did not correlate with WM microstructure in the CP group. Cognitive flexibility was associated with FA in regions known to contain connections with the frontal lobe (such as the superior longitudinal fasciculus and cingulum) as well as regions not known to contain tracts directly connected with the frontal lobe (such as the posterior corona radiata, posterior thalamic radiation, retrolenticular part of internal capsule, tapetum, body and splenium of corpus callosum). CONCLUSION: The widespread loss in the integrity of WM tissue is mainly located in the parietal lobe and related to IQ in dyskinetic CP. Unexpectedly, executive functions are only related with WM microstructure in regions containing fronto-cortical and posterior cortico-subcortical pathways, and not being specifically related to the state of fronto-striatal pathways which might be due to brain reorganization. Further studies of this nature may improve our understanding of the neurobiological bases of cognitive impairments after early brain insult.


Assuntos
Encéfalo/patologia , Paralisia Cerebral/patologia , Função Executiva/fisiologia , Inteligência/fisiologia , Substância Branca/patologia , Adulto , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Testes de Inteligência , Masculino , Adulto Jovem
18.
PLoS One ; 11(8): e0159540, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27487011

RESUMO

Diffusion MRI (dMRI) tractography analyses are difficult to perform in the presence of brain pathology. Automated methods that rely on cortical parcellation for structural connectivity studies often fail, while manually defining regions is extremely time consuming and can introduce human error. Both methods also make assumptions about structure-function relationships that may not hold after cortical reorganisation. Seeding tractography with functional-MRI (fMRI) activation is an emerging method that reduces these confounds, but inherent smoothing of fMRI signal may result in the inclusion of irrelevant pathways. This paper describes a novel fMRI-seeded dMRI-analysis pipeline based on surface-meshes that reduces these issues and utilises machine-learning to generate task specific white matter pathways, minimising the requirement for manually-drawn ROIs. We directly compared this new strategy to a standard voxelwise fMRI-dMRI approach, by investigating correlations between clinical scores and dMRI metrics of thalamocortical and corticomotor tracts in 31 children with unilateral cerebral palsy. The surface-based approach successfully processed more participants (87%) than the voxel-based approach (65%), and provided significantly more-coherent tractography. Significant correlations between dMRI metrics and five clinical scores of function were found for the more superior regions of these tracts. These significant correlations were stronger and more frequently found with the surface-based method (15/20 investigated were significant; R2 = 0.43-0.73) than the voxelwise analysis (2 sig. correlations; 0.38 & 0.49). More restricted fMRI signal, better-constrained tractography, and the novel track-classification method all appeared to contribute toward these differences.


Assuntos
Paralisia Cerebral/diagnóstico por imagem , Imagem de Tensor de Difusão/métodos , Imageamento por Ressonância Magnética/métodos , Substância Branca/diagnóstico por imagem , Adolescente , Criança , Feminino , Humanos , Aprendizado de Máquina , Masculino , Imagem Multimodal
20.
Res Dev Disabil ; 55: 368-76, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27280312

RESUMO

AIMS: To investigate the extent of white matter damage in children with unilateral cerebral palsy (UCP) caused by periventricular white matter lesions comparing between unilateral and bilateral lesions; and to investigate a relationship between white matter microstructure and hand function. METHODS AND PROCEDURES: Diffusion MRI images from 46 children with UCP and 18 children with typical development (CTD) were included. Subjects were grouped by side of hemiparesis and unilateral or bilateral lesions. A voxel-wise white matter analysis was performed to identify regions where fractional anisotropy (FA) was significantly different between UCP groups and CTD; and where FA correlated with either dominant or impaired hand function (using Jebsen Taylor Hand Function Test). OUTCOMES AND RESULTS: Children with unilateral lesions had reduced FA in the corticospinal tract of the affected hemisphere. Children with bilateral lesions had widespread reduced FA extending into all lobes. In children with left hemiparesis, impaired hand function correlated with FA in the contralateral corticospinal tract. Dominant hand function correlated with FA in the posterior thalamic radiations as well as multiple other regions in both left and right hemiparesis groups. CONCLUSIONS AND IMPLICATIONS: Periventricular white matter lesions consist of focal and diffuse components. Focal lesions may cause direct motor fibre insult resulting in motor impairment. Diffuse white matter injury is heterogeneous, and may contribute to more global dysfunction.


Assuntos
Encéfalo/diagnóstico por imagem , Paralisia Cerebral/diagnóstico por imagem , Leucomalácia Periventricular/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Adolescente , Anisotropia , Encéfalo/fisiopatologia , Paralisia Cerebral/fisiopatologia , Criança , Imagem de Difusão por Ressonância Magnética , Feminino , Lateralidade Funcional , Humanos , Leucomalácia Periventricular/fisiopatologia , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Tratos Piramidais/diagnóstico por imagem , Tratos Piramidais/fisiopatologia , Tálamo/diagnóstico por imagem , Tálamo/fisiopatologia , Substância Branca/fisiopatologia
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