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1.
Int J Mol Sci ; 20(13)2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31248061

RESUMO

Chronic pain is a condition in which pain progresses from an acute to chronic state and persists beyond the healing process. Chronic pain impairs function and decreases patients' quality of life. In recent years, efforts have been made to deepen our understanding of chronic pain and to develop better treatments to alleviate chronic pain. In this review, we summarize the results of previous studies, focusing on the mechanisms underlying chronic pain development and the identification of neural areas related to chronic pain. We review the association between chronic pain and negative affective states. Further, we describe the structural and functional changes in brain structures that accompany the chronification of pain and discuss various neurotransmitter families involved. Our review aims to provide guidance for the development of future therapeutic approaches that could be used in the management of chronic pain.


Assuntos
Afeto , Encéfalo/patologia , Encéfalo/fisiopatologia , Dor Crônica/etiologia , Dor Crônica/fisiopatologia , Animais , Biomarcadores , Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Dor Crônica/terapia , Gerenciamento Clínico , Humanos , Sistema Límbico/metabolismo , Sistema Límbico/patologia , Sistema Límbico/fisiopatologia , Vias Neurais , Transdução de Sinais
2.
J Neurooncol ; 143(3): 483-493, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31073964

RESUMO

PURPOSE: After treatment, pediatric brain tumor survivors (PBTS) face emotional and behavioral challenges, perhaps due to tumor or treatment-related changes in brain structures involved in emotion regulation, including those with fronto-limbic connections. We hypothesized that relative to healthy controls (HCs), PBTS would exhibit greater difficulties with behavior and emotional functioning, and display reduced mean fractional anisotropy (mFA) in white matter tracts with fronto-limbic connections including the cingulum bundle (CB), inferior fronto-occipital fasciculus (IFOF), and uncinate fasciculus (UF). We further predicted that mFA would account for variance in the relationship between group and emotional/behavioral outcome. METHODS: Eleven 8-16 year old PBTS and 14 HCs underwent MRI, including diffusion tensor imaging to assess white matter microstructure. Tractography quantified mFA of selected tracts. Parents rated children's emotional and behavioral functioning. RESULTS: Compared to HCs, caregivers of PBTS reported poorer behavioral regulation and greater internalizing and externalizing symptoms. Relative to HCs, PBTS had lower mFA within the bilateral CB, IFOF, and UF (ds = 0.59-1.15). Across groups, several medium-to-large correlations linked tract mFA and increased internalizing, externalizing, and poor behavioral regulation. Tract mFA also accounted for significant variance in the group-outcome association. CONCLUSIONS: Reduced mFA in fronto-limbic associated tracts may be associated with reduced behavioral regulation following pediatric brain tumor. PBTS with treatment known to impact white matter may be most susceptible. Research with larger, longitudinal samples should clarify this relationship, allow for multiple mediators across time, and consider factors like tumor and treatment type.


Assuntos
Neoplasias Encefálicas/fisiopatologia , Sobreviventes de Câncer/estatística & dados numéricos , Emoções/fisiologia , Lobo Frontal/patologia , Sistema Límbico/patologia , Comportamento Problema , Substância Branca/patologia , Adolescente , Anisotropia , Mapeamento Encefálico/métodos , Neoplasias Encefálicas/psicologia , Estudos de Casos e Controles , Criança , Imagem de Tensor de Difusão/métodos , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Taxa de Sobrevida
3.
Neurobiol Aging ; 76: 194-200, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30739076

RESUMO

Previous multimodal magnetic resonance imaging (MRI) studies of parkinsonian syndromes have focused primarily on motor-related basal ganglia structures. The present study investigated MRI changes in nonmotor-related limbic structures in 35 Parkinson's disease, 16 multiple system atrophy parkinsonian subtype, 17 progressive supranuclear palsy, and 37 control subjects. Mean diffusivity (MD), fractional anisotropy, transverse relaxation rate (R2*), quantitative susceptibility mapping, and volume measurements were obtained from the amygdala, hippocampus, and nucleus accumbens (NAc) to examine differences between groups and to test for associations with clinical scores. Compared with controls, Parkinson's disease subjects had lower NAc volume; multiple system atrophy parkinsonian subtype subjects had higher NAc transverse relaxation rate; and progressive supranuclear palsy subjects had higher amygdala and hippocampus MD and lower hippocampus fractional anisotropy (p's ≤ 0.008). Among parkinsonian subjects, amygdala and hippocampus MD associated positively with Unified Parkinson's Disease Rating Scale nonmotor and activities of daily living scores (p's ≤ 0.005). Together, these findings support the inclusion of limbic structures in future MRI studies of parkinsonian syndromes.


Assuntos
Sistema Límbico/diagnóstico por imagem , Sistema Límbico/patologia , Imagem por Ressonância Magnética , Imagem Multimodal , Neuroimagem , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas , Paralisia Supranuclear Progressiva
4.
Transl Psychiatry ; 9(1): 72, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718456

RESUMO

Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD) have been associated with difficulties recognizing and responding to social cues. Neuroimaging studies have begun to map the social brain; however, the specific neural substrates contributing to social deficits in neurodevelopmental disorders remain unclear. Three hundred and twelve children underwent structural magnetic resonance imaging of the brain (controls = 32, OCD = 44, ADHD = 77, ASD = 159; mean age = 11). Their social deficits were quantified on the Social Communication Questionnaire (SCQ) and the Reading the Mind in the Eyes Test (RMET). Multivariable regression models were used to examine the structural neuroimaging correlates of social deficits, with both a region of interest and a whole-brain vertex-wise approach. For the region of interest analysis, social brain regions were grouped into three networks: (1) lateral mentalization (e.g., temporal-parietal junction), (2) frontal cognitive (e.g., orbitofrontal cortex), and (3) subcortical affective (e.g., limbic system) regions. Overall, social communication deficits on the SCQ were associated with thinner cortices in the left lateral regions and the right insula, and decreased volume in the ventral striatum, across diagnostic groups (p = 0.006 to <0.0001). Smaller subcortical volumes were associated with more severe social deficits on the SCQ in ASD and ADHD, and less severe deficits in OCD. On the RMET, larger amygdala/hippocampal volumes were associated with fewer deficits across groups. Overall, patterns of associations were similar in ASD and ADHD, supporting a common underlying biology and the blurring of the diagnostic boundaries between these disorders.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/patologia , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Espectro Autista/patologia , Transtorno do Espectro Autista/fisiopatologia , Córtex Cerebral/patologia , Sistema Límbico/patologia , Transtorno de Comunicação Social/patologia , Transtorno de Comunicação Social/fisiopatologia , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Criança , Feminino , Humanos , Sistema Límbico/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Transtorno Obsessivo-Compulsivo/patologia , Transtorno Obsessivo-Compulsivo/fisiopatologia , Transtorno de Comunicação Social/diagnóstico por imagem , Transtorno de Comunicação Social/etiologia
5.
J Neuropsychiatry Clin Neurosci ; 31(2): 152-158, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30458664

RESUMO

OBJECTIVE: The selection of a bitemporal (BT) or right unilateral (RUL) electrode placement affects the efficacy and side effects of ECT. Previous studies have not entirely described the neurobiological underpinnings of such differential effects. Recent neuroimaging research on gray matter volumes is contributing to our understanding of the mechanism of action of ECT and could clarify the differential mechanisms of BT and RUL ECT. METHODS: To assess the whole-brain gray matter volumetric changes observed after treating patients with treatment-resistant depression with BT or RUL ECT, the authors used MRI to assess 24 study subjects with treatment-resistant depression (bifrontotemporal ECT, N=12; RUL ECT, N=12) at two time points (before the first ECT session and after ECT completion). RESULTS: Study subjects receiving BT ECT showed gray matter volume increases in the bilateral limbic system, but subjects treated with RUL ECT showed gray matter volume increases limited to the right hemisphere. The authors observed significant differences between the two groups in midtemporal and subcortical limbic structures in the left hemisphere. CONCLUSIONS: These findings highlight that ECT-induced gray matter volume increases may be specifically observed in the stimulated hemispheres. The authors suggest that electrode placement may relevantly contribute to the development of personalized ECT protocols.


Assuntos
Córtex Cerebral/patologia , Transtorno Depressivo Resistente a Tratamento/terapia , Eletroconvulsoterapia/métodos , Sistema Límbico/patologia , Adulto , Córtex Cerebral/diagnóstico por imagem , Feminino , Humanos , Sistema Límbico/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
6.
Sci Transl Med ; 10(461)2018 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-30282695

RESUMO

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation in the huntingtin (HTT) protein, resulting in acquisition of toxic functions. Previous studies have shown that lowering mutant HTT has the potential to be broadly beneficial. We previously identified HTT single-nucleotide polymorphisms (SNPs) tightly linked to the HD mutation and developed antisense oligonucleotides (ASOs) targeting HD-SNPs that selectively suppress mutant HTT. We tested allele-specific ASOs in a mouse model of HD. Both early and late treatment reduced cognitive and behavioral impairments in mice. To determine the translational potential of the treatment, we examined the effect of ASO administration on HTT brain expression in nonhuman primates. The treatment induced robust HTT suppression throughout the cortex and limbic system, areas implicated in cognition and psychiatric function. The results suggest that ASOs specifically targeting mutated HTT might have therapeutic effects on HD-mediated cognitive impairments.


Assuntos
Cognição , Proteína Huntingtina/metabolismo , Doença de Huntington/metabolismo , Doença de Huntington/fisiopatologia , Animais , Ansiedade/complicações , Ansiedade/patologia , Ansiedade/fisiopatologia , Atrofia/patologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Feminino , Humanos , Doença de Huntington/complicações , Doença de Huntington/patologia , Sistema Límbico/patologia , Masculino , Proteínas Mutantes/metabolismo , Oligonucleotídeos Antissenso/farmacologia , Primatas
8.
Brain Res ; 1700: 31-40, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29964024

RESUMO

Maternal care in the rat is an ancient behavioral response to specific multisensory inputs widely integrated in a complex forebrain, limbic and brain stem network to meet the basic needs of the young. Early undernutrition interferes with the morphofunctional organization of the brain, including maternal circuitry. The late-emerging effects of pre- and neonatal undernutrition on nest building and pup retrieval by lactating Wistar rats were correlated with dendritic arbor and perikaryon measurements (Golgi-Cox) in layer II pyramidal neurons of the anterior cingulate cortex, layer III pyramidal neurons of the medial prefrontal cortex and multipolar basolateral amygdala neurons examined on lactation days 4 and 12. In the underfed group, pregnant F0 dams received different percentages of a balanced diet. After birth, prenatally underfed (F1) pups continued the undernutrition by remaining with a nipple-ligated mother for 12 h. Weaning occurred at 25 days of age, and pups were subsequently provided an ad libitum diet. At 90 days of age, F1 dams were maternally tested. Early underfed dams showed significant reductions in nest building and prolonged retrieval latencies for grasping pups by inappropriate body areas. The behavioral alterations were concurrent with highly significant reductions in the somatic cross-sectional area and perimeter, spine density and dendritic crossings of cingulate cells and medial prefrontal cortical pyramids, as well as smaller effects on amygdala neurons. The anatomical findings suggest different postsynaptic organizations that may affect the neuronal excitability stages for the integration and encoding of cues triggering the altered maternal response components of early underfed dams.


Assuntos
Lactação/fisiologia , Sistema Límbico/patologia , Sistema Límbico/fisiopatologia , Desnutrição/fisiopatologia , Desnutrição/psicologia , Comportamento Materno/fisiologia , Animais , Animais Recém-Nascidos , Feminino , Lactação/psicologia , Masculino , Neurônios/patologia , Neurônios/fisiologia , Gravidez , Distribuição Aleatória , Ratos Wistar
9.
Neuroimage ; 181: 16-29, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29890329

RESUMO

This work presents an automatically annotated fiber cluster (AAFC) method to enable identification of anatomically meaningful white matter structures from the whole brain tractography. The proposed method consists of 1) a study-specific whole brain white matter parcellation using a well-established data-driven groupwise fiber clustering pipeline to segment tractography into multiple fiber clusters, and 2) a novel cluster annotation method to automatically assign an anatomical tract annotation to each fiber cluster by employing cortical parcellation information across multiple subjects. The novelty of the AAFC method is that it leverages group-wise information about the fiber clusters, including their fiber geometry and cortical terminations, to compute a tract anatomical label for each cluster in an automated fashion. We demonstrate the proposed AAFC method in an application of investigating white matter abnormality in emotional processing and sensorimotor areas in major depressive disorder (MDD). Seven tracts of interest related to emotional processing and sensorimotor functions are automatically identified using the proposed AAFC method as well as a comparable method that uses a cortical parcellation alone. Experimental results indicate that our proposed method is more consistent in identifying the tracts across subjects and across hemispheres in terms of the number of fibers. In addition, we perform a between-group statistical analysis in 31 MDD patients and 62 healthy subjects on the identified tracts using our AAFC method. We find statistical differences in diffusion measures in local regions within a fiber tract (e.g. 4 fiber clusters within the identified left hemisphere cingulum bundle (consisting of 14 clusters) are significantly different between the two groups), suggesting the ability of our method in identifying potential abnormality specific to subdivisions of a white matter structure.


Assuntos
Córtex Cerebral/patologia , Transtorno Depressivo Maior/patologia , Imagem de Tensor de Difusão/métodos , Emoções , Sistema Límbico/patologia , Tálamo/patologia , Substância Branca/patologia , Adulto , Córtex Cerebral/diagnóstico por imagem , Transtorno Depressivo Maior/diagnóstico por imagem , Feminino , Humanos , Sistema Límbico/diagnóstico por imagem , Masculino , Fibras Nervosas Mielinizadas/patologia , Vias Neurais/diagnóstico por imagem , Vias Neurais/patologia , Tratos Piramidais/diagnóstico por imagem , Tratos Piramidais/patologia , Córtex Sensório-Motor/diagnóstico por imagem , Córtex Sensório-Motor/patologia , Tálamo/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Adulto Jovem
10.
Synapse ; 72(8): e22036, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29740871

RESUMO

Aging is a stage of life where cognitive and motor functions are impaired. This is because oxidative and inflammatory processes exacerbate neurodegeneration, which affects dendritic morphology and neuronal communication of limbic regions with memory loss. Recently, the use of trophic substances has been proposed to prevent neuronal deterioration. The neuropeptide-12 (N-PEP-12) has been evaluated in elderly patients with dementia, showing improvements in cognitive tasks due to acts as a neurotrophic factor. In the present work, we evaluated the effect of N-PEP-12 on motor activity and recognition memory, as well as its effects on dendritic morphology and the immunoreactivity of GFAP, Synaptophysin (SYP), and BDNF in neurons of the prefrontal cortex (PFC), dorsal hippocampus (DH) and nucleus accumbens (NAcc) of aged rats. The results show that N-PEP-12 improved the recognition memory, but the motor activity was not modified compared to the control animals. N-PEP-12 increases the density of dendritic spines and the total dendritic length in neurons of the PFC (layers 3 and 5) and in DH (CA1 and CA3). Interestingly NAcc neurons showed a reduction in the number of dendritic spines. In the N-PEP-12 animals, when evaluating the immunoreactivity for SYP and BDNF, there was an increase in the three brain regions, while the mark for GFAP decreased significantly. Our results suggest that N-PEP-12 promotes neuronal plasticity in the limbic system of aged animals, which contributes to improving recognition memory. In this sense, N-PEP-12 can be considered as a pharmacological alternative to prevent or delay brain aging and control senile dementias.


Assuntos
Envelhecimento/efeitos dos fármacos , Aminoácidos/farmacologia , Sistema Límbico/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Nootrópicos/farmacologia , /efeitos dos fármacos , Envelhecimento/metabolismo , Envelhecimento/patologia , Envelhecimento/psicologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Dendritos/efeitos dos fármacos , Dendritos/metabolismo , Dendritos/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Sistema Límbico/metabolismo , Sistema Límbico/patologia , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Plasticidade Neuronal/fisiologia , Ratos Sprague-Dawley , Sinaptofisina/metabolismo
11.
Brain Imaging Behav ; 12(6): 1569-1582, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29442274

RESUMO

The human sense of smell is closely associated with morphological differences of the fronto-limbic system, specifically the piriform cortex and medial orbitofrontal cortex (mOFC). Still it is unclear whether cortical volume in the core olfactory areas and connected brain regions are shaped differently in individuals who suffer from lifelong olfactory deprivation relative to healthy normosmic individuals. To address this question, we examined if regional variations in gray matter volume were associated with smell ability in seventeen individuals with isolated congenital olfactory impairment (COI) matched with sixteen normosmic controls. All subjects underwent whole-brain magnetic resonance imaging, and voxel-based morphometry was used to estimate regional variations in grey matter volume. The analyses showed that relative to controls, COI subjects had significantly larger grey matter volumes in left middle frontal gyrus and right superior frontal sulcus (SFS). COI subjects with severe olfactory impairment (anosmia) had reduced grey matter volume in the left mOFC and increased volume in right piriform cortex and SFS. Within the COI group olfactory ability, measured with the "Sniffin' Sticks" test, was positively associated with larger grey matter volume in right posterior cingulate and parahippocampal cortices whereas the opposite relationship was observed in controls. Across COI subjects and controls, better olfactory detection threshold was associated with smaller volume in right piriform cortex, while olfactory identification was negatively associated with right SFS volume. Our findings suggest that lifelong olfactory deprivation trigger changes in the cortical volume of prefrontal and limbic brain regions previously linked to olfactory memory.


Assuntos
Sistema Límbico/diagnóstico por imagem , Transtornos do Olfato/congênito , Transtornos do Olfato/diagnóstico por imagem , Córtex Pré-Frontal/diagnóstico por imagem , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Humanos , Processamento de Imagem Assistida por Computador , Sistema Límbico/patologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Transtornos do Olfato/patologia , Percepção Olfatória , Tamanho do Órgão , Córtex Pré-Frontal/patologia
12.
Annu Rev Clin Psychol ; 14: 259-289, 2018 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-29401045

RESUMO

Although antisocial personality disorder (APD) is one of the most researched personality disorders, it is still surprisingly resistant to treatment. This lack of clinical progress may be partly due to the failure to view APD as a neurodevelopmental disorder and to consider early interventions. After first defining what constitutes a neurodevelopmental disorder, this review evaluates the extent to which APD meets neurodevelopmental criteria, covering structural and functional brain imaging, neurocognition, genetics and epigenetics, neurochemistry, and early health risk factors. Prevention and intervention strategies for APD are then outlined, focusing on addressing early biological and health systems, followed by forensic and clinical implications. It is argued both that APD meets criteria for consideration as a neurodevelopmental disorder and that consideration should be given both to the possibility that early onset conduct disorder is neurodevelopmental in nature, and also to the inclusion of psychopathy as a specifier in future Diagnostic and Statistical Manual revisions of APD.


Assuntos
Transtorno da Personalidade Antissocial , Sistema Límbico , Transtornos do Neurodesenvolvimento , Córtex Pré-Frontal , Transtorno da Personalidade Antissocial/diagnóstico por imagem , Transtorno da Personalidade Antissocial/genética , Transtorno da Personalidade Antissocial/patologia , Transtorno da Personalidade Antissocial/fisiopatologia , Humanos , Sistema Límbico/crescimento & desenvolvimento , Sistema Límbico/patologia , Sistema Límbico/fisiopatologia , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Córtex Pré-Frontal/crescimento & desenvolvimento , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia
13.
J Nucl Med ; 59(4): 682-690, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29348321

RESUMO

Animal studies suggest an important role for the metabotropic glutamate receptor subtype 5 (mGlu5) in the pathophysiology of alcohol dependence, but direct human evidence is lacking. The goal of this study was to investigate cerebral mGlu5 availability in alcohol-dependent subjects versus controls using 18F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile (18F-FPEB) PET. Methods: Dynamic 90-min 18F-FPEB scans combined with arterial blood sampling were acquired for 16 recently abstinent alcohol-dependent subjects and 32 age-matched controls. Regional mGlu5 availability was quantified by the 18F-FPEB total distribution volume using both a voxel-by-voxel and a volume-of-interest analysis with partial-volume effect correction. Alcohol consumption within the last 3 mo was assessed by questionnaires and by hair ethyl glucuronide analysis. Craving was assessed using the Desire for Alcohol Questionnaire. Results: mGlu5 availability was lower in mainly limbic regions of alcohol-dependent subjects than in controls (P < 0.05, familywise error-corrected), ranging from 14% in the posterior cingulate cortex to 36% in the caudate nucleus. Lower mGlu5 availability was associated with higher hair ethyl glucuronide levels for most regions and was related to a lower level of craving specifically in the middle frontal gyrus, cingulate cortex, and inferolateral temporal lobe. Conclusion: These findings provide human in vivo evidence that limbic mGlu5 has a role in the pathophysiology of alcohol dependence, possibly involved in a compensatory mechanism helping to reduce craving during abstinence.


Assuntos
Alcoolismo/metabolismo , Sistema Límbico/metabolismo , Receptor de Glutamato Metabotrópico 5/metabolismo , Alcoolismo/diagnóstico por imagem , Alcoolismo/patologia , Atrofia/diagnóstico por imagem , Estudos de Casos e Controles , Feminino , Humanos , Sistema Límbico/diagnóstico por imagem , Sistema Límbico/patologia , Masculino , Pessoa de Meia-Idade , Nitrilos , Tomografia por Emissão de Pósitrons , Piridinas
14.
Life Sci ; 193: 40-46, 2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-29223539

RESUMO

AIMS: Experimental and clinical studies have demonstrated that components of renin-angiotensin system are elevated in the hippocampus in epileptogenic conditions. In the present work, we explored the changes in the expression of angiotensin II receptor, type 1 (AT1 receptor) in limbic structures, as well as the effect of the AT1 receptor antagonist losartan in a model of comorbid hypertension and epilepsy. MAIN METHODS: The expression of AT1 receptors was compared between spontaneously hypertensive rats (SHRs) and Wistar rats by using immunohistochemistry in the kainate (KA) model of temporal lobe epilepsy (TLE). The effect of losartan was studied on AT1 receptor expression in epileptic rats that were treated for a period of 4weeks after status epilepticus. KEY FINDINGS: The naive and epileptic SHRs were characterized by stronger protein expression of AT1 receptor than normotensive Wistar rats in the CA1, CA3a, CA3b, CA3c field and the hilus of the dentate gyrus of the dorsal hippocampus but fewer cells were immunostained in the piriform cortex. Increased AT1 immunostaining was observed in the basolateral amygdala of epileptic SHRs but not of epileptic Wistar rats. Losartan exerted stronger and structure-dependent suppression of AT1 receptor expression in SHRs compared to Wistar rats. SIGNIFICANCE: Our results confirm the important role of AT1 receptor in epilepsy and suggest that the AT1receptor antagonists could be used as a therapeutic strategy for treatment of comorbid hypertension and epilepsy.


Assuntos
Losartan/farmacologia , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Angiotensinas , Animais , Pressão Sanguínea/efeitos dos fármacos , Comorbidade , Modelos Animais de Doenças , Epilepsia/tratamento farmacológico , Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Hipertensão/tratamento farmacológico , Ácido Caínico/efeitos adversos , Ácido Caínico/metabolismo , Sistema Límbico/patologia , Losartan/metabolismo , Losartan/uso terapêutico , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Sistema Renina-Angiotensina/efeitos dos fármacos
15.
Prog Neuropsychopharmacol Biol Psychiatry ; 87(Pt B): 263-268, 2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-28501595

RESUMO

The transition from acute to chronic pain is accompanied by increased engagement of emotional and motivational circuits. Adaptations within this corticolimbic circuitry contribute to the cellular and behavioral maladaptations associated with chronic pain. Central regions within the corticolimbic brain include the mesolimbic dopamine system, the amygdala, and the medial prefrontal cortex. The evidence reviewed herein supports the notion that chronic pain induces significant changes within these corticolimbic regions that contribute to the chronicity and intractability of pain. In addition, pain-induced changes in corticolimbic circuitry are poised to impact motivated behavior and reward responsiveness to environmental stimuli, and may modulate the addiction liability of drugs of abuse, such as opioids.


Assuntos
Córtex Cerebral/fisiopatologia , Dor Crônica/patologia , Sistema Límbico/fisiopatologia , Vias Neurais/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/patologia , Animais , Córtex Cerebral/patologia , Dor Crônica/psicologia , Emoções/fisiologia , Humanos , Sistema Límbico/patologia , Motivação/fisiologia , Transtornos Relacionados ao Uso de Substâncias/psicologia
16.
Exp Neurol ; 299(Pt A): 172-196, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29056362

RESUMO

Lewy body disorders are characterized by the emergence of α-synucleinopathy in many parts of the central and peripheral nervous systems, including in the telencephalon. Dense α-synuclein+ pathology appears in regio inferior of the hippocampus in both Parkinson's disease and dementia with Lewy bodies and may disturb cognitive function. The preformed α-synuclein fibril model of Parkinson's disease is growing in use, given its potential for seeding the self-propagating spread of α-synucleinopathy throughout the mammalian brain. Although it is often assumed that the spread occurs through neuroanatomical connections, this is generally not examined vis-à-vis the uptake and transport of tract-tracers infused at precisely the same stereotaxic coordinates. As the neuronal connections of the hippocampus are historically well defined, we examined the first-order spread of α-synucleinopathy three months following fibril infusions centered in the mouse regio inferior (CA2+CA3), and contrasted this to retrograde and anterograde transport of the established tract-tracers FluoroGold and biotinylated dextran amines (BDA). Massive hippocampal α-synucleinopathy was insufficient to elicit memory deficits or loss of cells and synaptic markers in this model of early disease processes. However, dense α-synuclein+ inclusions in the fascia dentata were negatively correlated with memory capacity. A modest compensatory increase in synaptophysin was evident in the stratum radiatum of cornu Ammonis in fibril-infused animals, and synaptophysin expression correlated inversely with memory function in fibril but not PBS-infused mice. No changes in synapsin I/II expression were observed. The spread of α-synucleinopathy was somewhat, but not entirely consistent with FluoroGold and BDA axonal transport, suggesting that variables other than innervation density also contribute to the materialization of α-synucleinopathy. For example, layer II entorhinal neurons of the perforant pathway exhibited somal α-synuclein+ inclusions as well as retrogradely labeled FluoroGold+ somata. However, some afferent brain regions displayed dense retrograde FluoroGold label and no α-synuclein+ inclusions (e.g. medial septum/diagonal band), supporting the selective vulnerability hypothesis. The pattern of inclusions on the contralateral side was consistent with specific spread through commissural connections (e.g. stratum pyramidale of CA3), but again, not all commissural projections exhibited α-synucleinopathy (e.g. hilar mossy cells). The topographical extent of inclusions is displayed here in high-resolution images that afford viewers a rich opportunity to dissect the potential spread of pathology through neural circuitry. Finally, the results of this expository study were leveraged to highlight the challenges and limitations of working with preformed α-synuclein fibrils.


Assuntos
Doença por Corpos de Lewy/patologia , Neurofibrilas , alfa-Sinucleína , Animais , Comportamento Animal , Modelos Animais de Doenças , Hipocampo/patologia , Corpos de Inclusão/patologia , Doença por Corpos de Lewy/psicologia , Sistema Límbico/patologia , Transtornos da Memória/patologia , Transtornos da Memória/psicologia , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/patologia , Transmissão Sináptica , Telencéfalo/patologia
17.
J Clin Endocrinol Metab ; 103(1): 115-124, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29053851

RESUMO

Context: Low birth weight (LBW; <2500 g) is linked to the development of insulin resistance and limbic-hypothalamic-pituitary-adrenal (LHPA) axis hyperactivity. Objective: Our first aim was to study insulin action, LHPA axis function, and limbic brain structures in young, healthy LBW men vs normal birthweight (NBW) controls (part 1). Our second aim was to investigate the effects of escitalopram vs placebo in LBW men in the LHPA axis and insulin sensitivity (part 2). Design Setting, Participants, and Intervention: The maximal (Rdmax) and submaximal (Rdsubmax) rates of insulin-stimulated glucose turnover, LHPA axis, and brain morphology were examined in 40 LBW men and 20 matched NBW men using two-stage hyperinsulinemic euglycemic clamp, 24-hour hormone plasma profiles, and magnetic resonance imaging. Subsequently, all LBW subjects underwent randomized and double-blind treatment with escitalopram 20 mg/d or placebo for 3 months followed by a complete reexamination. Main Outcome Measures (Part 2): Changes in Rdmax/Rdsubmax and plasma-free cortisol 24-hour area under the curve. Results: In LBW vs NBW, Rdsubmax and Rdmax were ∼16% (P = 0.01) and ∼12% (P = 0.01) lower, respectively, and 24-hour free cortisol levels were ∼20% higher (P = 0.02), primarily driven by a ∼99% increase at 05:00 am (P < 0.001). Furthermore, these changes were related to structural alterations within left thalamus and ventromedial prefrontal cortex. However, in LBW men, exposure to escitalopram normalized the free cortisol levels and improved the Rdsubmax by ∼24% (P = 0.04) compared with placebo. Conclusions: LBW vs NBW displayed alterations in key brain structures modulating the LHPA axis, elevated free cortisol levels, and insulin resistance. Escitalopram administration ameliorated these defects, suggesting a potential for LHPA axis modulation compounds to improve insulin action in LBW subjects.


Assuntos
Encefalopatias/complicações , Citalopram/uso terapêutico , Síndrome de Cushing/tratamento farmacológico , Recém-Nascido de Baixo Peso , Resistência à Insulina , Sistema Límbico/patologia , Adulto , Glicemia/metabolismo , Estudos de Casos e Controles , Síndrome de Cushing/etiologia , Síndrome de Cushing/metabolismo , Método Duplo-Cego , Seguimentos , Técnica Clamp de Glucose , Humanos , Insulina/metabolismo , Masculino , Prognóstico , Inibidores de Captação de Serotonina/uso terapêutico , Adulto Jovem
18.
Alzheimers Dement ; 14(3): 330-339, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29100980

RESUMO

INTRODUCTION: We sought to assess the individual and combined contribution of limbic and neocortical α-synuclein, tau, and amyloid ß (Aß) to duration of illness in dementia with Lewy bodies (DLB). METHODS: Quantitative digital pathology of limbic and neocortical α-synuclein, tau, and Aß was assessed in 49 patients with clinically probable DLB. Regression modeling examined the unique and shared contribution of each pathology to the variance of illness duration. RESULTS: Patients with diffuse Lewy body disease had more severe pathology of each type and a shorter duration of illness than individuals with transitional Lewy body disease. The three pathologies accounted for 25% of the total variance of duration of illness, with 19% accounted for by α-synuclein alone or in combination with tau and Aß. When the diffuse Lewy body disease group was examined separately, α-synuclein deposition significantly exceeded that of tau and Aß. In this model, 20% of 24% total variance in the model for duration of illness was accounted for independently by α-synuclein. DISCUSSION: In DLB, α-synuclein is an important predictor of disease duration, both independently and synergistically with tau and Aß.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Doença por Corpos de Lewy/metabolismo , Sistema Límbico/metabolismo , Neocórtex/metabolismo , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo , Idoso , Progressão da Doença , Feminino , Humanos , Doença por Corpos de Lewy/patologia , Sistema Límbico/patologia , Masculino , Neocórtex/patologia , Estudos Prospectivos , Fatores de Tempo
19.
Prog Neuropsychopharmacol Biol Psychiatry ; 87(Pt B): 216-223, 2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-29079140

RESUMO

Stress has multifaceted effects on pain. On the one hand, it is a powerful inhibitor of nociception and inflammation; on the other hand, it contributes to enhanced pathological states including the establishment and continuation of chronic pain. These seemingly paradoxical effects can be better understood by investigating how stress-induced plasticity in particular brain circuitry contributes to the chronic pain state. This review presents the rationale and evidence for the interactions between stress and pain, emphasizing underlying mechanisms and putting forth the hypothesis that stress partly mediates the deleterious effects of pain on the corticolimbic system. First, a general description of the corticolimbic circuitry predisposing and amplifying chronic pain will be discussed, followed by an overview of the neurotoxic effects of stress hormones on this circuitry. Recent studies show that the resulting perturbations to these brain circuits have significant consequences both for chronic pain and for general regulation of the stress response, primarily through feedback mechanisms controlling the hypothalamic-pituitary-adrenal axis. This overlap in effected circuitry provides a key point of comparison between stress and pain, and the similarities between the plasticity induced by chronic pain and chronic stress will be examined here. Chronic pain patients have been shown to exhibit maladaptive stress responses in general and in response to pain; the cause of this response and its consequence on pain severity will then be reviewed. Finally, factors that have been shown to lead to resilience or vulnerability for chronic pain and maladaptive stress responses will be summarized.


Assuntos
Córtex Cerebral , Dor Crônica , Sistema Límbico , Estresse Psicológico/patologia , Animais , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Dor Crônica/patologia , Dor Crônica/fisiopatologia , Dor Crônica/psicologia , Hormônios/metabolismo , Humanos , Sistema Límbico/metabolismo , Sistema Límbico/patologia , Sistema Límbico/fisiopatologia
20.
Parkinsonism Relat Disord ; 46 Suppl 1: S80-S82, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28709746

RESUMO

The name functional rather than psychogenic is getting to be more widely used for terminology of this condition. It is better accepted by patients and keeps an open mind in searching for greater understanding of the pathophysiology. Advances in the pathophysiology show an overactive limbic system with connections to the motor system. Moreover, there is a disruption of the self-agency network, possibly due to a failure of feedforward signaling. There has recently been more success in treating patients. The strongest evidence is for intensive physical therapy coupled with at least some psychological support. Psychotherapy with cognitive behavioral therapy may well also be useful.


Assuntos
Transtornos dos Movimentos , Psicoterapia/métodos , Humanos , Sistema Límbico/patologia , Transtornos dos Movimentos/etiologia , Transtornos dos Movimentos/psicologia , Transtornos dos Movimentos/terapia
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