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1.
Nat Commun ; 12(1): 3321, 2021 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-34059669

RESUMO

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder. The mechanisms underlying ASD are unclear. Astrocyte alterations are noted in ASD patients and animal models. However, whether astrocyte dysfunction is causal or consequential to ASD-like phenotypes in mice is unresolved. Type 2 inositol 1,4,5-trisphosphate 6 receptors (IP3R2)-mediated Ca2+ release from intracellular Ca2+ stores results in the activation of astrocytes. Mutations of the IP3R2 gene are associated with ASD. Here, we show that both IP3R2-null mutant mice and astrocyte-specific IP3R2 conditional knockout mice display ASD-like behaviors, such as atypical social interaction and repetitive behavior. Furthermore, we show that astrocyte-derived ATP modulates ASD-like behavior through the P2X2 receptors in the prefrontal cortex and possibly through GABAergic synaptic transmission. These findings identify astrocyte-derived ATP as a potential molecular player in the pathophysiology of ASD.


Assuntos
Trifosfato de Adenosina/metabolismo , Astrócitos/patologia , Transtorno do Espectro Autista/patologia , Sinalização do Cálcio/fisiologia , Receptores de Inositol 1,4,5-Trifosfato/deficiência , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Comportamento Animal , Cálcio/metabolismo , Modelos Animais de Doenças , Neurônios GABAérgicos/fisiologia , Humanos , Receptores de Inositol 1,4,5-Trifosfato/genética , Masculino , Camundongos , Camundongos Knockout , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia , Transmissão Sináptica/fisiologia
2.
Medicine (Baltimore) ; 100(23): e26281, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34115028

RESUMO

BACKGROUND AND OBJECTIVE: Previous studies have shown that the default-mode network (DMN) has a substantial role in patients with major depressive disorder (MDD). However, there is a shortage of information regarding variations in the functional connectivity (FC) of the DMN of treatment-naive patients with first-episode MDD. The present study aims to explore the FC of the DMN in such patients. METHODS: The study population consisted of 33 patients and 35 controls, paired regarding age, gender, education level, and health condition. Depression severity was assessed through the Hamilton Depression Scale (HAM-D), and subjects underwent evaluation during the resting-state through functional magnetic resonance imaging (rs-fMRI). To assess the result, we used FC and ICA. We used Spearman's correlation test to detect potential correlations between anomalous FC and severity of HAM-D scores. RESULTS: We have found a decreased FC in the left medial orbitofrontal gyrus (MOFG) and right marginal gyrus (SMG) in depressive patients compared to controls. There was a negative correlation between abnormal FC in the right SMG and HAM-D scores. We have not found any increase in FC of the DMN in treatment-naive, first-episode of MDD patients. CONCLUSIONS: Our study provided evidence of a negative correlation between abnormal FC in the DMN and severity of depression symptoms measured by HAM-D in treatment-naive MDD patients. This finding could shed some light on the relevance of DMN for understanding the pathophysiology of cognitive impairment in MDD.


Assuntos
Mapeamento Encefálico/métodos , Rede de Modo Padrão/fisiopatologia , Transtorno Depressivo Maior , Imageamento por Ressonância Magnética/métodos , Córtex Pré-Frontal , Adulto , Cognição/fisiologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Conectoma/métodos , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Masculino , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiopatologia , Escalas de Graduação Psiquiátrica
3.
Nat Commun ; 12(1): 3166, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-34039978

RESUMO

Stress is a significant risk factor for the development of major depressive disorder (MDD), yet the underlying mechanisms remain unclear. Preclinically, adaptive and maladaptive stress-induced changes in glutamatergic function have been observed in the medial prefrontal cortex (mPFC). Here, we examine stress-induced changes in human mPFC glutamate using magnetic resonance spectroscopy (MRS) in two healthy control samples and a third sample of unmedicated participants with MDD who completed the Maastricht acute stress task, and one sample of healthy control participants who completed a no-stress control manipulation. In healthy controls, we find that the magnitude of mPFC glutamate response to the acute stressor decreases as individual levels of perceived stress increase. This adaptative glutamate response is absent in individuals with MDD and is associated with pessimistic expectations during a 1-month follow-up period. Together, this work shows evidence for glutamatergic adaptation to stress that is significantly disrupted in MDD.


Assuntos
Transtorno Depressivo Maior/psicologia , Ácido Glutâmico/metabolismo , Pessimismo/psicologia , Córtex Pré-Frontal/fisiopatologia , Estresse Psicológico/metabolismo , Adaptação Fisiológica , Adolescente , Adulto , Anedonia , Estudos de Casos e Controles , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Feminino , Seguimentos , Ácido Glutâmico/análise , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/metabolismo , Estresse Fisiológico , Estresse Psicológico/fisiopatologia , Adulto Jovem
4.
Int J Mol Sci ; 22(8)2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923533

RESUMO

It has been established that the selective α2A adrenoceptor agonist guanfacine reduces hyperactivity and improves cognitive impairment in patients with attention-deficit/hyperactivity disorder (ADHD). The major mechanisms of guanfacine are considered to involve the activation of the postsynaptic α2A adrenoceptor of glutamatergic pyramidal neurons in the frontal cortex, but the effects of chronic guanfacine administration on catecholaminergic and glutamatergic transmissions associated with the orbitofrontal cortex (OFC) are yet to be clarified. The actions of guanfacine on catecholaminergic transmission, the effects of acutely local and systemically chronic (for 7 days) administrations of guanfacine on catecholamine release in pathways from the locus coeruleus (LC) to OFC, the ventral tegmental area (VTA) and reticular thalamic-nucleus (RTN), from VTA to OFC, from RTN to the mediodorsal thalamic-nucleus (MDTN), and from MDTN to OFC were determined using multi-probe microdialysis with ultra-high performance liquid chromatography. Additionally, the effects of chronic guanfacine administration on the expression of the α2A adrenoceptor in the plasma membrane fraction of OFC, VTA and LC were examined using a capillary immunoblotting system. The acute local administration of therapeutically relevant concentrations of guanfacine into the LC decreased norepinephrine release in the OFC, VTA and RTN without affecting dopamine release in the OFC. Systemically, chronic administration of therapeutically relevant doses of guanfacine for 14 days increased the basal release of norepinephrine in the OFC, VTA, RTN, and dopamine release in the OFC via the downregulation of the α2A adrenoceptor in the LC, OFC and VTA. Furthermore, systemically, chronic guanfacine administration did not affect intrathalamic GABAergic transmission, but it phasically enhanced thalamocortical glutamatergic transmission. The present study demonstrated the dual actions of guanfacine on catecholaminergic transmission-acute attenuation of noradrenergic transmission and chronic enhancement of noradrenergic transmission and thalamocortical glutamatergic transmission. These dual actions of guanfacine probably contribute to the clinical effects of guanfacine against ADHD.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Guanfacina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Tálamo/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Animais , Dopamina/metabolismo , Ácido Glutâmico/metabolismo , Guanfacina/administração & dosagem , Guanfacina/uso terapêutico , Masculino , Norepinefrina/metabolismo , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 2/genética , Receptores Adrenérgicos alfa 2/metabolismo , Tálamo/metabolismo , Tálamo/fisiopatologia , Ácido gama-Aminobutírico/metabolismo
5.
Int J Mol Sci ; 22(7)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807276

RESUMO

Generalized anxiety disorder (GAD) is marked by uncontrollable, persistent worry and exaggerated response to uncertainty. Here, we review and summarize the findings from the GAD literature that employs functional neuroimaging methods. In particular, the present review focuses on task-based blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies. We find that select brain regions often regarded as a part of a corticolimbic circuit (e.g., amygdala, anterior cingulate cortex, prefrontal cortex) are consistently targeted for a priori hypothesis-driven analyses, which, in turn, shows varying degrees of abnormal BOLD responsivity in GAD. Data-driven whole-brain analyses show the insula and the hippocampus, among other regions, to be affected by GAD, depending on the task used in each individual study. Overall, while the heterogeneity of the tasks and sample size limits the generalizability of the findings thus far, some promising convergence can be observed in the form of the altered BOLD responsivity of the corticolimbic circuitry in GAD.


Assuntos
Transtornos de Ansiedade/diagnóstico por imagem , Transtornos de Ansiedade/fisiopatologia , Ansiedade/fisiopatologia , Tonsila do Cerebelo/fisiopatologia , Ansiedade/metabolismo , Transtornos de Ansiedade/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Córtex Cerebral/fisiopatologia , Emoções/fisiologia , Neuroimagem Funcional/métodos , Humanos , Sistema Límbico/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Córtex Pré-Frontal/fisiopatologia
6.
Neuron ; 109(9): 1479-1496.e6, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33765445

RESUMO

The Akt family of kinases exerts many of its cellular effects via the activation of the mammalian target of rapamycin (mTOR) kinase through a series of intermediary proteins. Multiple lines of evidence have identified Akt-family kinases as candidate schizophrenia and bipolar disorder genes. Although dysfunction of the prefrontal cortex (PFC) is a key feature of both schizophrenia and bipolar disorder, no studies have comprehensively assessed potential alterations in Akt-mTOR pathway activity in the PFC of either disorder. Here, we examined the activity and expression profile of key proteins in the Akt-mTOR pathway in bipolar disorder and schizophrenia homogenates from two different PFC subregions. Our findings identify reduced Akt-mTOR PFC signaling in a subset of bipolar disorder subjects. Using a reverse-translational approach, we demonstrated that Akt hypofunction in the PFC is sufficient to give rise to key cognitive phenotypes that are paralleled by alterations in synaptic connectivity and function.


Assuntos
Transtorno Bipolar/metabolismo , Disfunção Cognitiva/metabolismo , Córtex Pré-Frontal/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Transtorno Bipolar/patologia , Transtorno Bipolar/fisiopatologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Feminino , Humanos , Masculino , Neurônios/patologia , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia
7.
Drug Alcohol Depend ; 221: 108593, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33611027

RESUMO

BACKGROUND: Craving is a major contributor to drug-seeking and relapse. Although the ventral striatum (VS) is a primary neural correlate of craving, strategies aimed at manipulating VS function have not resulted in efficacious treatments. This incongruity may be because the VS does not influence craving in isolation. Instead, craving is likely mediated by communication between the VS and other neural substrates. Thus, we examined how striatal functional connectivity (FC) with key nodes of networks involved in addiction affects relief of craving, which is an important step in identifying viable treatment targets. METHODS: Twenty-four nicotine-dependent non-abstinent women completed two resting-state (rs) fMRI scans, one before and one following smoking a cigarette in the scanner, and provided craving ratings before and after smoking the cigarette. A seed-based approach was used to examine rsFC between the VS, putamen and germane craving-related brain regions; the dorsolateral prefrontal cortex (dlPFC), the posterior cingulate cortex, and the anterior ventral insula. RESULTS: Smoking a cigarette was associated with a decrease in craving. Relief of craving correlated with increases in right dlPFC- bilateral VS (r = 0.57, p = 0.003, corrected) as did increased right dlPFC-left putamen coupling (r = 0.62, p = 0.001, corrected). CONCLUSIONS: Smoking-induced relief of craving is associated with enhanced rsFC between the dlPFC, a region that plays a pivotal role in decision making, and the striatum, the neural structure underlying motivated behavior. These findings are highly consistent with a burgeoning literature implicating dlPFC-striatal interactions as a neurobiological substrate of craving.


Assuntos
Fissura , Nicotina , Córtex Pré-Frontal/fisiologia , Tabagismo/fisiopatologia , Adulto , Comportamento Aditivo , Encéfalo/fisiopatologia , Mapeamento Encefálico , Córtex Cerebral/fisiopatologia , Corpo Estriado , Feminino , Giro do Cíngulo/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Córtex Pré-Frontal/fisiopatologia , Fumar/fisiopatologia , Fumar Tabaco
8.
Eur J Pharmacol ; 896: 173883, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33513334

RESUMO

The lesions induced by Ibotenic acid (IA) emulate some of the symptoms associated with schizophrenia, such as impaired working memory that is predominantly organized by the medial prefrontal cortex (mPFC), or difficulties in social interactions that aremainly organized by the amygdala (AMG). The plastic capacity of dendritic spines in neurons of the mPFC and AMG is modulated by molecules that participate in the known deterioration of working memory, although the influence of these on the socialization of schizophrenic patients is unknown. Here, the effect of a neonatal IA induced lesion on social behavior and working memory was evaluated in adult rats, along with the changes in cytoarchitecture of dendritic spines and their protein content, specifically the postsynaptic density protein 95 (PSD-95), Synaptophysin (Syn), AMPA receptors, and brain-derived neurotrophic factor (BDNF). Both working memory and social behavior were impaired, and the density of the spines, as well as their PSD-95, Syn, AMPA receptor and BDNF content was lower in IA lesioned animals. The proportional density of thin, mushroom, stubby and wide spines resulted in plastic changes that suggest the activation of compensatory processes in the face of the adverse effects of the lesion. In addition, the reduction in the levels of the modulating factors also suggests that the signaling pathways in which such factors are implicated would be altered in the brains of patients with schizophrenia. Accordingly, the experimental study of such signaling pathways is likely to aid the development of more effective pharmacological strategies for the treatment of schizophrenia.


Assuntos
Tonsila do Cerebelo/patologia , Comportamento Animal , Espinhas Dendríticas/patologia , Plasticidade Neuronal , Córtex Pré-Frontal/patologia , Esquizofrenia/patologia , Psicologia do Esquizofrênico , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/fisiopatologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Espinhas Dendríticas/metabolismo , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large/metabolismo , Ácido Ibotênico , Masculino , Aprendizagem em Labirinto , Memória de Curto Prazo , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Ratos Sprague-Dawley , Receptores de AMPA/metabolismo , Esquizofrenia/induzido quimicamente , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia , Comportamento Social , Sinaptofisina/metabolismo
9.
Nat Med ; 27(2): 232-238, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33462447

RESUMO

Nearly one billion people worldwide suffer from obsessive-compulsive behaviors1,2, yet our mechanistic understanding of these behaviors is incomplete, and effective therapeutics are unavailable. An emerging perspective characterizes obsessive-compulsive behaviors as maladaptive habit learning3,4, which may be associated with abnormal beta-gamma neurophysiology of the orbitofrontal-striatal circuitry during reward processing5,6. We target the orbitofrontal cortex with alternating current, personalized to the intrinsic beta-gamma frequency of the reward network, and show rapid, reversible, frequency-specific modulation of reward- but not punishment-guided choice behavior and learning, driven by increased exploration in the setting of an actor-critic architecture. Next, we demonstrate that chronic application of the procedure over 5 days robustly attenuates obsessive-compulsive behavior in a non-clinical population for 3 months, with the largest benefits for individuals with more severe symptoms. Finally, we show that convergent mechanisms underlie modulation of reward learning and reduction of obsessive-compulsive symptoms. The results contribute to neurophysiological theories of reward, learning and obsessive-compulsive behavior, suggest a unifying functional role of rhythms in the beta-gamma range, and set the groundwork for the development of personalized circuit-based therapeutics for related disorders.


Assuntos
Corpo Estriado/diagnóstico por imagem , Transtorno Obsessivo-Compulsivo/terapia , Córtex Pré-Frontal/diagnóstico por imagem , Estimulação Elétrica Nervosa Transcutânea , Adulto , Mapeamento Encefálico , Comportamento Compulsivo/diagnóstico por imagem , Comportamento Compulsivo/fisiopatologia , Comportamento Compulsivo/terapia , Corpo Estriado/fisiopatologia , Corpo Estriado/efeitos da radiação , Feminino , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Transtorno Obsessivo-Compulsivo/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Córtex Pré-Frontal/efeitos da radiação
10.
Am J Psychiatry ; 178(4): 343-351, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33472390

RESUMO

OBJECTIVE: Identifying neural correlates of response to psychological treatment may inform targets for interventions designed to treat psychiatric disorders. This study examined the extent to which baseline functioning in reward circuitry is associated with response to psychotherapy in youths with anxiety disorders. METHODS: A randomized clinical trial of cognitive-behavioral therapy compared with supportive therapy was conducted in youths with anxiety disorders. Before treatment, 72 youths (9-14 years old) with anxiety disorders and 37 group-matched healthy comparison youths completed a monetary reward functional MRI task. Treatment response was defined categorically as at least a 35% reduction in diagnostician-rated anxiety severity from pre- to posttreatment assessment. Pretreatment neural activation in the striatum and medial prefrontal cortex (mPFC) during monetary wins relative to losses was examined in relation to treatment response. RESULTS: Responders, nonresponders, and healthy youths differed significantly in mPFC activation to rewards versus losses at baseline. Youths with anxiety exhibited higher mPFC activity relative to healthy youths, although this may have been driven by differences in depressive symptoms. Planned comparisons between treatment responders (N=48) and nonresponders (N=24) also revealed greater pretreatment neural activation in a cluster encompassing the subgenual anterior cingulate cortex and nucleus accumbens among responders. CONCLUSIONS: Striatal activation to reward receipt may not differentiate youths with anxiety from healthy youths. However, higher striatal responsivity to rewards may allow youths with anxiety to improve during treatment, potentially through greater engagement in therapy. Function in reward circuitry may guide development of treatments for youths with anxiety.


Assuntos
Transtornos de Ansiedade/terapia , Encéfalo/diagnóstico por imagem , Terapia Cognitivo-Comportamental/métodos , Recompensa , Adolescente , Transtornos de Ansiedade/diagnóstico por imagem , Transtornos de Ansiedade/fisiopatologia , Transtornos de Ansiedade/psicologia , Encéfalo/fisiopatologia , Criança , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/fisiopatologia , Depressão/psicologia , Feminino , Neuroimagem Funcional , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Núcleo Accumbens/diagnóstico por imagem , Núcleo Accumbens/fisiopatologia , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiopatologia , Psicoterapia/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
11.
Drug Alcohol Depend ; 219: 108498, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33440326

RESUMO

BACKGROUND: Family history (FH) of substance use disorders (SUDs) is known to elevate SUD risk in offspring. However, the influence of FH SUDs has been confounded by the effect of externalizing psychopathologies in the addiction risk neuroimaging literature. Thus, the current study aimed to assess the association between parental SUDs and offspring functional connectivity in samples matched for psychopathology and demographics. METHODS: Ninety 11-12-year-old participants with externalizing disorders were included in the study (48 FH+, 42 FH-). We conducted independent component analyses (ICA) and seed-based analyses (orbitofrontal cortex; OFC, nucleus accumbens (NAcc), dorsolateral prefrontal cortex) with resting state data. RESULTS: FH+ adolescents showed stronger functional connectivity between the right lateral OFC seed and anterior cingulate cortex compared to FH- adolescents (p < 0.05, corrected). Compared to FH-, FH+ adolescents showed stronger negative functional connectivity between the left lateral OFC seed and right postcentral gyrus and between the left NAcc seed and right middle occipital gyrus (p < 0.05, corrected). Poorer emotion regulation was associated with more negative connectivity between right occipital/left NAcc among FH+ adolescents based on the seed-based analysis. FH- adolescents had stronger negative functional connectivity between ventral attention/salience networks and dorsal attention/visuospatial networks in the ICA. CONCLUSIONS: Both analytic methods found group differences in functional connectivity between brain regions associated with executive functioning and regions associated with sensory input (e.g., postcentral gyrus, occipital regions). We speculate that families densely loaded for SUD may confer risk by altered neurocircuitry that is associated with emotion regulation and valuation of external stimuli beyond what would be explained by externalizing psychopathology alone.


Assuntos
Transtornos Relacionados ao Uso de Substâncias/psicologia , Adolescente , Atenção , Função Executiva , Feminino , Giro do Cíngulo/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Núcleo Accumbens/fisiopatologia , Pais , Córtex Pré-Frontal/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia
12.
Drug Alcohol Depend ; 219: 108503, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33444899

RESUMO

BACKGROUND: The neural substrates underlying the relapse behavior of heroin dependents (HD) who received long-term methadone maintenance treatment (MMT) have yet to be thoroughly expounded. This study investigated the relapse-related intrinsic functional hubs of HD and their functional integration feature at whole brain network level. METHODS: 57 male HD receiving MMT and 49 matched healthy controls (HC) were enrolled. All of the subjects received resting-state functional magnetic resonance imaging scan. And the 57 patients were assigned a 26-month follow-up for collecting illegal drug use information. Of them, 11 were non-relapsers and 46 relapsers. We analyzed the voxel-based degree centrality (DC) to reveal the differences in nodule centrality between HD and HC, conducted Pearson partial-correlation analysis to confirm the relationship between relapse frequency and DC value of the nodes with significant intergroup differences, and finally compared the functional connectivity (FC) of the relapse-related hubs between non-relapsers and relapsers. RESULTS: We found the DC values of right insula and left nucleus accumbens (NAc) were negatively correlated with relapse frequency. Compared with the non-relapsers, the relapsers had a significant decreased FC between left NAc and inhibitory control circuitry, including left dorsolateral prefrontal cortex, left inferior frontal gyrus and motor regions. CONCLUSIONS: These findings suggest that the neural substrates of relapse vulnerability in HD undergoing MMT are the intrinsic functional hubs of introceptive and reward systems and the latter modulates relapse behavior via interaction with inhibitory control circuit.


Assuntos
Encéfalo/fisiopatologia , Dependência de Heroína/tratamento farmacológico , Metadona/uso terapêutico , Tratamento de Substituição de Opiáceos , Adulto , Mapeamento Encefálico/métodos , Córtex Cerebral/fisiopatologia , Doença Crônica , Feminino , Heroína/uso terapêutico , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/fisiopatologia , Recidiva
13.
Epilepsia ; 62(1): 107-119, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33238045

RESUMO

OBJECTIVE: To utilize traumatic brain injury (TBI) as a model for investigating functioning during acute stress experiences in psychogenic nonepileptic seizures (PNES) and to identify neural mechanisms underlying the link between changes in processing of stressful experiences and mental health symptoms in PNES. METHODS: We recruited 94 participants: 50 with TBI only (TBI-only) and 44 with TBI and PNES (TBI + PNES). Participants completed mood (Beck Depression Inventory-II), anxiety (Beck Anxiety Inventory), and posttraumatic stress disorder (PTSD) symptom (PTSD Checklist-Specific Event) assessments before undergoing functional magnetic resonance imaging during an acute psychosocial stress task. Linear mixed-effects analyses identified clusters of significant interactions between group and neural responses to stressful math performance and stressful auditory feedback conditions within limbic brain regions (volume-corrected α = .05). Spearman rank correlation tests compared mean cluster signals to symptom assessments (false discovery rate-corrected α = .05). RESULTS: Demographic and TBI-related measures were similar between groups; TBI + PNES demonstrated worse clinical symptom severity compared to TBI-only. Stressful math performance induced relatively greater reactivity within dorsomedial prefrontal cortex (PFC) and right hippocampal regions and relatively reduced reactivity within left hippocampal and dorsolateral PFC regions for TBI + PNES compared to TBI-only. Stressful auditory feedback induced relatively reduced reactivity within ventral PFC, cingulate, hippocampal, and amygdala regions for TBI + PNES compared to TBI-only. Changes in responses to stressful math within hippocampal and dorsal PFC regions were correlated with increased mood, anxiety, and PTSD symptom severity. SIGNIFICANCE: Corticolimbic functions underlying processing of stressful experiences differ between patients with TBI + PNES and those with TBI-only. Relationships between these neural responses and symptom assessments suggest potential pathophysiologic mechanisms in PNES.


Assuntos
Lesões Encefálicas Traumáticas/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Transtorno Conversivo/diagnóstico por imagem , Convulsões/diagnóstico por imagem , Estresse Psicológico/diagnóstico por imagem , Adulto , Ansiedade/psicologia , Transtornos de Ansiedade/psicologia , Encéfalo/fisiopatologia , Lesões Encefálicas Traumáticas/fisiopatologia , Lesões Encefálicas Traumáticas/psicologia , Transtorno Conversivo/fisiopatologia , Transtorno Conversivo/psicologia , Depressão/psicologia , Transtorno Depressivo Maior/psicologia , Transtorno Distímico/psicologia , Feminino , Neuroimagem Funcional , Hipocampo/diagnóstico por imagem , Hipocampo/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiopatologia , Convulsões/fisiopatologia , Convulsões/psicologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Estresse Psicológico/fisiopatologia
14.
Neuroimage ; 224: 117428, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33038536

RESUMO

Childhood maltreatment (CM) is regarded as an important risk factor for major depressive disorder (MDD). However, the neural links corresponding to the process of early CM experience producing brain alterations and then leading to depression later remain unclear. To explore the neural basis of the effects of CM on MDD and the potential role of microRNA-9 (miR-9) in these processes, we recruited 40 unmedicated MDD patients and 34 healthy controls (HCs) to complete resting-state fMRI scans and peripheral blood miR-9 tests. The neural substrates of CM, miR-9, and depression, as well as their interactive effects on intrinsic amygdala functional connectivity (AFC) networks were investigated in MDD patients. Two-step mediation analysis was separately employed to explore whether AFC strength mediates the association among CM severity, miR-9 levels, and depression. A support vector classifier (SVC) model of machine learning was used to distinguish MDD patients from HCs. MDD patients showed higher miR-9 levels that were negatively correlated with CM scores and depressive severity. Overlapping effects of CM, miR-9, and depressive severity on bilateral AFC networks in MDD patients were primarily located in the prefrontal-striatum pathway and limbic system. The connection of amygdala to prefrontal-limbic circuits could mediate the effects of CM severity on the miR-9 levels, as well as the impacts of miR-9 levels on the severity of depression in MDD patients. Furthermore, the SVC model, which integrated miR-9 levels, CM severity, and AFC strength in prefrontal-limbic regions, had good power in differentiating MDD patients from HCs (accuracy 85.1%). MiR-9 may play a crucial role in the process of CM experience-produced brain changes targeting prefrontal-limbic regions and that subsequently leads to depression. The present neuroimaging-epigenetic results provide new insight into our understanding of MDD pathophysiology.


Assuntos
Sobreviventes Adultos de Maus-Tratos Infantis/psicologia , Tonsila do Cerebelo/diagnóstico por imagem , Transtorno Depressivo Maior/diagnóstico por imagem , MicroRNAs/metabolismo , Neostriado/diagnóstico por imagem , Córtex Pré-Frontal/diagnóstico por imagem , Adulto , Tonsila do Cerebelo/fisiopatologia , Estudos de Casos e Controles , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/psicologia , Feminino , Neuroimagem Funcional , Humanos , Sistema Límbico/diagnóstico por imagem , Sistema Límbico/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Análise de Mediação , Pessoa de Meia-Idade , Neostriado/fisiopatologia , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Índice de Gravidade de Doença , Máquina de Vetores de Suporte , Adulto Jovem
15.
Neuroimage ; 224: 117435, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33039622

RESUMO

Inhibitory control underlies the ability to inhibit inappropriate responses and involves processes that suppress motor excitability. Such motor modulatory effect has been largely described during action preparation but very little is known about the neural circuit responsible for its implementation. Here, we addressed this point by studying the degree to which the extent of preparatory suppression relates to brain morphometry. We investigated this relationship in patients suffering from severe alcohol use disorder (AUD) because this population displays an inconsistent level of preparatory suppression and major structural brain damage, making it a suitable sample to measure such link. To do so, 45 detoxified patients underwent a structural magnetic resonance imaging (MRI) and performed a transcranial magnetic stimulation (TMS) experiment, in which the degree of preparatory suppression was quantified. Besides, behavioral inhibition and trait impulsivity were evaluated in all participants. Overall, whole-brain analyses revealed that a weaker preparatory suppression was associated with a decrease in cortical thickness of a medial prefrontal cluster, encompassing parts of the anterior cingulate cortex and superior-frontal gyrus. In addition, a negative association was observed between the thickness of the supplementary area (SMA)/pre-SMA and behavioral inhibition abilities. Finally, we did not find any significant correlation between preparatory suppression, behavioral inhibition and trait impulsivity, indicating that they represent different facets of inhibitory control. Altogether, the current study provides important insight on the neural regions underlying preparatory suppression and allows highlighting that the excitability of the motor system represents a valuable read-out of upstream cognitive processes.


Assuntos
Alcoolismo/diagnóstico por imagem , Giro do Cíngulo/diagnóstico por imagem , Córtex Motor/diagnóstico por imagem , Inibição Neural/fisiologia , Córtex Pré-Frontal/diagnóstico por imagem , Adulto , Alcoolismo/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Espessura Cortical do Cérebro , Potencial Evocado Motor , Feminino , Giro do Cíngulo/fisiopatologia , Humanos , Comportamento Impulsivo , Inibição Psicológica , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Córtex Motor/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Estimulação Magnética Transcraniana
16.
Arch Phys Med Rehabil ; 102(2): 225-232, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32976843

RESUMO

OBJECTIVE: To compare the prefrontal cortex (PFC) activation and task performance during single- and dual-task conditions between typically developing (TD) children and children with hemiplegic cerebral palsy (HCP). DESIGN: A prospective, comparative design. SETTING: Research laboratory. PARTICIPANTS: Participants (N=21) included 12 TD children (age, 6.0±1.1y) and 9 children with HCP (age, 7.2±3.1). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: PFC activation was assessed by measuring the concentration of oxygenated hemoglobin while the children performed a shape-matching task with their more affected arm while sitting on a stable (single task) vs dynamic surface (dual task). The task performance was assessed with the total number of shapes matched, dual-task cost, and reaction time (RT). RESULTS: For both conditions, the children with HCP exhibited greater PFC activation, matched a fewer shapes, and had slower RT than the TD children. These differences were accentuated during the dual-task condition and the dual-task cost was greater. An increase in the PFC activation during the dual-task condition was tightly correlated with a higher dual-task cost in children with HCP (r=0.77, P=.01). CONCLUSIONS: Children with HCP appear to have a heightened amount of PFC activity while performing a dual task. The greater cortical activity may be a result of the finite attentional resources that are shared between both the motor as well as cognitive demands of the task. The cognitive-motor interference is likely exacerbated in children with HCP because of the structural and functional brain changes as a result of an insult to the developing brain.


Assuntos
Paralisia Cerebral/fisiopatologia , Cognição/fisiologia , Hemiplegia/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Análise e Desempenho de Tarefas , Criança , Feminino , Humanos , Masculino , Oxiemoglobinas/análise , Estudos Prospectivos , Extremidade Superior/fisiopatologia
17.
Drug Alcohol Depend ; 218: 108393, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33158664

RESUMO

BACKGROUND: Cortical regions that support cognitive control are increasingly well recognized, but the functional mechanisms that promote such control over emotional and behavioral hyperreactivity to alcohol in recently abstinent alcohol-dependent patients are still insufficiently understood. This study aimed to identify neurophysiological biomarkers of maintaining abstinence in alcohol-dependent individuals after alcohol treatment by investigating the resting-state EEG-based functional connectivity in the cognitive control network (CCN). METHODS: Lagged phase synchronization between CCN areas by means of eLORETA as well as the Barratt Impulsiveness Scale (BIS-11) and Beck Depression Inventory (BDI) were assessed in abstinent alcohol-dependent patients recruited from treatment centers. A preliminary prospective study design was used to classify participants into those who did and did not maintain abstinence during a follow-up period (median 12 months) after discharge from residential treatment. RESULTS: Alcohol-dependent individuals, who maintained abstinence (N = 18), showed significantly increased lagged phase synchronization between the left dorsolateral prefrontal cortex (DLPFC) and the left posterior parietal cortex (IPL) as well as between the right anterior insula cortex/frontal operculum (IA/FO) and the right inferior frontal junction (IFJ) in the delta band compared to those who later relapsed (N = 16). Regression analysis showed that the increased left frontoparietal delta connectivity in the early period of abstinence significantly predicted maintaining abstinence over the ensuing 12 months. Furthermore, right frontoinsular delta connectivity correlated negatively with impulsivity and depression measures. CONCLUSIONS: These results suggest that the increased delta resting-state functional connectivity in the CCN may be a promising neurophysiological predictor of maintaining abstinence in individuals with alcohol dependence.


Assuntos
Abstinência de Álcool/psicologia , Alcoolismo/diagnóstico , Adulto , Alcoolismo/fisiopatologia , Alcoolismo/terapia , Cognição/fisiologia , Emoções , Feminino , Humanos , Comportamento Impulsivo/fisiologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Lobo Parietal/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Prognóstico , Estudos Prospectivos
18.
Neuroimage ; 226: 117570, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33221445

RESUMO

Reading comprehension is a complex task that depends on multiple cognitive and linguistic processes. According to the updated Simple View of Reading framework, in adults, individual variation in reading comprehension can be largely explained by combined variance in three component abilities: (1) decoding accuracy, (2) fluency, and (3) language comprehension. Here we asked whether the neural correlates of the three components are different in adults with dyslexia as compared to typically-reading adults and whether the relative contribution of these correlates to reading comprehension is similar in the two groups. We employed a novel naturalistic fMRI reading task to identify the neural correlates of individual differences in the three components using whole-brain and literature-driven regions-of-interest approaches. Across all participants, as predicted by the Simple View framework, we found distinct patterns of associations with linguistic and domain-general regions for the three components, and that the left-hemispheric neural correlates of language comprehension in the angular and posterior temporal gyri made the largest contributions to explaining out-of-scanner reading comprehension performance. These patterns differed between the two groups. In typical adult readers, better fluency was associated with greater activation of left occipitotemporal regions, better comprehension with lesser activation in prefrontal and posterior parietal regions, and there were no significant associations with decoding. In adults with dyslexia, better fluency was associated with greater activation of bilateral inferior parietal regions, better comprehension was associated with greater activation in some prefrontal clusters and lower in others, and better decoding skills were associated with lesser activation of bilateral prefrontal and posterior parietal regions. Extending the behavioral findings of skill-level differences in the relative contribution of the three components to reading comprehension, the relative contributions of the neural correlates to reading comprehension differed based on dyslexia status. These findings reveal some of the neural correlates of individual differences in the three components and the underlying mechanisms of reading comprehension deficits in adults with dyslexia.


Assuntos
Encéfalo/diagnóstico por imagem , Compreensão , Dislexia/diagnóstico por imagem , Idioma , Leitura , Adolescente , Adulto , Encéfalo/fisiologia , Encéfalo/fisiopatologia , Mapeamento Encefálico , Estudos de Casos e Controles , Dislexia/fisiopatologia , Feminino , Neuroimagem Funcional , Humanos , Imageamento por Ressonância Magnética , Masculino , Lobo Occipital/diagnóstico por imagem , Lobo Occipital/fisiologia , Lobo Occipital/fisiopatologia , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/fisiologia , Lobo Parietal/fisiopatologia , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiologia , Córtex Pré-Frontal/fisiopatologia , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/fisiologia , Lobo Temporal/fisiopatologia , Adulto Jovem
19.
Am J Psychiatry ; 178(4): 333-342, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32731811

RESUMO

OBJECTIVE: Disrupted reward processing is implicated in the etiology of disruptive behavior disorders (DBDs) and callous-unemotional traits. However, neuroimaging investigations of reward processing underlying these phenotypes remain sparse. The authors examined neural sensitivity in response to reward anticipation and receipt among youths with DBDs, with and without callous-unemotional traits. METHODS: Data were obtained from the Adolescent Brain and Cognitive Development Study (mean age=9.51 years [SD=0.50]; 49% female). Reward-related activation during the monetary incentive delay task was examined across 16 brain regions, including the amygdala, anterior cingulate cortex (ACC), nucleus accumbens (NAcc), and orbitofrontal cortex (OFC). Latent variable modeling was used to examine network-level coactivation. The following diagnostic groups were compared: typically developing youths (N=693) and youths with DBDs (N=995), subdivided into those with callous-unemotional traits (DBD+CU, N=198) and without callous-unemotional traits (DBD only, N=276). RESULTS: During reward anticipation, youths in the overall DBD group (with and without callous-unemotional traits) showed decreased dorsal ACC activation compared with typically developing youths. The DBD-only group exhibited reduced ventral and dorsal striatal activity compared with the DBD+CU and typically developing groups. During reward receipt, youths with DBDs showed increased cortical (e.g., OFC) and subcortical (e.g., NAcc) regional activation compared with typically developing youths. The DBD+CU group demonstrated greater activation in several regions compared with those in the typically developing (e.g., amygdala) and DBD-only (e.g., dorsal ACC) groups. At the network level, the DBD-only group showed reduced anticipatory reward activation compared with the typically developing and DBD+CU groups, whereas youths in the DBD+CU group showed increased activation during reward receipt compared with those in the typically developing group. CONCLUSIONS: These findings advance our understanding of unique neuroetiologic pathways to DBDs and callous-unemotional traits.


Assuntos
Transtornos de Deficit da Atenção e do Comportamento Disruptivo/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Transtorno da Conduta/diagnóstico por imagem , Recompensa , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/fisiopatologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/fisiopatologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/psicologia , Encéfalo/fisiopatologia , Criança , Transtorno da Conduta/fisiopatologia , Transtorno da Conduta/psicologia , Feminino , Neuroimagem Funcional , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/fisiopatologia , Humanos , Masculino , Núcleo Accumbens/diagnóstico por imagem , Núcleo Accumbens/fisiopatologia , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiopatologia
20.
Psychopharmacology (Berl) ; 238(5): 1351-1361, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33241479

RESUMO

RATIONALE AND OBJECTIVES: Cognitive processing impairments have been associated with acute cannabis use, but there is mixed evidence regarding the cognitive effects of chronic cannabis use. Several neuroimaging studies have noted selective-attention processing differences in those who chronically use cannabis, but the neural dynamics governing the altered processing is unclear. METHODS: Twenty-four adults reporting at least weekly cannabis use in the past 6 months on the Cannabis Use Disorder Identification Test - Revised were compared to 24 demographically matched controls who reported no prior cannabis use. All participants completed a visual selective attention processing task while undergoing magnetoencephalography. Time-frequency windows of interest were identified using a data-driven method, and spectrally specific neural activity was imaged using a beamforming approach. RESULTS: All participants performed within normal range on the cognitive task. Regular cannabis users displayed an aberrant cognitive interference effect in the theta (4-8 Hz) frequency range shortly after stimulus onset (i.e., 0-250 ms) in the right occipital cortex. Cannabis users also exhibited altered functional connectivity between the right prefrontal cortex and right occipital cortices in comparison to controls. CONCLUSIONS: Individuals with a history of regular cannabis use exhibited abnormal theta interference activity in the occipital cortices, as well as altered prefrontal-occipital functional connectivity in the theta range during a visual selective attention task. Such differences may reflect compensatory processing, as these participants performed within normal range on the task. Understanding the neural dynamics in chronic, regular cannabis users may provide insight on how long-term and/or frequent use may affect neural networks underlying cognitive processes.


Assuntos
Atenção/fisiologia , Magnetoencefalografia , Uso da Maconha/psicologia , Adulto , Cognição , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Lobo Occipital/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Percepção Visual , Adulto Jovem
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