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BACKGROUND: Response inhibition - or the ability to withhold a suboptimal response - relies on the efficacy of fronto-striatal networks, and is impaired in neuropsychiatric disorders including addiction. Cortical paired associative stimulation (cPAS) is a form of transcranial magnetic stimulation (TMS) which can strengthen neuronal connections via spike-timing-dependent plasticity mechanisms. Here, we used cPAS targeting the fronto-striatal inhibitory network to modulate performance on a response inhibition measure in chronic alcohol use. METHODS: Fifty-five participants (20 patients with a formal alcohol use disorder (AUD) diagnosis (26-74 years, 6[30%] females) and 20 matched healthy controls (HCs) (27-73 years, 6[30%] females) within a larger sample of 35 HCs (23-84 years, 11[31.4%] females) underwent two randomized sessions of cPAS 1-week apart: right inferior frontal cortex stimulation preceding right presupplementary motor area stimulation by either 4 ms (excitation condition) or 100 ms (control condition), and were subsequently administered the Stop Signal Task (SST) in both sessions. RESULTS: HCs showed decreased stop signal reaction time in the excitation condition (t(19) = -3.01, p = 0.007, [CIs]:-35.6 to -6.42); this facilitatory effect was not observed for AUD (F(1,31) = 9.57, p = 0.004, CIs: -68.64 to -14.11). Individually, rates of SST improvement were substantially higher for healthy (72%) relative to AUD (13.6%) groups (OR: 2.33, p = 0.006, CIs:-3.34 to -0.55). CONCLUSION: In line with previous findings, cPAS improved response inhibition in healthy adults by strengthening the fronto-striatal network through putative long-term potentiation-like plasticity mechanisms. Furthermore, we identified a possible marker of impaired cortical excitability, and, thus, diminished capacity for cPAS-induced neuroplasticity in AUD with direct implications to a disorder-relevant cognitive process.
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Alcoolismo , Córtex Motor , Adulto , Feminino , Humanos , Masculino , Alcoolismo/terapia , Inibição Psicológica , Potenciação de Longa Duração/fisiologia , Plasticidade Neuronal/fisiologia , Estimulação Magnética Transcraniana , Pessoa de Meia-Idade , Idoso , Adulto Jovem , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Decision making is frequently associated with risk taking under uncertainty. Elevated intolerance of uncertainty is suggested to be a critical feature of obsessive-compulsive disorder (OCD). However, impairments of latent constructs of uncertainty processing and its neural correlates remain unclear in OCD. METHODS: In 83 participants (24 OCD patients treated with capsulotomy, 28 OCD control participants, and 31 healthy control participants), we performed magnetic resonance imaging using a card gambling task in which participants made decisions whether to bet or not that the next card would be larger than the current one. A hierarchical drift diffusion model was used to dissociate speed and amount of evidence accumulated before a decisional threshold (i.e., betting or no betting) was reached. RESULTS: High uncertainty was characterized by a smaller amount of evidence accumulation (lower thresholds), thus dissociating uncertainty from conflict tasks and highlighting the specificity of this task to test value-based uncertainty. OCD patients exhibited greater caution with poor performance and greater evidence accumulation overall along with slower speed of accumulation, particularly under low uncertainty. Bilateral dorsal anterior cingulate and anterior insula distinguished high- and low-uncertainty decision processes in healthy control participants but not in the OCD groups, indicating impairments in anticipation of differences in outcome variance and salience network activity. There were no behavioral or imaging differences relating to capsulotomy despite improvements in OCD symptoms. CONCLUSIONS: Our findings highlight greater impairments particularly in more certain trials in the OCD groups along with impaired neural differentiation of high and low uncertainty and suggest uncertainty processing as a trait cognitive endophenotype rather than a state-specific factor.
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Tomada de Decisões , Transtorno Obsessivo-Compulsivo , Humanos , Incerteza , Transtorno Obsessivo-Compulsivo/psicologia , Giro do CínguloRESUMO
Ablative procedures such as anterior capsulotomy are potentially effective in refractory obsessive-compulsive disorder (OCD). Converging evidence suggests the ventral internal capsule white matter tracts traversing the rostral cingulate and ventrolateral prefrontal cortex and thalamus is the optimal target for clinical efficacy across multiple deep brain stimulation targets for OCD. Here we ask which prefrontal regions and underlying cognitive processes might be implicated in the effects of capsulotomy by using both task fMRI and neuropsychological tests assessing OCD-relevant cognitive mechanisms known to map across prefrontal regions connected to the tracts targeted in capsulotomy. We tested OCD patients at least 6 months post-capsulotomy (n = 27), OCD controls (n = 33) and healthy controls (n = 34). We used a modified aversive monetary incentive delay paradigm with negative imagery and a within session extinction trial. Post-capsulotomy OCD subjects showed improved OCD symptoms, disability and quality of life with no differences in mood or anxiety or cognitive task performance on executive, inhibition, memory and learning tasks. Task fMRI revealed post-capsulotomy decreases in the nucleus accumbens during negative anticipation, and in the left rostral cingulate and left inferior frontal cortex during negative feedback. Post-capsulotomy patients showed attenuated accumbens-rostral cingulate functional connectivity. Rostral cingulate activity mediated capsulotomy improvement on obsessions. These regions overlap with optimal white matter tracts observed across multiple stimulation targets for OCD and might provide insights into further optimizing neuromodulation approaches. Our findings also suggest that aversive processing theoretical mechanisms may link ablative, stimulation and psychological interventions.
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Estimulação Encefálica Profunda , Transtorno Obsessivo-Compulsivo , Humanos , Qualidade de Vida , Procedimentos Neurocirúrgicos/métodos , Resultado do Tratamento , Transtorno Obsessivo-Compulsivo/cirurgia , Transtorno Obsessivo-Compulsivo/psicologia , Imageamento por Ressonância MagnéticaRESUMO
In this study, we designed a new transcranial magnetic stimulation (TMS) protocol using a dual-target accelerated transcranial magnetic stimulation (aTMS) for patients with treatment resistant depression (TRD). There are 58 TRD patients were recruited from the Second People's Hospital of Guizhou Province, who were, respectively, received dual-target (real continuous theta burst stimulation (cTBS) at right orbitofrontal cortex (OFC) and real repetitive transcranial magnetic stimulation (rTMS) at left dorsolateral prefrontal cortex (DLPFC)), single- target (sham cTBS at right OFC and real rTMS at left DLPFC), and sham stimulation (sham cTBS at right OFC and sham rTMS at left DLPFC). Resting-state functional magnetic resonance imaging (rs-fMRI) was acquired before and after aTMS treatment to compare characteristics of brain activities by use of amplitude of low-frequency fluctuations (ALFF), fractional low-frequency fluctuations (fALFF) and functional connectivity (FC). At the same time, Hamilton Depression Scale-24 (HAMD24) were conducted to assess the effect. HAMD24 scores reduced significantly in dual group comparing to the single and sham group. Dual-target stimulation decreased not only the ALFF values of right fusiform gyrus (FG) and fALFF values of the left superior temporal gyrus (STG), but also the FC between the right FG and the bilateral middle frontal gyrus (MFG), left triangular part of inferior frontal gyrus (IFG). Higher fALFF value in left STG at baseline may predict better reaction for bilateral arTMS. Dual-targe stimulation can significantly change resting-state brain activities and help to improve depressive symptoms.
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BACKGROUND: Language deficits frequently occur during the prodromal stages of Alzheimer's disease (AD). However, the characteristics of linguistic impairment and its underlying mechanism(s) remain to be explored for the early diagnosis of AD. METHODS: The percentage of silence duration (PSD) of 324 subjects was analyzed, including patients with AD, amnestic mild cognitive impairment (aMCI), and normal controls (NC) recruited from the China multi-center cohort, and the diagnostic efficiency was replicated from the Pitt center cohort. Furthermore, the specific language network involved in the fragmented speech was analyzed using task-based functional magnetic resonance. RESULTS: In the China cohort, PSD increased significantly in aMCI and AD patients. The area under the curve of the receiver operating characteristic curves is 0.74, 0.84, and 0.80 in the classification of NC/aMCI, NC/AD, and NC/aMCI+AD. In the Pitt center cohort, PSD was verified as a reliable diagnosis biomarker to differentiate mild AD patients from NC. Next, in response to fluency tasks, clusters in the bilateral inferior frontal gyrus, precentral gyrus, left inferior temporal gyrus, and inferior parietal lobule deactivated markedly in the aMCI/AD group (cluster-level P < 0.05, family-wise error (FWE) corrected). In the patient group (AD+aMCI), higher activation level of the right pars triangularis was associated with higher PSD in in both semantic and phonemic tasks. CONCLUSIONS: PSD is a reliable diagnostic biomarker for the early stage of AD and aMCI. At as early as aMCI phase, the brain response to fluency tasks was inhibited markedly, partly explaining why PSD was elevated simultaneously.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Testes Neuropsicológicos , Estudos Transversais , Fala , Disfunção Cognitiva/diagnóstico , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Encéfalo/patologia , Imageamento por Ressonância Magnética , Estudos de Coortes , BiomarcadoresRESUMO
OBJECTIVES: Substance use disorder (SUD) is characterized by compulsive use of addictive substances with considerable impact on both the medical system and society as a whole. The craving of substances leads to relapse in the majority of patients within one year of traditional treatments. In recent decades, neuromodulation approaches have emerged as potential novel treatments of SUD, but the ideal neural target remains contentious. MATERIALS AND METHODS: In this review, we discuss new insights on the anterior cingulate cortex (ACC) as a neuromodulation target for SUD. RESULTS AND CONCLUSION: First, we illustrate that the ACC serves as a central "hub" in addiction-related neural networks of cognitive functions, including, but not limited to, decision-making, cognitive inhibition, emotion, and motivation. Then, we summarize the literature targeting the ACC to treat SUDs via available neuromodulation approaches. Finally, we propose potential directions to improve the effect of stimulating the ACC in SUD treatment. We emphasize that the ACC can be divided into at least four sub-regions, which have distinctive functions and connections. Studies focusing on these sub-regions may help to develop more precise and effective ACC stimulation according to patients' symptom profiles and cognitive deficits.
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BACKGROUND: Identifying risk factors and mortality of individuals with Alzheimer's disease (AD) could have important implications for the clinical management of AD. OBJECTIVE: This pilot study aimed to examine the overall mortality of AD patients over a 10-year surveillance period in Shanghai, China. This study is an extension of our previous investigation on mortality of neurodegenerative diseases. METHODS: One hundred and thirty-two AD patients recruited from the memory clinics of two hospitals in Shanghai in 2007 were followed up until December 31, 2017 or death, representing a follow-up period of up to 10 years. Overall standardized mortality ratios (SMRs) were calculated, and predictors for survival at recruitment were estimated. RESULTS: Sixty-seven patients had died by December 31, 2017, and the SMR at 10 years of follow-up was 1.225 (95% confidence interval 0.944-1.563). Employing Cox's proportional hazard modeling, lower Mini-Mental State Examination score, and comorbid diabetes predicted poor survival in this cohort. CONCLUSION: This pilot study suggests a similar survival trend of patients with AD compared to the general population in Shanghai urban region. Poor cognitive status and comorbid diabetes had a negative impact on the survival of AD patients.
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Doença de Alzheimer/fisiopatologia , Diabetes Mellitus Tipo 2/epidemiologia , Mortalidade , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , China/epidemiologia , Estudos de Coortes , Comorbidade , Feminino , Seguimentos , Humanos , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Projetos Piloto , Modelos de Riscos Proporcionais , Fatores de RiscoRESUMO
A major hallmark of Parkinson's disease (PD) is the degeneration of dopaminergic neurons in the substantia nigra, and the causative mechanism is thought to be the activation of programmed neuronal death. Necroptosis is a regulated process of cell death triggered by RIPK1. Although the pathophysiology of PD has been studied extensively, the cellular mechanism underlying dopaminergic neuron death remains unclear. In this study, we detected a specific miRNA, miR-425, in response to MPTP toxicity and dopaminergic degeneration. In MPTP-treated mice, we observed necroptosis activation and miR-425 deficiency in the substantia nigra, which is correlated with dopaminergic neuron loss. This miRNA targeted RIPK1 transcripts and promoted the phosphorylation of MLKL and necroptosis. Similarly, in the brains of PD patients, miR-425 deficiency and necroptosis activation were also confirmed in dopaminergic neuron. Furthermore, we found that genetic knockdown of miR-425 aggravated MPTP-induced motor deficits and dopaminergic neurodegeneration via early upregulation of necroptotic genes. Intracerebral miR-425 mimics (AgomiR-425) treatment attenuated necroptosis activation and dopaminergic neuron loss, and improved locomotor behaviors. In conclusion, our study suggests that miR-425 deficiency triggers necroptosis of dopaminergic neurons, and targeting miR-425 in MPTP-treated mice restored dysfunctional dopaminergic neurodegeneration and ameliorated behavioral deficits. These findings identify brain delivery of miR-425 as a potential therapeutic approach for the treatment of PD.
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Neurônios Dopaminérgicos/metabolismo , MicroRNAs/metabolismo , Necroptose/genética , Degeneração Neural/genética , Doença de Parkinson/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Animais , Antagomirs/genética , Modelos Animais de Doenças , Dopamina/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Locomoção/efeitos dos fármacos , Locomoção/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , MicroRNAs/genética , Necroptose/efeitos dos fármacos , Neurotoxinas/farmacologia , Células PC12 , Doença de Parkinson/patologia , Ratos , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , TransfecçãoRESUMO
Rho-associated coiled-coil kinase 1 (ROCK1) is proposed to be implicated in Aß suppression; however, the role for ROCK1 in amyloidogenic metabolism of amyloid precursor protein (APP) to produce Aß was unknown. In the present study, we showed that ROCK1 kinase activity and its APP binding were enhanced in AD brain, resulting in increased ß-secretase cleavage of APP. Furthermore, we firstly confirmed that APP served as a substrate for ROCK1 and its major phosphorylation site was located at Ser655. The increased level of APP Ser655 phosphorylation was observed in the brain of APP/PS1 mice and AD patients compared to controls. Moreover, blockade of APP Ser655 phosphorylation, or inhibition of ROCK1 activity with either shRNA knockdown or Y-27632, ameliorated amyloid pathology and improved learning and memory in APP/PS1 mice. These findings suggest that activated ROCK1 targets APP Ser655 phosphorylation, which promotes amyloid processing and pathology. Inhibition of ROCK1 could be a potential therapeutic approach for AD.
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Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/metabolismo , Fosfosserina/metabolismo , Quinases Associadas a rho/metabolismo , Doença de Alzheimer/tratamento farmacológico , Amidas/farmacologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Células Cultivadas , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , RNA Interferente Pequeno/farmacologia , Quinases Associadas a rho/antagonistas & inibidoresRESUMO
BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is thought to be effective in alleviating cognitive symptoms in patients with amnestic mild cognitive impairment (aMCI), but the mechanisms related to network modification are poorly understood. OBJECTIVE: Here we tested rTMS efficacy and explored the effect of rTMS-induced changes in the default mode network (DMN) and their predictive value for treatment response. METHODS: Twenty-one subjects clinically diagnosed with aMCI were recruited to complete a 10-session randomized and sham-controlled rTMS treatment targeting the right dorsolateral prefrontal cortex. Resting-state functional magnetic resonance imaging in tandem with neuropsychological assessments were administered before and after the intervention. Changes in functional connectivity of the DMN and relevant brain regions, as well as the correlations between baseline functional connectivity and clinical rating scales were calculated in order to elucidate the mechanism of treatment response to rTMS therapy. RESULTS: Compared to the sham group, the rTMS group achieved improvement of neuropsychological performance and significant functional connectivity changes within the DMN. Group×Time interactions were found between posterior cingulate gyrus and right fusiform gyrus (F (1,19) â=â17.154, pâ=â0.001), and also left anterior cingulate gyrus (F (1,19) â=â3.908, pâ=â0.063), showing an rTMS-induced deactivation of functional connectivity within the DMN. Baseline functional connectivity analysis of seeds within the DMN in the rTMS group revealed negative correlation with AVLT-Recognition score changes. CONCLUSION: rTMS-induced hypoconnectivity within DMN is associated with clinical cognitive improvements in patients with aMCI. Further, pre-rTMS baseline activity of the DMN at rest may be a predictor for favorable rTMS treatment response.
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Disfunção Cognitiva/terapia , Estimulação Transcraniana por Corrente Contínua , Idoso , Idoso de 80 Anos ou mais , Amnésia/terapia , Cognição , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Causative mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) account for a majority of cases of familial Alzheimer disease (FAD) inherited in an autosomal-dominant pattern. For the sake of characterizing mutations, index patients from 148 families with FAD were enrolled from mainland China. Sanger sequencing of the genes APP, PSEN1, and PSEN2 was performed to characterize the mutation spectrum of the Chinese population. Thirteen of 148 (8.8%) individuals had possible pathogenic APP, PSEN1, or PSEN2 variants, including 2 (15.4%) APP variants, 8 (61.5%) PSEN1 variants, and 3 (23.1%) PSEN2 variants. PSEN1 variants represented the largest proportion in Chinese FAD, and PSEN2 variants are responsible for late-onset FAD in China. Analysis of genetic-clinical correlations permitted the conclusion that FAD phenotypes were mainly influenced by specific genetic defects.
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Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Mutação , Presenilina-1/genética , Presenilina-2/genética , Adulto , Idoso , Povo Asiático/genética , Feminino , Genes Dominantes , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , FenótipoRESUMO
BACKGROUND: Chinese guidelines for management of Parkinson's disease (PD) have been issued and updated regularly since 2006. We undertook a cross-sectional survey to evaluate the impact of the latest edition (2014) on current approaches to the management of PD based on previous pilot works. METHODS: Seven hundred and seventeen participants, divided into 3 groups (GPs, Neurologists, and Specialists), recruited from 138 randomly chosen hospitals from 30 cities across China, participated by completing the questionnaire describing their current approaches before and after the guidelines were issued. RESULTS: Considerable discrepancies in management were apparent across the three categories, with different selection of first-choice medication for PD patients. There were also variations in management of concurrent psychiatric symptoms and dementia. Notably, over 50% of participants reported improvements in PD recognition and management by following the guidelines. CONCLUSIONS: The increasing use of Chinese clinical practice guidelines for PD management is having a positive impact on the optimization of care, which in turn offers important economic benefits.