RESUMO
BACKGROUND: Alzheimer's disease (AD) is a major public health issue. Cognitive interventions such as computerized cognitive trainings (CCT) are effective in attenuating cognitive decline in AD. However, in those at risk of dementia related to AD, results are heterogeneous. Efficacy and feasibility of CCT needs to be explored in depth. Moreover, underlying mechanisms of CCT effects on the three cognitive domains typically affected by AD (episodic memory, semantic memory and spatial abilities) remain poorly understood. METHODS: In this bi-centric, randomized controlled trial (RCT) with parallel groups, participants (planned N = 162, aged 60-85 years) at risk for AD and with at least subjective cognitive decline will be randomized to one of three groups. We will compare serious game-based CCT against a passive wait list control condition and an active control condition (watching documentaries). Training will consist of daily at-home sessions for 10 weeks (50 sessions) and weekly on-site group meetings. Subsequently, the CCT group will continue at-home training for an additional twenty-weeks including monthly on-site booster sessions. Investigators conducting the cognitive assessments will be blinded. Group leaders will be aware of participants' group allocations. Primarily, we will evaluate change using a compound value derived from the comprehensive cognitive assessment for each of three cognitive domains. Secondary, longitudinal functional and structural magnetic resonance imaging (MRI) and evaluation of blood-based biomarkers will serve to investigate neuronal underpinnings of expected training benefits. DISCUSSION: The present study will address several shortcomings of previous CCT studies. This entails a comparison of serious game-based CCT with both a passive and an active control condition while including social elements crucial for training success and adherence, the combination of at-home and on-site training, inclusion of booster sessions and assessment of physiological markers. Study outcomes will provide information on feasibility and efficacy of serious game-based CCT in older adults at risk for AD and will potentially generalize to treatment guidelines. Moreover, we set out to investigate physiological underpinnings of CCT induced neuronal changes to form the grounds for future individually tailored interventions and neuro-biologically informed trainings. TRIAL REGISTRATION: This RCT was registered 1st of July 2020 at clinicaltrials.gov (Identifier NCT04452864).
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Memória Episódica , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/terapia , Cognição/fisiologia , Disfunção Cognitiva/psicologia , Disfunção Cognitiva/terapia , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
The initial stages of neurodegeneration are commonly marked by normal levels of cognitive and motor performance despite the presence of structural brain pathology. Compensation is widely assumed to account for this preserved behaviour, but despite the apparent simplicity of such a concept, it has proven incredibly difficult to demonstrate such a phenomenon and distinguish it from disease-related pathology. Recently, we developed a model of compensation whereby brain activation, behaviour and pathology, components key to understanding compensation, have specific longitudinal trajectories over three phases of progression. Here, we empirically validate our explicit mathematical model by testing for the presence of compensation over time in neurodegeneration. Huntington's disease is an ideal model for examining longitudinal compensation in neurodegeneration as it is both monogenic and fully penetrant, so disease progression and potential compensation can be monitored many years prior to diagnosis. We defined our conditions for compensation as non-linear longitudinal trajectories of brain activity and performance in the presence of linear neuronal degeneration and applied our model of compensation to a large longitudinal cohort of premanifest and early-stage Huntington's disease patients from the multisite Track-On HD study. Focusing on cognitive and motor networks, we integrated progressive volume loss, task and resting state functional MRI and cognitive and motor behaviour across three sequential phases of neurodegenerative disease progression, adjusted for genetic disease load. Multivariate linear mixed models were fitted and trajectories for each variable tested. Our conceptualization of compensation was partially realized across certain motor and cognitive networks at differing levels. We found several significant network trends that were more complex than that hypothesized in our model. These trends suggest changes to our theoretical model where the network effects are delayed relative to performance effects. There was evidence of compensation primarily in the prefrontal component of the cognitive network, with increased effective connectivity between the left and right dorsolateral prefrontal cortex. Having developed an operational model for the explicit testing of longitudinal compensation in neurodegeneration, it appears that general patterns of our framework are consistent with the empirical data. With the proposed modifications, our operational model of compensation can be used to test for both cross-sectional and longitudinal compensation in neurodegenerative disease with similar patterns to Huntington's disease.
Assuntos
Mapeamento Encefálico/métodos , Doença de Huntington/patologia , Doença de Huntington/terapia , Adulto , Encéfalo/patologia , Cognição/fisiologia , Estudos de Coortes , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Destreza Motora/fisiologia , Vias Neurais/fisiopatologia , Doenças Neurodegenerativas/patologia , Testes NeuropsicológicosRESUMO
Inter-hemispheric asymmetries are a common phenomenon of the human brain. Some evidence suggests that neurodegeneration related to aging and disease may preferentially affect the left-usually language- and motor-dominant-hemisphere. Here, we used activation likelihood estimation meta-analysis to assess gray matter (GM) loss and its lateralization in healthy aging and in neurodegeneration, namely, mild cognitive impairment (MCI), Alzheimer's dementia (AD), Parkinson's disease (PD), and Huntington's disease (HD). This meta-analysis, comprising 159 voxel-based morphometry publications (enrolling 4,469 patients and 4,307 controls), revealed that GM decline appeared to be asymmetric at trend levels but provided no evidence for increased left-hemisphere vulnerability. Regions with asymmetric GM decline were located in areas primarily affected by neurodegeneration. In HD, the left putamen showed converging evidence for more pronounced atrophy, while no consistent pattern was found in PD. In MCI, the right hippocampus was more atrophic than its left counterpart, a pattern that reversed in AD. The stability of these findings was confirmed using permutation tests. However, due to the lenient threshold used in the asymmetry analysis, further work is needed to confirm our results and to provide a better understanding of the functional role of GM asymmetries, for instance in the context of cognitive reserve and compensation. Hum Brain Mapp 38:5890-5904, 2017. © 2017 Wiley Periodicals, Inc.
Assuntos
Envelhecimento/patologia , Encéfalo/patologia , Substância Cinzenta/patologia , Doenças Neurodegenerativas/patologia , Encéfalo/diagnóstico por imagem , Lateralidade Funcional , Substância Cinzenta/diagnóstico por imagem , Humanos , Doenças Neurodegenerativas/diagnóstico por imagemRESUMO
Huntington's disease (HD) is a progressive neurodegenerative disorder that can be diagnosed with certainty decades before symptom onset. Studies using structural MRI have identified grey matter (GM) loss predominantly in the striatum, but also involving various cortical areas. So far, voxel-based morphometric studies have examined each brain region in isolation and are thus unable to assess the changes in the interrelation of brain regions. Here, we examined the structural covariance in GM volumes in pre-specified motor, working memory, cognitive flexibility, and social-affective networks in 99 patients with manifest HD (mHD), 106 presymptomatic gene mutation carriers (pre-HD), and 108 healthy controls (HC). After correction for global differences in brain volume, we found that increased GM volume in one region was associated with increased GM volume in another. When statistically comparing the groups, no differences between HC and pre-HD were observed, but increased positive correlations were evident for mHD, relative to pre-HD and HC. These findings could be explained by a HD-related neuronal loss heterogeneously affecting the examined network at the pre-HD stage, which starts to dominate structural covariance globally at the manifest stage. Follow-up analyses identified structural connections between frontoparietal motor regions to be linearly modified by disease burden score (DBS). Moderator effects of disease load burden became significant at a DBS level typically associated with the onset of unequivocal HD motor signs. Together with existing findings from functional connectivity analyses, our data indicates a critical role of these frontoparietal regions for the onset of HD motor signs.
Assuntos
Mapeamento Encefálico , Encéfalo/patologia , Encéfalo/fisiopatologia , Doença de Huntington/patologia , Modelos Neurológicos , Vias Neurais/patologia , Adulto , Cognição , Feminino , Humanos , Doença de Huntington/genética , Doença de Huntington/fisiopatologia , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Memória de Curto Prazo/fisiologia , Pessoa de Meia-Idade , Movimento/fisiologia , Vias Neurais/fisiopatologia , Testes Neuropsicológicos , Comportamento Social , Adulto JovemRESUMO
While the HTT CAG-repeat expansion mutation causing Huntington's disease (HD) is highly correlated with the rate of pathogenesis leading to disease onset, considerable variance in age-at-onset remains unexplained. Therefore, other factors must influence the pathogenic process. We asked whether these factors were related to natural biological variation in the sensory-motor system. In 243 participants (96 premanifest and 35 manifest HD; 112 controls), sensory-motor structural MRI, tractography, resting-state fMRI, electrophysiology (including SEP amplitudes), motor score ratings, and grip force as sensory-motor performance were measured. Following individual modality analyses, we used principal component analysis (PCA) to identify patterns associated with sensory-motor performance, and manifest versus premanifest HD discrimination. We did not detect longitudinal differences over 12 months. PCA showed a pattern of loss of caudate, grey and white matter volume, cortical thickness in premotor and sensory cortex, and disturbed diffusivity in sensory-motor white matter tracts that was connected to CAG repeat length. Two further major principal components appeared in controls and HD individuals indicating that they represent natural biological variation unconnected to the HD mutation. One of these components did not influence HD while the other non-CAG-driven component of axial versus radial diffusivity contrast in white matter tracts were associated with sensory-motor performance and manifest HD. The first component reflects the expected CAG expansion effects on HD pathogenesis. One non-CAG-driven component reveals an independent influence on pathogenesis of biological variation in white matter tracts and merits further investigation to delineate the underlying mechanism and the potential it offers for disease modification. Hum Brain Mapp 37:4615-4628, 2016. © 2016 Wiley Periodicals, Inc.
Assuntos
Doença de Huntington/diagnóstico por imagem , Doença de Huntington/fisiopatologia , Córtex Sensório-Motor/diagnóstico por imagem , Córtex Sensório-Motor/fisiopatologia , Substância Branca/diagnóstico por imagem , Substância Branca/fisiopatologia , Adulto , Variação Biológica Individual , Mapeamento Encefálico , Estudos Transversais , Imagem de Tensor de Difusão , Potenciais Somatossensoriais Evocados , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/fisiopatologia , Força da Mão/fisiologia , Humanos , Doença de Huntington/genética , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Atividade Motora/fisiologia , Tamanho do Órgão , Análise de Componente Principal , Sintomas Prodrômicos , Descanso , Expansão das Repetições de TrinucleotídeosRESUMO
Clinical Alzheimer's disease affects both cerebral hemispheres to a similar degree in clinically typical cases. However, in atypical variants like logopenic progressive aphasia, neurodegeneration often presents asymmetrically. Yet, no in vivo imaging study has investigated whether lateralized neurodegeneration corresponds to lateralized amyloid-ß burden. Therefore, using combined (11)C-Pittsburgh compound B and (18)F-fluorodeoxyglucose positron emission tomography, we explored whether asymmetric amyloid-ß deposition in Alzheimer's disease is associated with asymmetric hypometabolism and clinical symptoms. From our database of patients who underwent positron emission tomography with both (11)C-Pittsburgh compound B and (18)F-fluorodeoxyglucose (n = 132), we included all amyloid-positive patients with prodromal or mild-to-moderate Alzheimer's disease (n = 69). The relationship between (11)C-Pittsburgh compound B binding potential and (18)F-fluorodeoxyglucose uptake was assessed in atlas-based regions of interest covering the entire cerebral cortex. Lateralizations of amyloid-ß and hypometabolism were tested for associations with each other and with type and severity of cognitive symptoms. Positive correlations between asymmetries of Pittsburgh compound B binding potential and hypometabolism were detected in 6 of 25 regions (angular gyrus, middle frontal gyrus, middle occipital gyrus, superior parietal gyrus, inferior and middle temporal gyrus), i.e. hypometabolism was more pronounced on the side of greater amyloid-ß deposition (range: r = 0.41 to 0.53, all P < 0.001). Stronger leftward asymmetry of amyloid-ß deposition was associated with more severe language impairment (P < 0.05), and stronger rightward asymmetry with more severe visuospatial impairment (at trend level, P = 0.073). Similarly, patients with predominance of language deficits showed more left-lateralized amyloid-ß burden and hypometabolism than patients with predominant visuospatial impairment and vice versa in several cortical regions. Associations between amyloid-ß deposition and hypometabolism or cognitive impairment were predominantly observed in brain regions with high amyloid-ß load. The relationship between asymmetries of amyloid-ß deposition and hypometabolism in cortical regions with high amyloid-ß load is in line with the detrimental effect of amyloid-ß burden on neuronal function. Asymmetries were also concordant with lateralized cognitive symptoms, indicating their clinical relevance.
Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Transtornos Cognitivos/etiologia , Lateralidade Funcional/fisiologia , Doenças do Sistema Nervoso/etiologia , Idoso , Idoso de 80 Anos ou mais , Transtornos Cognitivos/classificação , Feminino , Fluordesoxiglucose F18/metabolismo , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Estudos Retrospectivos , Estatísticas não Paramétricas , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
BACKGROUND: Preclinical Alzheimer's disease (AD) is one possible cause of subjective cognitive decline (SCD). Normal task performance despite ongoing neurodegeneration is typically considered as neuronal compensation, which is reflected by greater neuronal activity. Compensatory brain activity has been observed in frontal as well as parietal regions in SCD, but data are scarce, especially outside the memory domain. OBJECTIVE: To investigate potential compensatory activity in SCD. Such compensatory activity is particularly expected in participants where blood-based biomarkers indicated amyloid positivity as this implies preclinical AD. METHODS: 52 participants with SCD (mean age: 71.00±5.70) underwent structural and functional neuroimaging (fMRI), targeting episodic memory and spatial abilities, and a neuropsychological assessment. The estimation of amyloid positivity was based on plasma amyloid-ß and phosphorylated tau (pTau181) measures. RESULTS: Our fMRI analyses of the spatial abilities task did not indicate compensation, with only three voxels exceeding an uncorrected threshold at pâ<â0.001. This finding was not replicated in a subset of 23 biomarker positive individuals. CONCLUSION: Our results do not provide conclusive evidence for compensatory brain activity in SCD. It is possible that neuronal compensation does not manifest at such an early stage as SCD. Alternatively, it is possible that our sample size was too small or that compensatory activity may be too heterogeneous to be detected by group-level statistics. Interventions based on the individual fMRI signal should therefore be explored.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Idoso , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides , Disfunção Cognitiva/psicologia , Imageamento por Ressonância Magnética , Testes Neuropsicológicos , Lobo Parietal , Biomarcadores , Encéfalo/diagnóstico por imagemRESUMO
We assessed the structure-function relationship of the human cholinergic system and hypothesized that structural measures are associated with short-latency sensory afferent inhibition (SAI), an electrophysiological measure of central cholinergic signal transmission. Healthy volunteers (n = 36) and patients with mild cognitive impairment (MCI, n = 20) underwent median nerve SAI and 3T structural MRI to determine the volume of the basal forebrain and the thalamus. Patients with MCI had smaller basal forebrain (p < 0.001) or thalamus volumes (p < 0.001) than healthy volunteers. Healthy SAI responders (> 10% SAI) had more basal forebrain volume than non-responders (p = 0.004) or patients with MCI (p < 0.001). More basal forebrain volume was associated with stronger SAI in healthy volunteers (r = 0.33, p < 0.05) but not patients with MCI. There was no significant relationship between thalamus volumes and SAI. Basal forebrain volume is associated with cholinergic function (SAI) in healthy volunteers but not in MCI patients. The in-vivo investigation of the structure-function relationship could further our understanding of the human cholinergic system in patients with suspected or known cholinergic system degeneration.
Assuntos
Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/fisiopatologia , Colinérgicos/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Tálamo/metabolismo , Tálamo/fisiopatologia , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Inibição Neural/fisiologia , Testes NeuropsicológicosRESUMO
Transcranial magnetic stimulation (TMS) is a well-established tool in probing cortical plasticity in vivo. Changes in corticomotor excitability can be induced using paired associative stimulation (PAS) protocol, in which TMS over the primary motor cortex is conditioned with an electrical peripheral nerve stimulation of the contralateral hand. PAS with an inter-stimulus interval of 25 ms induces long-term potentiation (LTP)-like effects in cortical excitability. However, the response to a PAS protocol tends to vary substantially across individuals. In this study, we used univariate and multivariate data-driven methods to investigate various previously proposed determinants of inter-individual variability in PAS efficacy, such as demographic, cognitive, clinical, neurophysiological, and neuroimaging measures. Forty-one right-handed participants, comprising 22 patients with amnestic mild cognitive impairment (MCI) and 19 healthy controls (HC), underwent the PAS protocol. Prior to stimulation, demographic, genetic, clinical, as well as structural and resting-state functional MRI data were acquired. The two groups did not differ in any of the variables, except by global cognitive status. Univariate analysis showed that only 61% of all participants were classified as PAS responders, irrespective of group membership. Higher PAS response was associated with lower TMS intensity and with higher resting-state connectivity within the sensorimotor network, but only in responders, as opposed to non-responders. We also found an overall positive correlation between PAS response and structural connectivity within the corticospinal tract, which did not differ between groups. A multivariate random forest (RF) model identified age, gender, education, IQ, global cognitive status, sleep quality, alertness, TMS intensity, genetic factors, and neuroimaging measures (functional and structural connectivity, gray matter (GM) volume, and cortical thickness as poor predictors of PAS response. The model resulted in low accuracy of the RF classifier (58%; 95% CI: 42 - 74%), with a higher relative importance of brain connectivity measures compared to the other variables. We conclude that PAS variability in our sample was not well explained by factors known to influence PAS efficacy, emphasizing the need for future replication studies.
RESUMO
Huntington's disease (HD) is a genetically caused neurodegenerative disorder characterized by heterogeneous motor, psychiatric, and cognitive symptoms. Although motor symptoms may be the most prominent presentation, cognitive symptoms such as memory deficits and executive dysfunction typically co-occur. We used functional magnetic resonance imaging (fMRI) and task fMRI-based dynamic causal modeling (DCM) to evaluate HD-related changes in the neural network underlying working memory (WM). Sixty-four pre-symptomatic HD mutation carriers (preHD), 20 patients with early manifest HD symptoms (earlyHD), and 83 healthy control subjects performed an n-back fMRI task with two levels of WM load. Effective connectivity was assessed in five predefined regions of interest, comprising bilateral inferior parietal cortex, left anterior cingulate cortex, and bilateral dorsolateral prefrontal cortex. HD mutation carriers performed less accurately and more slowly at high WM load compared with the control group. While between-group comparisons of brain activation did not reveal differential recruitment of the cortical WM network in mutation carriers, comparisons of brain connectivity as identified with DCM revealed a number of group differences across the whole WM network. Most strikingly, we observed decreasing connectivity from several regions toward right dorsolateral prefrontal cortex (rDLPFC) in preHD and even more so in earlyHD. The deterioration in rDLPFC connectivity complements results from previous studies and might mirror beginning cortical neural decline at premanifest and early manifest stages of HD. We were able to characterize effective connectivity in a WM network of HD mutation carriers yielding further insight into patterns of cognitive decline and accompanying neural deterioration.
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Spatial disorientation is a frequent symptom in Alzheimer's disease and in mild cognitive impairment (MCI). In the clinical routine, spatial orientation is less often tested with real-world navigation but rather with 2D visuoconstructive tasks. However, reports about the association between the two types of tasks are sparse. Additionally, spatial disorientation has been linked to volume of the right hippocampus but it remains unclear whether right hippocampal subregions have differential involvement in real-world navigation. Yet, this would help uncover different functional roles of the subregions, which would have important implications for understanding the neuronal underpinnings of navigation skills. We compared patients with amnestic MCI (aMCI; n = 25) and healthy elderly controls (HC; n = 25) in a real-world navigation task that engaged different spatial processes. The association between real-world navigation and different visuoconstructive tasks was tested (i.e., figures from the Consortium to Establish a Registry for Alzheimer's Disease; CERAD, the Rey-Osterrieth Complex Figure task; and clock drawing). Furthermore, the relation between spatial navigation and volume of right hippocampal subregions was examined. Linear regression and relative weight analysis were applied for statistical analyses. Patients with aMCI were significantly less able to correctly navigate through a route compared to HC but had comparable map drawing and landmark recognition skills. The association between visuoconstructive tasks and real-world navigation was only significant when using the visuospatial memory component of the Rey figure. In aMCI, more volume of the right hippocampal tail was significantly associated with better navigation skills, while volume of the right CA2/3 region was a significant predictor in HC. Standard visuoconstructive tasks (e.g., the CERAD figures or clock drawing) are not sufficient to detect real-world spatial disabilities in aMCI. Consequently, more complex visuoconstructive tasks (i.e., the Rey figure) should be routinely included in the assessment of cognitive functions in the context of AD. Moreover, in those elderly individuals with impaired complex visuospatial memory, route finding behaviour should be evaluated in detail. Regarding the contribution of hippocampal subregions to spatial navigation, the right hippocampal tail seems to be particularly important for patients with aMCI, while the CA2/3 region appears to be more relevant in HC.
Assuntos
Amnésia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/psicologia , Hipocampo/diagnóstico por imagem , Memória Espacial , Navegação Espacial , Idoso , Idoso de 80 Anos ou mais , Amnésia/diagnóstico por imagem , Amnésia/fisiopatologia , Amnésia/psicologia , Disfunção Cognitiva/fisiopatologia , Feminino , Hipocampo/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Aprendizagem Espacial/fisiologia , Memória Espacial/fisiologia , Navegação Espacial/fisiologia , Percepção Visual/fisiologiaRESUMO
Huntington's disease (HD) is a progressive neurodegenerative disorder that can be genetically confirmed with certainty decades before clinical onset. This allows the investigation of functional and structural changes in HD many years prior to disease onset, which may reveal important mechanistic insights into brain function, structure and organization in general. While regional atrophy is present at early stages of HD, it is still unclear if both hemispheres are equally affected by neurodegeneration and how the extent of asymmetry affects domain-specific functional decline. Here, we used whole-brain voxel-based analysis to investigate cross-sectional and longitudinal hemispheric asymmetries in grey matter (GM) volume in 56 manifest HD (mHD), 83 pre-manifest HD (preHD), and 80 healthy controls (HC). Furthermore, a regression analysis was used to assess the relationship between neuroanatomical asymmetries and decline in motor and cognitive measures across the disease spectrum. The cross-sectional analysis showed striatal leftward-biased GM atrophy in mHD, but not in preHD, relative to HC. Longitudinally, no net 36-month change in GM asymmetries was found in any of the groups. In the regression analysis, HD-related decline in quantitative-motor (Q-Motor) performance was linked to lower GM volume in the left superior parietal cortex. These findings suggest a stronger disease effect targeting the left hemisphere, especially in those with declining motor performance. This effect did not change over a period of three years and may indicate a compensatory role of the right hemisphere in line with recent functional imaging studies.
Assuntos
Encéfalo/patologia , Lateralidade Funcional/fisiologia , Substância Cinzenta/diagnóstico por imagem , Doença de Huntington/patologia , Adulto , Atrofia , Encéfalo/diagnóstico por imagem , Transtornos Cognitivos/etiologia , Correlação de Dados , Estudos Transversais , Feminino , Substância Cinzenta/patologia , Humanos , Doença de Huntington/complicações , Doença de Huntington/diagnóstico por imagem , Processamento de Imagem Assistida por Computador , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Adulto JovemRESUMO
Increased amygdala activation is consistently found in patients suffering from social anxiety disorder (SAD), a psychiatric condition characterized by an intense fear of social situations and scrutiny. Disruptions in the amygdalar-frontal network in SAD may explain the inability of frontal regions to appropriately down-regulate amygdalar hyper-activation. In this study, we measured 15 SAD patients and 15 healthy controls during an affective counting Stroop task with emotional faces to assess the interaction of affective stimuli with a cognitive task in SAD, as well as to investigate the causal interactions between the amygdala and the medial orbitofrontal cortex (OFC) using dynamic causal modeling (DCM). Here we show for the first time that differences in OFC-amygdala effective connectivity between SAD patients and healthy controls are influenced by cognitive load during task processing. In SAD patients relative to controls dysfunctional amygdala regulation was observed during passive viewing of harsh faces This could be linked to ongoing self-initiated cognitive processes (such as rumination and anticipation of negative events) that hinder successful amygdala regulation. However, between-group differences diminished during cognitive processing, suggesting that attentional load interfered with emotional processing in both patients and controls.
Assuntos
Tonsila do Cerebelo/diagnóstico por imagem , Emoções/fisiologia , Rede Nervosa/diagnóstico por imagem , Fobia Social/diagnóstico por imagem , Adulto , Tonsila do Cerebelo/fisiopatologia , Atenção , Mapeamento Encefálico , Medo/fisiologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Rede Nervosa/fisiopatologia , Fobia Social/fisiopatologia , Adulto JovemRESUMO
OBJECTIVE: Paired associative stimulation (PAS) is a widely used transcranial magnetic stimulation (TMS) paradigm to induce synaptic long-term potentiation (LTP)-like plasticity in the intact human brain. The PAS effect is reduced in Alzheimer's dementia (AD) but has not yet been assessed in patients with mild cognitive impairment (MCI). METHODS: PAS was assessed in a group of 24 MCI patients and 24 elderly controls. MCI patients were further stratified by their cognitive profile as well as hippocampal atrophy and Apolipoprotein E (ApoE) genotype. RESULTS: There was no difference in PAS effects between MCI patients and healthy controls. MCI patients tended to show a higher response rate and an average PAS effect. PAS effects were not correlated with markers of disease severity or ApoE genotype but were more pronounced in individuals with shorter sleep duration and in MCI subjects with higher ratings of subjective alertness. CONCLUSIONS: Contrary to our initial hypothesis, there was no clear difference in PAS between MCI patients and healthy controls. SIGNIFICANCE: Our results argue against a continuous reduction of LTP-like plasticity along the spectrum of clinical MCI when stratified by MCI-subtype, APOE genotype or hippocampus atrophy.
Assuntos
Envelhecimento/fisiologia , Disfunção Cognitiva/fisiopatologia , Córtex Motor/fisiologia , Plasticidade Neuronal/fisiologia , Aprendizagem por Associação de Pares/fisiologia , Estimulação Magnética Transcraniana/métodos , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/diagnóstico , Potencial Evocado Motor/fisiologia , Feminino , Humanos , MasculinoRESUMO
Acetylcholine is critically involved in modulating learning and memory function, which both decline in neurodegeneration. It remains unclear to what extent structural and functional changes in the cholinergic system contribute to episodic memory dysfunction in mild cognitive impairment (MCI), in addition to hippocampal degeneration. A better understanding is critical, given that the cholinergic system is the main target of current symptomatic treatment in mild to moderate Alzheimer's disease. We simultaneously assessed the structural and functional integrity of the cholinergic system in 20 patients with MCI and 20 matched healthy controls and examined their effect on verbal episodic memory via multivariate regression analyses. Mediating effects of either cholinergic function or hippocampal volume on the relationship between cholinergic structure and episodic memory were computed. In MCI, a less intact structure and function of the cholinergic system was found. A smaller cholinergic structure was significantly correlated with a functionally more active cholinergic system in patients, but not in controls. This association was not modulated by age or disease severity, arguing against compensational processes. Further analyses indicated that neither functional nor structural changes in the cholinergic system influence verbal episodic memory at the MCI stage. In fact, those associations were fully mediated by hippocampal volume. Although the cholinergic system is structurally and functionally altered in MCI, episodic memory dysfunction results primarily from hippocampal neurodegeneration, which may explain the inefficiency of cholinergic treatment at this disease stage.
Assuntos
Acetilcolina/metabolismo , Disfunção Cognitiva/complicações , Disfunção Cognitiva/patologia , Transtornos da Memória/etiologia , Aprendizagem Verbal/fisiologia , Idoso , Idoso de 80 Anos ou mais , Potencial Evocado Motor/fisiologia , Feminino , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Transtornos da Memória/diagnóstico por imagem , Memória Episódica , Pessoa de Meia-Idade , Inibição Neural/fisiologia , Testes Neuropsicológicos , Prosencéfalo/diagnóstico por imagem , Prosencéfalo/metabolismo , Análise de Regressão , Estimulação Magnética TranscranianaRESUMO
Deficits in motor functioning are one of the hallmarks of Huntington's disease (HD), a genetically caused neurodegenerative disorder. We applied functional magnetic resonance imaging (fMRI) and dynamic causal modeling (DCM) to assess changes that occur with disease progression in the neural circuitry of key areas associated with executive and cognitive aspects of motor control. Seventy-seven healthy controls, 62 pre-symptomatic HD gene carriers (preHD), and 16 patients with manifest HD symptoms (earlyHD) performed a motor finger-tapping fMRI task with systematically varying speed and complexity. DCM was used to assess the causal interactions among seven pre-defined regions of interest, comprising primary motor cortex, supplementary motor area (SMA), dorsal premotor cortex, and superior parietal cortex. To capture heterogeneity among HD gene carriers, DCM parameters were entered into a hierarchical cluster analysis using Ward's method and squared Euclidian distance as a measure of similarity. After applying Bonferroni correction for the number of tests, DCM analysis revealed a group difference that was not present in the conventional fMRI analysis. We found an inhibitory effect of complexity on the connection from parietal to premotor areas in preHD, which became excitatory in earlyHD and correlated with putamen atrophy. While speed of finger movements did not modulate the connection from caudal to pre-SMA in controls and preHD, this connection became strongly negative in earlyHD. This second effect did not survive correction for multiple comparisons. Hierarchical clustering separated the gene mutation carriers into three clusters that also differed significantly between these two connections and thereby confirmed their relevance. DCM proved useful in identifying group differences that would have remained undetected by standard analyses and may aid in the investigation of between-subject heterogeneity.
RESUMO
LTP-like plasticity measured by visual evoked potentials (VEP) can be induced in the intact human brain by presenting checkerboard reversals. Also associated with LTP-like plasticity, around two third of participants respond to transcranial magnetic stimulation (TMS) with a paired-associate stimulation (PAS) protocol with a potentiation of their motor evoked potentials. LTP-like processes are also required for verbal and motor learning tasks. We compared effect sizes, responder rates and intercorrelations as well as the potential influence of attention between these four assessments in a group of 37 young and healthy volunteers. We observed a potentiation effect of the N75 and P100 VEP component which positively correlated with plasticity induced by PAS. Subjects with a better subjective alertness were more likely to show PAS and VEP potentiation. No correlation was found between the other assessments. Effect sizes and responder rates of VEP potentiation were higher compared to PAS. Our results indicate a high variability of LTP-like effects and no evidence for a system-specific nature. As a consequence, studies wishing to assess individual levels of LTP-like plasticity should employ a combination of multiple assessments.
RESUMO
BACKGROUND: Cognitive and motor task performance in premanifest Huntington's disease (HD) gene-carriers is often within normal ranges prior to clinical diagnosis, despite loss of brain volume in regions involved in these tasks. This indicates ongoing compensation, with the brain maintaining function in the presence of neuronal loss. However, thus far, compensatory processes in HD have not been modeled explicitly. Using a new model, which incorporates individual variability related to structural change and behavior, we sought to identify functional correlates of compensation in premanifest-HD gene-carriers. METHODS: We investigated the modulatory effects of regional brain atrophy, indexed by structural measures of disease load, on the relationship between performance and brain activity (or connectivity) using task-based and resting-state functional MRI. FINDINGS: Consistent with compensation, as atrophy increased performance-related activity increased in the right parietal cortex during a working memory task. Similarly, increased functional coupling between the right dorsolateral prefrontal cortex and a left hemisphere network in the resting-state predicted better cognitive performance as atrophy increased. Such patterns were not detectable for the left hemisphere or for motor tasks. INTERPRETATION: Our findings provide evidence for active compensatory processes in premanifest-HD for cognitive demands and suggest a higher vulnerability of the left hemisphere to the effects of regional atrophy.
Assuntos
Doença de Huntington/diagnóstico , Doença de Huntington/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Mapeamento Encefálico , Estudos de Casos e Controles , Conectoma , Feminino , Heterozigoto , Humanos , Proteína Huntingtina , Doença de Huntington/genética , Doença de Huntington/patologia , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Memória de Curto Prazo , Mutação , Proteínas do Tecido Nervoso/genética , Desempenho PsicomotorRESUMO
Several models of neural compensation in healthy aging have been suggested to explain brain activity that aids to sustain cognitive function. Applying recently suggested criteria of "attempted" and "successful" compensation, we reviewed existing literature on compensatory mechanisms in preclinical Huntington's disease (HD) and amnestic mild cognitive impairment (aMCI). Both disorders constitute early stages of neurodegeneration ideal for examining compensatory mechanisms and developing targeted interventions. We strived to clarify whether compensation criteria derived from healthy aging populations can be applied to early neurodegeneration. To concentrate on the close coupling of cognitive performance and brain activity, we exclusively addressed task fMRI studies. First, we found evidence for parallels in compensatory mechanisms between healthy aging and neurodegenerative disease. Several studies fulfilled criteria of attempted compensation, while reports of successful compensation were largely absent, which made it difficult to conclude on. Second, comparing working memory studies in preclinical HD and aMCI, we identified similar compensatory patterns across neurodegenerative disorders in lateral and medial prefrontal cortex. Such patterns included an inverted U-shaped relationship of neurodegeneration and compensatory activity spanning from preclinical to manifest disease. Due to the lack of studies systematically targeting all criteria of compensation, we propose an exemplary study design, including the manipulation of compensating brain areas by brain stimulation. Furthermore, we delineate the benefits of targeted interventions by non-invasive brain stimulation, as well as of unspecific interventions such as physical activity or cognitive training. Unambiguously detecting compensation in early neurodegenerative disease will help tailor interventions aiming at sustained overall functioning and delayed clinical disease onset.