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BACKGROUND: In this study, we aimed at investigating the possible association of urinary symptoms with whole-brain MRI resting-state functional connectivity (FC) alterations from distinct striatal subregions in a large cohort of early PD patients. METHODS: Seventy-nine drug-naive PD patients (45 PD-urinary+/34 PD-urinary-) and 38 healthy controls (HCs) were consecutively enrolled. Presence/absence of urinary symptoms were assessed by means of the Nonmotor Symptom Scale - domain 7. Using an a priori connectivity-based domain-specific parcellation, we defined three ROIs (per each hemisphere) for different striatal functional subregions (sensorimotor, limbic and cognitive) from which seed-based FC voxel-wise analyses were conducted over the whole brain. RESULTS: Compared to PD-urinary-, PD-urinary+ patients showed increased FC between striatal regions and motor and premotor/supplementary motor areas as well as insula/anterior dorsolateral PFC. Compared to HC, PD-urinary+ patients presented decreased FC between striatal regions and parietal, insular and cingulate cortices. CONCLUSIONS: Our findings revealed a specific pattern of striatal FC alteration in PD patients with urinary symptoms, potentially associated to altered stimuli perception and sensorimotor integration even in the early stages. These results may potentially help clinicians to design more effective and tailored rehabilitation and neuromodulation protocols for PD patients.
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Corpo Estriado , Imageamento por Ressonância Magnética , Doença de Parkinson , Humanos , Doença de Parkinson/fisiopatologia , Doença de Parkinson/diagnóstico por imagem , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/fisiopatologia , Vias Neurais/fisiopatologia , Vias Neurais/diagnóstico por imagemRESUMO
Epidemiological studies have shown that Parkinson's disease (PD) patients with probable REM sleep behavior disorder (pRBD) present an increased risk of worse cognitive progression over the disease course. The aim of this study was to investigate, using resting-state functional MRI (RS-fMRI), the functional connectivity (FC) changes associated with the presence of pRBD in a cohort of newly diagnosed, drug-naive and cognitively unimpaired PD patients compared to healthy controls (HC). Fifty-six drug-naïve patients (25 PD-pRBD+ and 31 PD-pRBD-) and 23 HC underwent both RS-fMRI and clinical assessment. Single-subject and group-level independent component analysis was used to analyze intra- and inter-network FC differences within the major large-scale neurocognitive networks, namely the default mode (DMN), frontoparietal (FPN), salience (SN) and executive-control (ECN) networks. Widespread FC changes were found within the most relevant neurocognitive networks in PD patients compared to HC. Moreover, PD-pRBD+ patients showed abnormal intrinsic FC within the DMN, ECN and SN compared to PD-pRBD-. Finally, PD-pRBD+ patients showed functional decoupling between left and right FPN. In the present study, we revealed that FC changes within the most relevant neurocognitive networks are already detectable in early drug-naïve PD patients, even in the absence of clinical overt cognitive impairment. These changes are even more evident in PD patients with RBD, potentially leading to profound impairment in cognitive processing and cognitive/behavioral integration, as well as to fronto-striatal maladaptive compensatory mechanisms.
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Disfunção Cognitiva , Doença de Parkinson , Transtorno do Comportamento do Sono REM , Humanos , Mapeamento Encefálico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/complicações , Imageamento por Ressonância Magnética , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Transtorno do Comportamento do Sono REM/diagnóstico por imagemRESUMO
BACKGROUND AND PURPOSE: Although the majority of migraine with aura (MwA) patients experience simple visual aura, a discrete percentage also report somatosensory, dysphasic or motor symptoms (the so-called complex auras). The wide aura clinical spectrum led to an investigation of whether the heterogeneity of the aura phenomenon could be produced by different neural correlates, suggesting an increased visual cortical excitability in complex MwA. The aim was to explore whether complex MwA patients are characterized by more pronounced connectivity changes of the visual network and whether functional abnormalities may extend beyond the visual network encompassing also the sensorimotor network in complex MwA patients compared to simple visual MwA patients. METHODS: By using a resting-state functional magnetic resonance imaging approach, the resting-state functional connectivity (RS-Fc) of both visual and sensorimotor networks in 20 complex MwA patients was compared with 20 simple visual MwA patients and 20 migraine without aura patients. RESULTS: Complex MwA patients showed a significantly higher RS-Fc of the left lingual gyrus, within the visual network, and of the right anterior insula, within the sensorimotor network, compared to both simple visual MwA and migraine without aura patients (p < 0.001). The abnormal right anterior insula RS-Fc was able to discriminate complex MwA patients from simple aura MwA patients as demonstrated by logistic regression analysis (area under the curve 0.83). CONCLUSION: Our findings suggest that higher extrastriate RS-Fc might promote cortical spreading depression onset representing the neural correlate of simple visual aura that can propagate to sensorimotor regions if an increased insula RS-Fc coexists, leading to complex aura phenotypes.
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Epilepsia , Enxaqueca com Aura , Enxaqueca sem Aura , Humanos , Imageamento por Ressonância Magnética/métodos , Enxaqueca com Aura/diagnóstico por imagemRESUMO
BACKGROUND: Anxiety symptoms are common in Parkinson's disease (PD). A link between anxiety and cognitive impairment in PD has been demonstrated. OBJECTIVES: Using resting-state functional magnetic resonance imaging, we investigated intrinsic brain network connectivity correlates of anxiety symptoms in a cohort of drug-naive, cognitively unimpaired patients with PD. METHODS: The intrinsic functional brain connectivity of 25 drug-naive, cognitively unimpaired PD patients with anxiety, 25 without anxiety, and 20 matched healthy controls was compared. All patients underwent a detailed behavioral and neuropsychological evaluation. Anxiety presence and severity were assessed using the Parkinson's Disease Anxiety Scale. Single-subject and group-level independent component analyses were used to investigate functional connectivity differences within and between the major resting-state networks. RESULTS: Decreased connectivity within the default-mode and sensorimotor networks (SMN), increased connectivity within the executive-control network (ECN), and divergent connectivity measures within salience and frontoparietal networks (SN and FPN) were detected in PD patients with anxiety compared with those without anxiety. Moreover, patients with anxiety showed a disrupted inter-network connectivity between SN and SMN, ECN, and FPN. Anxiety severity was correlated with functional abnormalities within these networks. CONCLUSIONS: Our findings demonstrated that an abnormal intrinsic connectivity within and between the most reported large-scale networks may represent a potential neural correlate of anxiety symptoms in drug-naive PD patients even in the absence of clinically relevant cognitive impairment. We hypothesize that these specific cognitive and limbic network architecture changes may represent a potential biomarker of treatment response in clinical trials. © 2020 International Parkinson and Movement Disorder Society.
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Doença de Parkinson , Preparações Farmacêuticas , Ansiedade/etiologia , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Humanos , Imageamento por Ressonância Magnética , Vias Neurais/diagnóstico por imagem , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagemRESUMO
The organization of brain functional connectivity (FC) has been shown to differ between sexes. Amyotrophic lateral sclerosis (ALS) is characterized by sexual dimorphism, showing sex-specific trends in site of onset, phenotypes, and prognosis. Here, we explored resting state (RS) FC differences within major large-scale functional networks between women and men in a sample of ALS patients, in comparison to healthy controls (HCs). A group-level independent component analysis (ICA) was performed on RS-fMRI time-series enabling spatial and spectral analyses of large-scale RS FC networks in 45 patients with ALS (20 F; 25 M) and 31 HCs (15 F; 16 M) with a focus on sex-related differences. A whole-brain voxel-based morphometry (VBM) was also performed to highlight atrophy differences. Between-sex comparisons showed: decreased FC in the right middle frontal gyrus and in the precuneus within the default mode network (DMN), in affected men compared to affected women; decreased FC in the right post-central gyrus (sensorimotor network), in the right inferior parietal gyrus (right fronto-parietal network) and increased FC in the anterior cingulate cortex and right insula (salience network), in both affected and non-affected men compared to women. When comparing affected men to affected women, VBM analysis revealed atrophy in men in the right lateral occipital cortex. Our results suggest that in ALS sex-related trends of brain functional and structural changes are more heavily represented in DMN and in the occipital cortex, suggesting that sex is an additional dimension of functional and structural heterogeneity in ALS.
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Esclerose Lateral Amiotrófica , Esclerose Lateral Amiotrófica/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Feminino , Giro do Cíngulo , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
OBJECTIVE: Advanced neuroimaging techniques may offer the potential to monitor disease progression in amyotrophic lateral sclerosis (ALS), a neurodegenerative, multisystem disease that still lacks therapeutic outcome measures. We aim to investigate longitudinal functional and structural magnetic resonance imaging (MRI) changes in a cohort of patients with ALS monitored for one year after diagnosis. METHODS: Resting state functional MRI, diffusion tensor imaging (DTI), and voxel-based morphometry analyses were performed in 22 patients with ALS examined by six-monthly MRI scans over one year. RESULTS: During the follow-up period, patients with ALS showed reduced functional connectivity only in some extramotor areas, such as the middle temporal gyrus in the left frontoparietal network after six months and in the left middle frontal gyrus in the default mode network after one year without showing longitudinal changes of cognitive functions. Moreover, after six months, we reported in the ALS group a decreased fractional anisotropy (P = .003, Bonferroni corrected) in the right uncinate fasciculus. Conversely, we did not reveal significant longitudinal changes of functional connectivity in the sensorimotor network, as well as of gray matter (GM) atrophy or of DTI metrics in motor areas, although clinical measures of motor disability showed significant decline throughout the three time points. CONCLUSION: Our findings highlighted that progressive impairment of extramotor frontotemporal networks may precede the appearance of executive and language dysfunctions and GM changes in ALS. Functional connectivity changes in cognitive resting state networks might represent candidate radiological markers of disease progression.
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Esclerose Lateral Amiotrófica/diagnóstico por imagem , Conectoma , Lobo Frontal/diagnóstico por imagem , Lobo Temporal/diagnóstico por imagem , Idoso , Esclerose Lateral Amiotrófica/diagnóstico , Progressão da Doença , Feminino , Lobo Frontal/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Lobo Temporal/patologiaRESUMO
Fatigue is a common and disabling nonmotor manifestation in patients with Parkinson's disease (PD), and the supplementary motor area (SMA) has been implicated in its pathophysiology. SMA is usually divided in its rostro-caudal axis, with the rostral (pre-) SMA playing a major role in motor planning, and the caudal (proper) SMA related to movement execution. To investigate brain functional connectivity of SMA subregions in de novo, drug-naïve PD patients affected by fatigue, 17 patients with fatigue, 18 without fatigue, and 16 matched healthy controls were recruited. All the participants were not depressed and did not suffer from daytime sleepiness. Parkinson Fatigue Scale (PFS) was used for fatigue screening (cut-off > 3.3 points) and severity rating. Seed-based resting-state functional MRI was used to compare the functional connectivity from bilateral SMA subregions to the whole brain. Voxel-based morphometry analysis was employed to test whether functional connectivity results were related to brain structural differences. PD-related fatigue was associated with an increased connectivity between the left pre-SMA and the left postcentral gyrus as well as a decreased connectivity between the left SMA proper and the left middle frontal gyrus (ps < 0.01). These patterns of functional connectivity were tightly correlated with PFS scores (Pearson's rs < 0.01). No structural brain changes were observed. In early PD, altered functional connectivity of both SMA subregions might play a crucial role in fatigue pathophysiology. These results offer new insights into the mechanisms responsible for fatigue in PD, suggesting possible targets for neuromodulation strategies oriented to modulate the SMA activity.
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Córtex Motor , Doença de Parkinson , Preparações Farmacêuticas , Mapeamento Encefálico , Fadiga/etiologia , Humanos , Imageamento por Ressonância Magnética , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagemRESUMO
BACKGROUND: Two-thirds of patients with migraine without aura (MwoA) complain ictal cutaneous allodynia (CA), clinical sign of central nociceptive pathway sensitization, and independent predictor for migraine chronification. AIM: We aimed to investigate whether functional abnormalities, structural, or microstructural changes of the main cognitive networks (default mode network [DMN], salience network [SN], and central executive network [CEN]) could predict the development of CA in patients with MwoA. METHODS: Baseline 3-Tesla MRI images of 50 patients with MwoA were analyzed between 2009 and 2015. Over a three-year period, patients were then stratified into 2 groups based on CA development and compared with matched healthy controls (HC). Group-level independent components analysis was used to investigate intrinsic functional connectivity (FC) differences within the cognitive resting-state networks. Voxel-based morphometry (VBM) was used to assess whether group differences in cognitive network FC were related to structural differences. Tract-based spatial statistical analyses (TBSS) were conducted to assess the microstructural properties of white matter tracts. We also compared internetwork connectivity between patients. Finally, a logistic regression analysis was used to investigate baseline imaging predictors of CA development. RESULTS AND DISCUSSION: We observed a significantly reduced FC of both DMN and CEN in patients with MwoA developing CA (MwoA d CA) when compared with both patients with MwoA not developing CA (MwoA nd CA) and HC. Within the DMN, the PCC/precuneus is a key hub aimed to anti-nociception and multisensory integration. The reduced intrinsic PCC/precuneus FC observed in patients with MwoA d CA could subtend abnormal inputs integration, from different sensory modalities, allowing the development of CA. On the other hand, within the CEN, a central role in pain modulation as well as in executive functions is played by ACC and MFG. Our finding of reduced ACC and MFG FC in MwoA d CA may represent the neuronal substrate of both subclinical impairment of complex executive functions and dysfunctional anti-nociceptive pathway, making these patients more prone to migraine chronification. TBSS analyses showed a statistically significant reduced corpus callosum (CC) FA in patients with MwoA d CA as previously demonstrated in migraine patients with other chronification factors such as medication overuse or affective disorders. No VBM differences in both global and local volumes were revealed between groups. No significant correlations have been found between the observed functional and microstructural changes and clinical parameters of disease severity. Logistic regression analysis indicated that the full model containing all predictors was statistically significant while the decreased ACC-FC was significantly associated with CA development. CONCLUSION: We suggest that DMN and CEN FC abnormalities as well as CC microstructural changes could represent a prognostic imaging biomarker able to identify migraine patients more prone to experiencing CA and therefore, more inclined to chronic migraine. In the new pharmacological scenario, it would be useful to address therapeutic resources to specific migraine populations with a high risk of more severe clinical phenotype.
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Córtex Cerebral/fisiopatologia , Corpo Caloso/patologia , Rede de Modo Padrão/fisiopatologia , Hiperalgesia , Enxaqueca sem Aura , Rede Nervosa/fisiopatologia , Adulto , Córtex Cerebral/diagnóstico por imagem , Doença Crônica , Conectoma , Corpo Caloso/diagnóstico por imagem , Rede de Modo Padrão/diagnóstico por imagem , Imagem de Tensor de Difusão , Feminino , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/fisiopatologia , Humanos , Hiperalgesia/diagnóstico por imagem , Hiperalgesia/etiologia , Hiperalgesia/patologia , Hiperalgesia/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Enxaqueca sem Aura/complicações , Enxaqueca sem Aura/diagnóstico por imagem , Enxaqueca sem Aura/patologia , Enxaqueca sem Aura/fisiopatologia , Rede Nervosa/diagnóstico por imagem , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/fisiopatologia , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiopatologia , Estudos ProspectivosRESUMO
BACKGROUND: Sex difference is related to specific clinical features in PD patients over the disease course. OBJECTIVES: To investigate the potential sex-difference effect on the spontaneous neuronal activity within the most reported resting-state networks in early untreated PD patients and its correlation with baseline and longitudinal clinical features. METHODS: Fifty-six drug-naïve PD patients (30/26 male/female) and 30 (15/15 male/female) matched controls were enrolled in the study. Topological and spectral resting-state functional MRI features of the sensorimotor, dorsal and ventral attention, frontoparietal, and default-mode networks were analyzed for possible sex-difference effects in both PD patients and controls groups. Additionally, a region-of-interest analysis was performed to test for a sex effect on basal ganglia connectivity. Multivariate ordinal regression was used to investigate whether connectivity findings at baseline were predictors of motor impairment over a 2-year follow-up period. RESULTS: Compared to female PD patients and controls, male PD patients showed an abnormal spectral composition of the sensorimotor and dorsal attention networks in the slow-5 band. The region-of-interest analysis showed an increased connectivity within the basal ganglia in female PD patients compared to males. Functional sensorimotor connectivity changes at baseline showed to be an independent predictor of disease severity at 2-year follow-up. CONCLUSIONS: Our findings revealed the presence of a disease-related, sex-specific cortical and subcortical connectivity pattern within the sensorimotor network, in the early stage of PD. We hypothesize that these findings may be related to the presence of different sex-specific nigrostriatal dopaminergic pathways and might predict PD progression. © 2019 International Parkinson and Movement Disorder Society.
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Encéfalo/fisiopatologia , Vias Neurais/fisiopatologia , Doença de Parkinson/fisiopatologia , Idoso , Atenção/fisiologia , Mapeamento Encefálico/métodos , Dopamina/metabolismo , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Fatores SexuaisRESUMO
BACKGROUND: Despite the growing body of advanced studies investigating the neuronal correlates of pain processing in patients with migraine without aura (MwoA), only few similar studies have been conducted in patients with migraine with aura (MwA). Therefore, we aimed to explore the functional brain response to trigeminal noxious heat stimulation in patients with MwA. METHODS: Seventeen patients with MwA and 15 age- and sex-matched healthy controls (HC) underwent whole-brain blood oxygen level-dependent (BOLD) fMRI during trigeminal noxious heat stimulation. To examine the specificity of any observed differences between patients with MwA and HC, the functional response of neural pathways to trigeminal noxious heat stimulation in patients with MwA was compared with 18 patients with MwoA. Secondary analyses investigated the correlations between BOLD signal changes and clinical parameters of migraine severity. RESULTS: We observed a robust cortical and subcortical pattern of BOLD response to trigeminal noxious heat stimulation across all participants. Patients with MwA showed a significantly increased activity in higher cortical areas known to be part of a distributed network involved in advanced visual processing, including lingual gyrus, inferior parietal lobule, inferior frontal gyrus and medial frontal gyrus. Moreover, a significantly greater cerebellar activation was observed in patients with MwA when compared with both patients with MwA and HC. Interestingly, no correlations were found between migraine severity parameters and magnitude of BOLD response in patients with MwA. CONCLUSION: Our findings, characterized by abnormal visual pathway response to trigeminal noxious heat stimulation, support the role of a functional integration between visual and trigeminal pain networks in the pathophysiological mechanisms underlying migraine with aura. Moreover, they expand the concept of "neurolimbic-pain network" as a model of MwoA including both limbic dysfunction and cortical dys-excitability. Indeed, we suggest a model of "neurolimbic-visual-pain network" in MwA patients, characterized by dysfunctional correlations between pain-modulating circuits not only with the cortical limbic areas but with advanced visual areas as well. Furthermore, the abnormal cerebellar response to trigeminal noxious heat stimulation may suggest a dysfunctional cerebellar inhibitory control on thalamic sensory gating, impinging on the advanced visual processing cortical areas in patients with MwA.
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Cerebelo/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Enxaqueca com Aura/diagnóstico por imagem , Rede Nervosa/diagnóstico por imagem , Núcleos do Trigêmeo/diagnóstico por imagem , Córtex Visual/diagnóstico por imagem , Adulto , Cerebelo/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Enxaqueca com Aura/fisiopatologia , Rede Nervosa/fisiopatologia , Vias Neurais/fisiopatologia , Nociceptividade/fisiologia , Dor/diagnóstico por imagem , Dor/fisiopatologia , Medição da Dor/métodos , Estudos Prospectivos , Distribuição Aleatória , Tálamo/diagnóstico por imagem , Tálamo/fisiopatologia , Núcleos do Trigêmeo/fisiopatologia , Córtex Visual/fisiopatologia , Vias Visuais/diagnóstico por imagem , Vias Visuais/fisiopatologia , Adulto JovemRESUMO
Mirror movements (MM) might be observed in congenital and acquired neurodegenerative conditions but their anatomic-functional underpinnings are still largely elusive. This study investigated the spectral changes of resting-state functional connectivity in Kallmann Syndrome (hypogonadotropic hypogonadism with hypo/anosmia with or without congenital MM) searching for insights into the phenomenon of MM. Forty-four Kallmann syndrome patients (21 with MM) and 24 healthy control subjects underwent task (finger tapping) and resting-state functional MRI. The spatial pattern of task-related activations was used to mask regions and select putative motor networks in a spatially independent component analysis of resting-state signals. For each resting-state independent component time-course power spectrum, we extracted the relative contribution of four separate bands: slow-5 (0.01-0.027 Hz), slow-4 (0.027-0.073 Hz), slow-3 (0.073-0.198 Hz), slow-2 (0.198-0.25 Hz), and analyzed the variance between groups. For the sensorimotor network, the analysis revealed a significant group by frequency interaction (P = 0.002) pointing to a frequency shift in the spectral content among subgroups with lower slow-5 band and higher slow-3 band contribution in Kallmann patients with MM versus controls (P = 0.028) and with lower slow-5 band contribution between patients with and without MM (P = 0.057). In specific regions, as obtained from hand motor activation task analysis, spectral analyses demonstrated a lower slow-5 band contribution in Kallmann patients with MM versus both controls and patients without MM (P < 0.05). In Kallmann syndrome, the peculiar phenomenon of bimanual synkinesis is associated at rest with regionally and spectrally selective functional connectivity changes pointing to a distinctive cortical and subcortical functional reorganization. Hum Brain Mapp 39:42-53, 2018. © 2017 Wiley Periodicals, Inc.
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Encéfalo/fisiopatologia , Síndrome de Kallmann/fisiopatologia , Transtornos dos Movimentos/fisiopatologia , Adulto , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Feminino , Dedos/fisiopatologia , Humanos , Síndrome de Kallmann/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Atividade Motora/fisiologia , Transtornos dos Movimentos/diagnóstico por imagem , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , DescansoRESUMO
PURPOSE: Advances in computational network analysis have enabled the characterization of topological properties of human brain networks (connectomics) from high angular resolution diffusion imaging (HARDI) MRI structural measurements. In this study, the effect of changing the diffusion weighting (b value) and sampling (number of gradient directions) was investigated in ten healthy volunteers, with specific focus on graph theoretical network metrics used to characterize the human connectome. METHODS: Probabilistic tractography based on the Q-ball reconstruction of HARDI MRI measurements was performed and structural connections between all pairs of regions from the automated anatomical labeling (AAL) atlas were estimated, to compare two HARDI schemes: low b value (b = 1000) and low direction number (n = 32) (LBLD); high b value (b = 3000) and high number (n = 54) of directions (HBHD). RESULTS: LBLD and HBHD data sets produced connectome images with highly overlapping hub structure. Overall, the HBHD scheme yielded significantly higher connection probabilities between cortical and subcortical sites and allowed detecting more connections. Small worldness and modularity were reduced in HBHD data. The clustering coefficient was significantly higher in HBHD data indicating a higher level of segregation in the resulting connectome for the HBHD scheme. CONCLUSION: Our results demonstrate that the HARDI scheme as an impact on structural connectome measures which is not automatically implied by the tractography outcome. As the number of gradient directions and b values applied may introduce a bias in the assessment of network properties, the choice of a given HARDI protocol must be carefully considered when comparing results across connectomic studies.
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Conectoma , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Voluntários Saudáveis , Humanos , Processamento de Imagem Assistida por Computador , Imageamento Tridimensional , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Impulse control disorders can be triggered by dopamine replacement therapies in patients with PD. Using resting-state functional MRI, we investigated the intrinsic brain network connectivity at baseline in a cohort of drug-naive PD patients who successively developed impulse control disorders over a 36-month follow-up period compared with patients who did not. METHODS: Baseline 3-Tesla MRI images of 30 drug-naive PD patients and 20 matched healthy controls were analyzed. The impulse control disorders' presence and severity at follow-up were assessed by the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease Rating Scale. Single-subject and group-level independent component analysis was used to investigate functional connectivity differences within the major resting-state networks. We also compared internetwork connectivity between patients. Finally, a multivariate Cox regression model was used to investigate baseline predictors of impulse control disorder development. RESULTS: At baseline, decreased connectivity in the default-mode and right central executive networks and increased connectivity in the salience network were detected in PD patients with impulse control disorders at follow-up compared with those without. Increased default-mode/central executive internetwork connectivity was significantly associated with impulse control disorders development (P < 0.05). CONCLUSIONS: Our findings demonstrated that abnormal brain connectivity in the three large-scale networks characterizes drug-naive PD patients who will eventually develop impulse control disorders while on dopaminergic treatment. We hypothesize that these divergent cognitive and limbic network connectivity changes could represent a potential biomarker and an additional risk factor for the emergence of impulse control disorders. © 2017 International Parkinson and Movement Disorder Society.
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Encéfalo/diagnóstico por imagem , Transtornos Disruptivos, de Controle do Impulso e da Conduta/diagnóstico por imagem , Transtornos Disruptivos, de Controle do Impulso e da Conduta/etiologia , Vias Neurais/diagnóstico por imagem , Doença de Parkinson/complicações , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Imageamento Tridimensional , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Análise de Regressão , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Treatment-related motor complications may develop progressively over the course of Parkinson's disease (PD). OBJECTIVE: We investigated intrinsic brain networks functional connectivity (FC) at baseline in a cohort of early PD patients which successively developed treatment-related motor complications over 4 years. METHODS: Baseline MRI images of 88 drug-naïve PD patients and 20 healthy controls were analyzed. After the baseline assessments, all PD patients were prescribed with dopaminergic treatment and yearly clinically re-assessed. At the 4-year follow-up, 36 patients have developed treatment-related motor complications (PD-Compl) whereas 52 had not (PD-no-Compl). Single-subject and group-level independent component analyses were used to investigate FC changes within the major large-scale resting-state networks at baseline. A multivariate Cox regression model was used to explore baseline predictors of treatment-related motor complications at 4-year follow-up. RESULTS: At baseline, an increased FC in the right middle frontal gyrus within the frontoparietal network as well as a decreased connectivity in the left cuneus within the default-mode network were detected in PD-Compl compared with PD-no-Compl. PD-Compl patients showed a preserved sensorimotor FC compared to controls. FC differences were found to be independent predictors of treatment-related motor complications over time. CONCLUSION: Our findings demonstrated that specific FC differences may characterize drug-naïve PD patients more prone to develop treatment-related complications. These findings may reflect the presence of an intrinsic vulnerability across frontal and prefrontal circuits, which may be potentially targeted as a future biomarker in clinical trials.
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Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico/métodos , Dopamina , Imageamento por Ressonância Magnética/métodosRESUMO
Pseudobulbar affect (PBA), referring to exaggerated or inappropriate episodes of laughing and/or crying without an apparent motivating stimulus, has been mainly attributed to bilateral degeneration of corticobulbar tracts. We aimed at exploring brain functional connectivity (FC) correlates of PBA in patients with amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, frequently associated with PBA. Resting state functional MRI (RS-fMRI) independent component (ICA) and seed-based analyses and voxel-based morphometry (VBM) whole-brain analysis were performed on 27 ALS patients (13 with PBA; 14 without PBA) and 26 healthy controls (HC), for investigating functional and structural abnormalities in ALS patients compared to HC and in patients with PBA compared to patients without PBA. Between-patient analysis revealed different FC patterns, especially regarding decreased FC in several areas of cognitive (default mode, frontoparietal, salience) and sensory-motor networks in patients with PBA compared to those without PBA. However, no significant differences were found in gray matter atrophy. Seed-based analysis showed increased FC between middle cerebellar peduncles and posterior cingulate cortex and decreased FC between middle cerebellar peduncles and left middle frontal gyrus in patients with PBA compared to patients without PBA. Our findings suggest that some alterations of fronto-tempo-parietal-cerebellar circuits could be related to PBA in ALS. In particular, the abnormal FC between cerebellum and posterior cingulate cortex and left middle frontal gyrus in patients with PBA compared to patients without PBA highlights a crucial role of the cerebellum in regulating emotion expression in patients with ALS.
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Esclerose Lateral Amiotrófica , Imageamento por Ressonância Magnética , Humanos , Encéfalo/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Córtex CerebralRESUMO
INTRODUCTION: Fatigue is defined as a symptom of exhaustion unexplained by drug effects or psychiatric disorders and comprises two main components (i.e., central or "mental" and peripheral or "physical" components), both influencing global disability in amyotrophic lateral sclerosis (ALS). We aim at investigating the clinical correlations between "physical" and "mental" components of fatigue, measured by the Multidimensional Fatigue Inventory scale, and motor and cognitive/behavioral disability in a large sample of patients with ALS. We also investigated the correlations between these measures of fatigue and resting-state functional connectivity of brain functional magnetic resonance imaging (RS-fMRI) large-scale networks in a subset of patients. METHODS: One hundred and thirty ALS patients were assessed for motor disability, cognitive and behavioral dysfunctions, fatigue, anxiety, apathy, and daytime sleepiness. Moreover, the collected clinical parameters were correlated with RS-fMRI functional connectivity changes in the large-scale brain networks of 30 ALS patients who underwent MRI. RESULTS: Multivariate correlation analysis revealed that "physical" fatigue was related to anxiety and respiratory dysfunction, while "mental" fatigue was related to memory impairment and apathy. Moreover, the mental fatigue score was directly related to functional connectivity in the right and left insula (within the salience network), and inversely related to functional connectivity in the left middle temporal gyrus (within the default mode network). CONCLUSIONS: Although the "physical" component of fatigue may be influenced by the disease itself, in ALS the "mental" component of fatigue correlates with cognitive and behavioral impairment, as well as with alterations of functional connectivity in extra-motor networks.
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Esclerose Lateral Amiotrófica , Pessoas com Deficiência , Transtornos Motores , Humanos , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/diagnóstico por imagem , Encéfalo , Imageamento por Ressonância Magnética/métodos , Fadiga Mental/diagnóstico por imagem , Fadiga Mental/etiologia , CogniçãoRESUMO
Background: Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme ß-glucocerebrosidase (GCase), are the most frequent genetic risk factor for Parkinson's disease (PD). GBA-related PD (GBA-PD) patients have higher risk of dementia and reduced survival than non-carriers. Preclinical studies and one open-label trial in humans demonstrated that the chaperone ambroxol (ABX) increases GCase levels and modulates α-synuclein levels in the blood and cerebrospinal fluid (CSF). Methods and analysis: In this multicentre, double-blind, placebo-controlled, phase II clinical trial, we randomise patients with GBA-PD in a 1:1 ratio to either oral ABX 1.2 g/day or placebo. The duration of treatment is 52 weeks. Each participant is assessed at baseline and weeks 12, 26, 38, 52 and 78. Changes in the Montreal Cognitive Assessment score and the frequency of mild cognitive impairment and dementia between baseline and weeks 52 are the primary outcome measures. Secondary outcome measures include changes in validated scales/questionnaires assessing motor and non-motor symptoms. Neuroimaging features and CSF neurodegeneration markers are used as surrogate markers of disease progression. GCase activity, ABX and α-synuclein levels are also analysed in blood and CSF. A repeated-measures analysis of variance will be used for elaborating results. The primary analysis will be by intention to treat. Ethics and dissemination: The study and protocols have been approved by the ethics committee of centres. The study is conducted according to good clinical practice and the Declaration of Helsinki. The trial findings will be published in peer-reviewed journals and presented at conferences. Trial registration numbers: NCT05287503, EudraCT 2021-004565-13.
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In Kallmann syndrome (KS), the peculiar phenomenon of bimanual synkinesis or mirror movement (MM) has been associated with a spectral shift, from lower to higher frequencies, of the resting-state fMRI signal of the large-scale sensorimotor brain network (SMN). To possibly determine whether a similar frequency specificity exists across different functional connectivity SMN states, and to capture spontaneous transitions between them, we investigated the dynamic spectral changes of the SMN functional connectivity in KS patients with and without MM symptom. Brain MRI data were acquired at 3 Tesla in 39 KS patients (32 without MM, KSMM-, seven with MM, KSMM+) and 26 age- and sex-matched healthy control (HC) individuals. The imaging protocol included 20-min rs-fMRI scans enabling detailed spectro-temporal analyses of large-scale functional connectivity brain networks. Group independent component analysis was used to extract the SMN. A sliding window approach was used to extract the dynamic spectral power of the SMN functional connectivity within the canonical physiological frequency range of slow rs-fMRI signal fluctuations (0.01-0.25 Hz). K-means clustering was used to determine (and count) the most recurrent dynamic states of the SMN and detect the number of transitions between them. Two most recurrent states were identified, for which the spectral power peaked at a relatively lower (state 1) and higher (state 2) frequency. Compared to KS patients without MM and HC subjects, the SMN of KS patients with MM displayed significantly larger spectral power changes in the slow 3 canonical sub-band (0.073-0.198 Hz) and significantly fewer transitions between state 1 (less recurrent) and state 2 (more recurrent). These findings demonstrate that the presence of MM in KS patients is associated with reduced spontaneous transitions of the SMN between dynamic functional connectivity states and a higher recurrence and an increased spectral power change of the high-frequency state. These results provide novel information about the large-scale brain functional dynamics that could help to understand the pathologic mechanisms of bimanual synkinesis in KS syndrome and, potentially, other neurological disorders where MM may also occur.
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Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that is increasingly used as a nonpharmacological intervention against cognitive impairment in Alzheimer's disease (AD) and other dementias. Although rTMS has been shown to modify cognitive performances and brain functional connectivity (FC) in many neurological and psychiatric diseases, there is still no evidence about the possible relationship between executive performances and resting-state brain FC following rTMS in patients with mild cognitive impairment (MCI). In this preliminary study, we aimed to evaluate the possible effects of rTMS of the bilateral dorsolateral prefrontal cortex (DLPFC) in 27 MCI patients randomly assigned to two groups: one group received high-frequency (10 Hz) rTMS (HF-rTMS) for four weeks (n = 11), and the other received sham stimulation (n = 16). Cognitive and psycho-behavior scores, based on the Repeatable Battery for the Assessment of Neuropsychological Status, Beck Depression Inventory-II, Beck Anxiety Inventory, Apathy Evaluation Scale, and brain FC, evaluated by independent component analysis of resting state functional MRI (RS-fMRI) networks, together with the assessment of regional atrophy measures, evaluated by whole-brain voxel-based morphometry (VBM), were measured at baseline, after five weeks, and six months after rTMS stimulation. Our results showed significantly increased semantic fluency (p = 0.026) and visuo-spatial (p = 0.014) performances and increased FC within the salience network (p ≤ 0.05, cluster-level corrected) at the short-term timepoint, and increased FC within the left fronto-parietal network (p ≤ 0.05, cluster-level corrected) at the long-term timepoint, in the treated group but not in the sham group. Conversely, regional atrophy measures did not show significant longitudinal changes between the two groups across six months. Our preliminary findings suggest that targeting DLPFC by rTMS application may lead to a significant long-term increase in FC in MCI patients in a RS network associated with executive functions, and this process might counteract the progressive cortical dysfunction affecting this domain.
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OBJECTIVE: To assess the performance of a combination of three quantitative MRI markers (iron deposition, basal neuronal metabolism, and regional atrophy) for differential diagnosis between amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS). METHODS: In total, 33 ALS, 12 PLS, and 28 healthy control (HC) subjects underwent a 3T MRI study including single- and multi-echo sequences for gray matter (GM) volumetry and quantitative susceptibility mapping (QSM) and a pseudo-continuous arterial spin labeling (ASL) sequence for cerebral blood flow (CBF) measurement. Mean values of QSM, CBF, and GM volumes were extracted in the motor cortex, basal ganglia, thalamus, amygdala, and hippocampus. A generalized linear model was applied to the three measures to binary discriminate between groups. The diagnostic performances were evaluated via receiver operating characteristic analyses. RESULTS: A significant discrimination was obtained: between ALS and HCs in the left and right motor cortex, where QSM increases were respectively associated with disability scores and disease duration; between PLS and ALS in the left motor cortex, where PLS patients resulted significantly more atrophic; between ALS and HC in the right motor cortex, where GM volumes were associated with upper motor neuron scores. Significant discrimination between ALS and HC was achieved in subcortical structures only combining all three parameters. INTERPRETATION: While increased QSM values in the motor cortex of ALS patients is a consolidated finding, combining QSM, CBF, and GM volumetry shows higher diagnostic potential for differentiating ALS patients from HC subjects and, in the motor cortex, between ALS and PLS.