RESUMO
BACKGROUND: Disconjugate eye movements are essential for depth perception in frontal-eyed species, but their underlying neural substrates are largely unknown. Lesions in the midbrain can cause disconjugate eye movements. While vertically disconjugate eye movements have been linked to defective visuo-vestibular integration, the pathophysiology and neuroanatomy of horizontally disconjugate eye movements remains elusive. METHODS: A patient with a solitary focal midbrain lesion was examined using detailed clinical ocular motor assessments, binocular videooculography and diffusion-weighted MRI, which was co-registered to a high-resolution cytoarchitectonic MR-atlas. RESULTS: The patient exhibited both vertically and horizontally disconjugate eye alignment and nystagmus. Binocular videooculography showed a strong correlation of vertical and horizontal oscillations during fixation but not in darkness. Oscillation intensities and waveforms were modulated by fixation, illumination, and gaze position, suggesting shared visual- and vestibular-related mechanisms. The lesion was mapped to a functionally ill-defined area of the dorsal midbrain, adjacent to the posterior commissure and sparing nuclei with known roles in vertical gaze control. CONCLUSION: A circumscribed region in the dorsal midbrain appears to be a key node for disconjugate eye movements in both vertical and horizontal planes. Lesioning this area produces a unique ocular motor syndrome mirroring hallmarks of developmental strabismus and nystagmus. Further circuit-level studies could offer pivotal insights into shared pathomechanisms of acquired and developmental disorders affecting eye alignment.
Assuntos
Mesencéfalo , Humanos , Movimentos Oculares/fisiologia , Mesencéfalo/diagnóstico por imagem , Mesencéfalo/fisiopatologia , Mesencéfalo/patologia , Nistagmo Patológico/fisiopatologia , Nistagmo Patológico/etiologia , Nistagmo Patológico/diagnóstico por imagem , Transtornos da Motilidade Ocular/fisiopatologia , Transtornos da Motilidade Ocular/etiologiaRESUMO
Social defeat activates midbrain cells, promoting sleep and reducing anxiety in mice.
Assuntos
Ansiedade , Mesencéfalo , Sono , Derrota Social , Estresse Psicológico , Animais , Ansiedade/fisiopatologia , Mesencéfalo/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Estresse Psicológico/fisiopatologiaRESUMO
The pedunculopontine nucleus (PPN) is a locomotor command area containing glutamatergic neurons that control locomotor initiation and maintenance. These motor actions are deficient in Parkinson's disease (PD), where dopaminergic neurodegeneration alters basal ganglia activity. Being downstream of the basal ganglia, the PPN may be a suitable target for ameliorating parkinsonian motor symptoms. Here, we use in vivo cell-type specific PPN activation to restore motor function in two mouse models of parkinsonism made by acute pharmacological blockage of dopamine transmission. With a combination of chemo- and opto-genetics, we show that excitation of caudal glutamatergic PPN neurons can normalize the otherwise severe locomotor deficit in PD, whereas targeting the local GABAergic population only leads to recovery of slow locomotion. The motor rescue driven by glutamatergic PPN activation is independent of activity in nearby locomotor promoting glutamatergic Cuneiform neurons. Our observations point to caudal glutamatergic PPN neurons as a potential target for neuromodulatory restoration of locomotor function in PD.
Assuntos
Mesencéfalo/metabolismo , Neurônios/metabolismo , Doença de Parkinson/metabolismo , Transtornos Parkinsonianos/metabolismo , Animais , Modelos Animais de Doenças , Dopamina/metabolismo , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , Feminino , Masculino , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Doença de Parkinson/fisiopatologia , Transtornos Parkinsonianos/fisiopatologia , Núcleo Tegmental Pedunculopontino/metabolismo , Núcleo Tegmental Pedunculopontino/fisiopatologiaRESUMO
Motor deficits after stroke reflect both, focal lesion and network alterations in brain regions distant from infarction. This remote network dysfunction may be caused by aberrant signals from cortical motor regions travelling via mesencephalic locomotor region (MLR) to other locomotor circuits. A method for modulating disturbed network activity is deep brain stimulation. Recently, we have shown that high frequency stimulation (HFS) of the MLR in rats has restored gait impairment after photothrombotic stroke (PTS). However, it remains elusive which cerebral regions are involved by MLR-stimulation and contribute to the improvement of locomotion. Seventeen male Wistar rats underwent photothrombotic stroke of the right sensorimotor cortex and implantation of a microelectrode into the right MLR. 2-[18F]Fluoro-2-deoxyglucose ([18F]FDG)-positron emission tomography (PET) was conducted before stroke and thereafter, on day 2 and 3 after stroke, without and with MLR-HFS, respectively. [18F]FDG-PET imaging analyses yielded a reduced glucose metabolism in the right cortico-striatal thalamic loop after PTS compared to the state before intervention. When MLR-HFS was applied after PTS, animals exhibited a significantly higher uptake of [18F]FDG in the right but not in the left cortico-striatal thalamic loop. Furthermore, MLR-HFS resulted in an elevated glucose metabolism of right-sided association cortices related to the ipsilateral sensorimotor cortex. These data support the concept of diaschisis i.e., of dysfunctional brain areas distant to a focal lesion and suggests that MLR-HFS can reverse remote network effects following PTS in rats which otherwise may result in chronic motor symptoms.
Assuntos
Diásquise/fisiopatologia , Estimulação Elétrica/métodos , Mesencéfalo/fisiopatologia , Córtex Sensório-Motor/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Animais , Modelos Animais de Doenças , Masculino , Tomografia por Emissão de Pósitrons , Ratos , Ratos WistarRESUMO
Pain decreases the activity of many ventral tegmental area (VTA) dopamine (DA) neurons, yet the underlying neural circuitry connecting nociception and the DA system is not understood. Here we show that a subpopulation of lateral parabrachial (LPB) neurons is critical for relaying nociceptive signals from the spinal cord to the substantia nigra pars reticulata (SNR). SNR-projecting LPB neurons are activated by noxious stimuli and silencing them blocks pain responses in two different models of pain. LPB-targeted and nociception-recipient SNR neurons regulate VTA DA activity directly through feed-forward inhibition and indirectly by inhibiting a distinct subpopulation of VTA-projecting LPB neurons thereby reducing excitatory drive onto VTA DA neurons. Correspondingly, ablation of SNR-projecting LPB neurons is sufficient to reduce pain-mediated inhibition of DA release in vivo. The identification of a neural circuit conveying nociceptive input to DA neurons is critical to our understanding of how pain influences learning and behavior.
Assuntos
Neurônios Dopaminérgicos , Mesencéfalo/fisiopatologia , Vias Neurais/fisiopatologia , Dor/fisiopatologia , Núcleos Parabraquiais/fisiopatologia , Medula Espinal/fisiopatologia , Animais , Comportamento Animal , Mapeamento Encefálico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios , Nociceptividade , Optogenética , Dor/psicologia , Manejo da Dor , Substância Negra/fisiopatologia , Área Tegmentar Ventral/fisiopatologiaRESUMO
Neuropathic pain is a debilitating condition that is often refractory to treatment. The network of neural substrates for pain transmission and control within the brain is complex and remains poorly understood. Through a combination of neuronal tracing, optogenetics, chemogenetics, electrophysiological recordings, and behavioral assessment, we demonstrate that activation of layer 5 pyramidal neurons in the ventrolateral orbitofrontal cortex (vlOFC) attenuates mechanical and thermal hypersensitivity and cold allodynia in mice with neuropathic pain induced by spared nerve injury (SNI). These vlOFC output neurons project to the posterior ventrolateral periaqueductal gray (vlPAG) region and receive inputs from the ventromedial thalamus (VM). Specific optogenetic and chemogenetic activation of the vlOFC-vlPAG and the VM-vlOFC circuits inhibits hypersensitivity associated with neuropathy. Thus, we reveal a modulatory role of the vlOFC and its projections to the vlPAG circuit in the processing of hypersensitive nociception.
Assuntos
Mesencéfalo/fisiopatologia , Neuralgia/etiologia , Optogenética/métodos , Traumatismos dos Nervos Periféricos/terapia , Córtex Pré-Frontal/fisiopatologia , Animais , Humanos , Camundongos , Neuralgia/fisiopatologia , Traumatismos dos Nervos Periféricos/complicaçõesRESUMO
A spinal cord injury usually spares some components of the locomotor circuitry. Deep brain stimulation (DBS) of the midbrain locomotor region and epidural electrical stimulation of the lumbar spinal cord (EES) are being used to tap into this spared circuitry to enable locomotion in humans with spinal cord injury. While appealing, the potential synergy between DBS and EES remains unknown. Here, we report the synergistic facilitation of locomotion when DBS is combined with EES in a rat model of severe contusion spinal cord injury leading to leg paralysis. However, this synergy requires high amplitudes of DBS, which triggers forced locomotion associated with stress responses. To suppress these undesired responses, we link DBS to the intention to walk, decoded from cortical activity using a robust, rapidly calibrated unsupervised learning algorithm. This contingency amplifies the supraspinal descending command while empowering the rats into volitional walking. However, the resulting improvements may not outweigh the complex technological framework necessary to establish viable therapeutic conditions.
Assuntos
Estimulação Encefálica Profunda/métodos , Modelos Animais de Doenças , Vértebras Lombares/fisiopatologia , Córtex Motor/fisiopatologia , Traumatismos da Medula Espinal/terapia , Medula Espinal/fisiopatologia , Caminhada/fisiologia , Animais , Estimulação Elétrica/métodos , Feminino , Humanos , Locomoção/fisiologia , Mesencéfalo/fisiopatologia , Neurônios/fisiologia , Ratos Endogâmicos Lew , Traumatismos da Medula Espinal/fisiopatologiaRESUMO
RATIONALE: Prolonged use of cannabis, the most widely used illicit drug worldwide, has been consistently associated with impairment in memory and verbal learning. Although the neurophysiological underpinnings of these impairments have been investigated previously using functional magnetic resonance imaging (fMRI), while performing memory tasks, the results of these studies have been inconsistent and no clear picture has emerged yet. Furthermore, no previous studies have investigated trial-by-trial learning. OBJECTIVES: We aimed to investigate the neural underpinnings of impaired verbal learning in cannabis users as estimated over repeated learning trials. METHODS: We studied 21 adolescent-onset regular cannabis users and 21 non-users using fMRI performed at least 12 h after last cannabis use, while they performed a paired associate verbal learning task that allowed us to examine trial-by-trial learning. Brain activation during repeated verbal encoding and recall conditions of the task was indexed using the blood oxygen level-dependent haemodynamic response fMRI signal. RESULTS: There was a significant improvement in recall score over repeated trials indicating learning occurring across the two groups of participants. However, learning was significantly slower in cannabis users compared to non-users (p = 0.032, partial eta-squared = 0.108). While learning verbal stimuli over repeated encoding blocks, non-users displayed progressive increase in recruitment of the midbrain, parahippocampal gyrus and thalamus (p = 0.00939, partial eta-squared = 0.180). In contrast, cannabis users displayed a greater but disrupted activation pattern in these regions, which showed a stronger correlation with new word-pairs learnt over the same blocks in cannabis users than in non-users. CONCLUSIONS: These results suggest that disrupted medial temporal and midbrain function underlie slower learning in adolescent-onset cannabis users.
Assuntos
Imageamento por Ressonância Magnética/métodos , Fumar Maconha/psicologia , Aprendizagem Verbal/fisiologia , Adolescente , Adulto , Feminino , Humanos , Aprendizagem/fisiologia , Masculino , Memória/fisiologia , Rememoração Mental/fisiologia , Mesencéfalo/fisiopatologia , Giro Para-Hipocampal/fisiopatologia , Adulto JovemRESUMO
Epilepsy is a common brain network disorder associated with disrupted large-scale excitatory and inhibitory neural interactions. Recent resting-state fMRI evidence indicates that global signal (GS) fluctuations that have commonly been ignored are linked to neural activity. However, the mechanisms underlying the altered global pattern of fMRI spontaneous fluctuations in epilepsy remain unclear. Here, we quantified GS topography using beta weights obtained from a multiple regression model in a large group of epilepsy with different subtypes (98 focal temporal epilepsy; 116 generalized epilepsy) and healthy population (n = 151). We revealed that the nonuniformly distributed GS topography across association and sensory areas in healthy controls was significantly shifted in patients. Particularly, such shifts of GS topography disturbances were more widespread and bilaterally distributed in the midbrain, cerebellum, visual cortex, and medial and orbital cortex in generalized epilepsy, whereas in focal temporal epilepsy, these networks spread beyond the temporal areas but mainly remain lateralized. Moreover, we found that these abnormal GS topography patterns were likely to evolve over the course of a longer epilepsy disease. Our study demonstrates that epileptic processes can potentially affect global excitation/inhibition balance and shift the normal GS topological distribution. These progressive topographical GS disturbances in subcortical-cortical networks may underlie pathophysiological mechanisms of global fluctuations in human epilepsy.
Assuntos
Cerebelo/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Epilepsia/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Mesencéfalo/diagnóstico por imagem , Rede Nervosa/diagnóstico por imagem , Adolescente , Adulto , Cerebelo/fisiopatologia , Córtex Cerebral/fisiopatologia , Eletroencefalografia/métodos , Epilepsia/fisiopatologia , Feminino , Humanos , Masculino , Mesencéfalo/fisiopatologia , Rede Nervosa/fisiopatologia , Adulto JovemRESUMO
We report an 86-year-old woman who suffered sudden onset of diplopia while cooking. The patient presented with binocular diplopia, bilateral adduction weakness, convergence disorder and bilateral abduction nystagmus. Although brain MRI on admission detected no abnormality, a repeat MRI examination on the following day demonstrated a focal hyperintense lesion in the tegmentum of the midbrain on diffusion-weighted images. At 36 hours after admission, lower abdominal distension became apparent, and about 1 liter of urine was drained via a urethral catheter. Bladder filling sensation was not present, and we considered that the midbrain lesion had been responsible for the oculomotor disorder and urinary retention. As cerebral infarction was the most likely pathology of this lesion, an antiplatelet agent was administered. At two months after onset, the eye movement disorder was resolved and there was no diplopia. Bladder voiding also resumed at normal intervals. We considered that the bilateral medial longitudinal fasciculi and subgroups of the oculomotor nucleus, which contain motor neurons supplying the medial rectus muscle, had been responsible for the oculomotor disorder. The urinary retention was thought to have been caused by a lesion in the periaqueductal gray, which is one structure controlling micturition. This was a rare case of urinary retention due to a small midbrain infarction.
Assuntos
Infarto Cerebral/complicações , Mesencéfalo/diagnóstico por imagem , Transtornos da Motilidade Ocular/etiologia , Retenção Urinária/etiologia , Idoso de 80 Anos ou mais , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/fisiopatologia , Imagem de Difusão por Ressonância Magnética , Diplopia/etiologia , Feminino , Humanos , Mesencéfalo/fisiopatologia , Substância Cinzenta Periaquedutal/diagnóstico por imagem , Substância Cinzenta Periaquedutal/fisiopatologia , MicçãoRESUMO
Freezing of gait is a challenging sign of Parkinson's disease associated with disease severity and progression and involving the mesencephalic locomotor region. No predictive factor of freezing has been reported so far. The primary objective of this study was to identify predictors of freezing occurrence at 5 years. In addition, we tested whether functional connectivity of the mesencephalic locomotor region could explain the oculomotor factors at baseline that were predictive of freezing onset. We performed a prospective study investigating markers (parkinsonian signs, cognitive status and oculomotor recordings, with a particular focus on the antisaccade latencies) of disease progression at baseline and at 5 years. We identified two groups of patients defined by the onset of freezing at 5 years of follow-up; the 'Freezer' group was defined by the onset of freezing in the ON medication condition during follow-up (n = 17), while the 'non-Freezer' group did not (n = 8). Whole brain resting-state functional MRI was recorded at baseline to determine how antisaccade latencies were associated with connectivity of the mesencephalic locomotor region networks in patients compared to 25 age-matched healthy volunteers. Results showed that, at baseline and compared to the non-Freezer group, the Freezer group had equivalent motor or cognitive signs, but increased antisaccade latencies (P = 0.008). The 5-year course of freezing of gait was correlated with worsening antisaccade latencies (P = 0.0007). Baseline antisaccade latencies was also predictive of the freezing onset (χ2 = 0.008). Resting state connectivity of mesencephalic locomotor region networks correlated with (i) antisaccade latency differently in patients and healthy volunteers at baseline; and (ii) the further increase of antisaccade latency at 5 years. We concluded that antisaccade latency is a predictive marker of the 5-year onset of freezing of gait. Our study suggests that functional networks associated with gait and gaze control are concurrently altered during the course of the disease.
Assuntos
Encéfalo/fisiopatologia , Transtornos Neurológicos da Marcha/diagnóstico , Transtornos Neurológicos da Marcha/fisiopatologia , Doença de Parkinson/complicações , Movimentos Sacádicos , Idoso , Biomarcadores , Mapeamento Encefálico , Tecnologia de Rastreamento Ocular , Feminino , Transtornos Neurológicos da Marcha/complicações , Humanos , Imageamento por Ressonância Magnética , Masculino , Mesencéfalo/fisiopatologia , Pessoa de Meia-Idade , Vias Neurais/fisiopatologia , Doença de Parkinson/fisiopatologia , Sensibilidade e EspecificidadeRESUMO
Schizophrenia is a multifactorial developmental neuropsychiatric disorder. This study examined the interplay of maternal infection and postweaning social isolation, which are prenatal and postnatal risk factors, respectively. Pregnant mice received poly I:C or saline injection on gestation day 9 and the pups were weaned at postnatal day 28. After weaning, male offspring were randomly assigned into group-rearing and isolation-rearing groups. In their adulthood, we performed behavioral tests and characterized the histochemical features of their mesocorticolimbic structures. The sociability and anxiety levels were not affected by either manipulation, but synergistic effects of the two hits on stress-coping behavior was observed. Either of the single manipulations caused defects in sensorimotor gating, novel object recognition and spatial memory tests, but the combination of the two hits did not further exacerbate the disabilities. Prenatal infection increased the number of dopaminergic neurons in midbrain, whereas postweaning isolation decreased the GABAergic neurons in cortex. Single manipulation reduced the dendritic complexity and spine densities of neurons in the medial prefrontal cortex (mPFC) and dentate gyrus. Our results support the current perspective that disturbances in brain development during the prenatal or postnatal period influence the structure and function of the brain and together augment the susceptibility to mental disorders, such as schizophrenia.
Assuntos
Giro Denteado/fisiopatologia , Mesencéfalo/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Esquizofrenia/etiologia , Animais , Giro Denteado/efeitos dos fármacos , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Feminino , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/patologia , Masculino , Mesencéfalo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Poli I-C/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fatores de Risco , Esquizofrenia/fisiopatologiaRESUMO
INTRODUCTION: Core symptomatology in idiopathic normal pressure hydrocephalus (iNPH) points at dysfunction in the mesencephalon and pons indicating pathological changes in these regions, but only a few studies have addressed the issue. The aim of this study was to investigate diffusion (ADC) and perfusion patterns pre- and postoperatively in these areas in iNPH. METHODS: Twenty iNPH patients and 15 healthy controls were included. Patients underwent a clinical examination and brain MRI pre- and 3-6 months postoperatively. The MRI-scan included diffusion and dynamic susceptibility contrast perfusion weighted sequences. Regions of interest in the mesencephalon and pons were drawn on a FLAIR sequence and co-registered to ADC maps and perfusion data. RESULTS: There were no significant differences in pre or postoperative ADC compared to the control group, however postoperative ADC increased by 10% (p = 0.026) in the mesencephalon and 6% (p = 0.016) in the pons in all patients and also in the subgroup of shunt responders by 11% (p = 0.021) and 4% (p = 0.020), respectively. Preoperative relative cerebral blood flow (rCBF) was similar in iNPH patients and controls. Postoperatively, rCBF increased in shunt responders by 6% (p = 0.02) in the mesencephalon and 11% (p = 0.004) in the pons. This increase correlated with the degree of clinical improvement (rs = 0.80, p = 0.031 and rs = 0.66, p = 0.021, respectively). CONCLUSION: The postoperative increase in ADC and the correlation between postoperative increase in rCBF and clinical improvement in the mesencephalon and pons shown in this study point at an involvement of these areas in the core pathophysiology and its reversibility in iNPH.
Assuntos
Encéfalo/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Hidrocefalia de Pressão Normal/patologia , Mesencéfalo/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Circulação Cerebrovascular/fisiologia , Feminino , Humanos , Hidrocefalia de Pressão Normal/diagnóstico por imagem , Hidrocefalia de Pressão Normal/cirurgia , Masculino , Pessoa de Meia-Idade , Ponte/fisiopatologia , Período Pós-OperatórioRESUMO
Mild traumatic brain injury (TBI), including concussions, can cause symptoms affecting physical or cognitive domains in the acute and chronic phases. In this study, we investigated the dynamic deformation of the brain stem, which might be important for these symptoms, using a human brain finite element model through reconstruction simulations of rear-end collisions in three different velocities. In all simulations, high maximum principal strain values were observed at the midbrain that were higher than those in the corpus callosum. These findings could provide some mechanical insights into brain disorders associated with mild TBI.
Assuntos
Análise de Elementos Finitos , Mesencéfalo/patologia , Modelos Biológicos , Aceleração , Concussão Encefálica/patologia , Concussão Encefálica/fisiopatologia , Humanos , Pressão Intracraniana , Mesencéfalo/fisiopatologia , Estresse MecânicoRESUMO
The past decade has witnessed exponentially growing interest in the lateral habenula (LHb) owing to new discoveries relating to its critical role in regulating negatively motivated behaviour and its implication in major depression. The LHb, sometimes referred to as the brain's 'antireward centre', receives inputs from diverse limbic forebrain and basal ganglia structures, and targets essentially all midbrain neuromodulatory systems, including the noradrenergic, serotonergic and dopaminergic systems. Its unique anatomical position enables the LHb to act as a hub that integrates value-based, sensory and experience-dependent information to regulate various motivational, cognitive and motor processes. Dysfunction of the LHb may contribute to the pathophysiology of several psychiatric disorders, especially major depression. Recently, exciting progress has been made in identifying the molecular and cellular mechanisms in the LHb that underlie negative emotional state in animal models of drug withdrawal and major depression. A future challenge is to translate these advances into effective clinical treatments.
Assuntos
Gânglios da Base/fisiologia , Gânglios da Base/fisiopatologia , Habenula/fisiologia , Habenula/fisiopatologia , Sistema Límbico/fisiologia , Sistema Límbico/fisiopatologia , Mesencéfalo/fisiologia , Mesencéfalo/fisiopatologia , Animais , Saúde , Humanos , Transtornos Mentais/fisiopatologia , Vias Neurais/fisiologia , Vias Neurais/fisiopatologiaRESUMO
Psychosis has been proposed to develop from dysfunction in a hippocampal-striatal-midbrain circuit, leading to aberrant salience processing. Here, we used functional magnetic resonance imaging (fMRI) during novelty salience processing to investigate this model in people at clinical high risk (CHR) for psychosis according to their subsequent clinical outcomes. Seventy-six CHR participants as defined using the Comprehensive Assessment of At-Risk Mental States (CAARMS) and 31 healthy controls (HC) were studied while performing a novelty salience fMRI task that engaged an a priori hippocampal-striatal-midbrain circuit of interest. The CHR sample was then followed clinically for a mean of 59.7 months (~5 y), when clinical outcomes were assessed in terms of transition (CHR-T) or non-transition (CHR-NT) to psychosis (CAARMS criteria): during this period, 13 individuals (17%) developed a psychotic disorder (CHR-T) and 63 did not. Functional activation and effective connectivity within a hippocampal-striatal-midbrain circuit were compared between groups. In CHR individuals compared to HC, hippocampal response to novel stimuli was significantly attenuated (P = .041 family-wise error corrected). Dynamic Causal Modelling revealed that stimulus novelty modulated effective connectivity from the hippocampus to the striatum, and from the midbrain to the hippocampus, significantly more in CHR participants than in HC. Conversely, stimulus novelty modulated connectivity from the midbrain to the striatum significantly less in CHR participants than in HC, and less in CHR participants who subsequently developed psychosis than in CHR individuals who did not become psychotic. Our findings are consistent with preclinical evidence implicating hippocampal-striatal-midbrain circuit dysfunction in altered salience processing and the onset of psychosis.
Assuntos
Atenção/fisiologia , Conectoma , Corpo Estriado/fisiopatologia , Hipocampo/fisiopatologia , Mesencéfalo/fisiopatologia , Rede Nervosa/fisiopatologia , Reconhecimento Visual de Modelos/fisiologia , Transtornos Psicóticos/fisiopatologia , Esquizofrenia/fisiopatologia , Adulto , Corpo Estriado/diagnóstico por imagem , Feminino , Seguimentos , Hipocampo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Mesencéfalo/diagnóstico por imagem , Rede Nervosa/diagnóstico por imagem , Sintomas Prodrômicos , Desempenho Psicomotor/fisiologia , Transtornos Psicóticos/diagnóstico por imagem , Esquizofrenia/diagnóstico por imagem , Adulto JovemRESUMO
BACKGROUND: The objective of this study was to evaluate ON-state resting state functional connectivity (FC) from the mesencephalic locomotor regions (MLR) to distributed sensorimotor cortical regions in patients with Freezing of Gait (FOG) and its association with gait performance. METHODS: 54 individuals with PD were recruited for this study (50% of whom had FOG). All individuals received a resting state functional MRI in the ON state, and underwent a series of gait assessments during single and dual task conditions. FC with the MLR was calculated using a whole brain seed to voxel approach wherein the left and right MLR seeds were extracted from a published atlas. General linear regression was used to determine differences in connectivity between the individuals with ('freezers') and without ('non-freezers') FOG as well as the correlation between MLR connectivity and gait performance in the freezers. RESULTS: Freezers had significantly higher MLR connectivity to a network of sensorimotor regions compared to non-freezers. Additionally, among the freezers, higher FC with these regions was related to longer single-task and dual-task performance. There were no regions in which non-freezers had higher connectivity than freezers (p < 0.05, FWE corrected clusters for all analyses). CONCLUSION: These data support the hypothesis that freezers have significantly higher ON-state FC between the MLR and a network of cortical structures than non-freezers. Additionally, this elevated connectivity is directly related to worsening FOG severity. These data add to a theoretical foundation which suggests that cortical hyperconnectivity to the MLR is central to the underlying pathophysiology of FOG.
Assuntos
Córtex Cerebral/fisiopatologia , Conectoma , Transtornos Neurológicos da Marcha/fisiopatologia , Mesencéfalo/fisiopatologia , Rede Nervosa/fisiopatologia , Doença de Parkinson/fisiopatologia , Desempenho Psicomotor/fisiologia , Idoso , Córtex Cerebral/diagnóstico por imagem , Feminino , Transtornos Neurológicos da Marcha/diagnóstico por imagem , Transtornos Neurológicos da Marcha/etiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Mesencéfalo/diagnóstico por imagem , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagemRESUMO
Parkinson's disease (PD) is a common progressive neurodegenerative disease. PD produces a pathological state in the intestine and disordered gut microbiota (GM), which may be important for the pathogenesis and progression of PD, but it is not clear. To explore the conditions and characteristics of intestinal pathology and GM disorders when PD-related injuries occur, we used twice 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) subacute administration with an interval of 3 weeks (each was an intraperitoneal injection of 25â¯mg/kg MPTP for 5 consecutive days). We observed the changes in intestinal and brain immune status, intestinal barrier function and GM in different injury states one day, one week, and three weeks after the first stimulus and one day and one week after the second stimulus. Our study found that two subacute administrations of MPTP induced dopaminergic (DAergic) neuron injury and inflammation in the midbrain and ileum, impaired intestinal barrier function and GM disorders closely related to administration. These changes recovered after the first administration, but after repeated administration, some indicators showed more dramatic changes than during the first administration. Our results suggest that the intestinal tract is sensitive to PD-related injury, and the GM is susceptible to disturbances caused by intestinal function, which may be concerned in local immune disorders of the intestine.
Assuntos
Neurônios Dopaminérgicos/fisiologia , Encefalite/fisiopatologia , Microbioma Gastrointestinal/fisiologia , Íleo/fisiopatologia , Mesencéfalo/fisiopatologia , Doença de Parkinson/fisiopatologia , Animais , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Encefalite/metabolismo , Íleo/patologia , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/microbiologia , Intoxicação por MPTP/fisiopatologia , Masculino , Mesencéfalo/patologia , Camundongos Endogâmicos C57BL , Doença de Parkinson/metabolismo , Doença de Parkinson/microbiologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Parkinson's disease (PD) is a progressive neuropathology characterized by motor and non-motor alterations. ß-sitosterol ß-d-glucoside (BSSG) is a neurotoxin whose prolonged oral administration in rats has been proposed as a new PD model. Herein, we demonstrate that a single, unilateral, and intranigral administration of BSSG also elicits bilateral sensorimotor alterations in the rat. Six behavioral tests evaluated the effect of different concentrations of BSSG (3, 6, 9, and 12 µg/µL DMSO) from 15 to 120 days after administration. The first behavioral alterations, which appeared on day 15, were unbalanced and uncoordinated gaits and a decrease in the sensorimotor cortex activity, as evidenced by the beam-walking and the vibrissae tests, respectively. After 30 days, the corridor test revealed hyposmia and a decreased locomotor activity in the open field. The last alteration was a depressive-like behavior, as shown by the forced swim test on days 60 and 120. According to the cylinder test, no locomotor asymmetry was observed over time with any BSSG concentrations tested. Also, a mesencephalic TH(+) cell loss (p < 0.05) was shown on day 30 when compared with the mock condition, and such a loss was even higher on day 120. At this time, the presence of pathological α-synuclein aggregates in the mesencephalon was documented. Our results show that the stereotaxic intranigral administration of BSSG reproduces some characteristics of oral administration, such as the progression of behavioral alterations, dopaminergic neurons loss, and the presence of Lewy body-like synuclein aggregations, in less time and resources.
Assuntos
Anosmia , Depressão , Neurônios Dopaminérgicos , Transtornos Neurológicos da Marcha , Locomoção , Mesencéfalo , Neurotoxinas/farmacologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson , Córtex Sensório-Motor , Sitosteroides/farmacologia , Animais , Anosmia/induzido quimicamente , Anosmia/patologia , Anosmia/fisiopatologia , Depressão/induzido quimicamente , Depressão/patologia , Depressão/fisiopatologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Transtornos Neurológicos da Marcha/induzido quimicamente , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/patologia , Transtornos Neurológicos da Marcha/fisiopatologia , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/patologia , Mesencéfalo/fisiopatologia , Neurotoxinas/administração & dosagem , Doença de Parkinson/complicações , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Ratos , Ratos Wistar , Córtex Sensório-Motor/fisiopatologia , Sitosteroides/administração & dosagem , Substância Negra/efeitos dos fármacosRESUMO
A developing theory is that individuals with alcohol use disorder (AUD) display exaggerated reactivity to threats that are uncertain (U-threat), which facilitates excessive drinking as a means of avoidance-based coping. There is a promising initial behavioral evidence supporting this theory; however, the neural bases of reactivity to U-threat in individuals with AUD have not been examined. The extent to which biomarkers of U-threat reactivity map onto drinking behaviors and coping motives for alcohol use is also unknown. The current study therefore examined group differences in behavioral and neural reactivity to U-threat in adults with and without AUD. The study also tested whether behavior and brain responses to U-threat correlate with problematic drinking and coping motivated drinking. Volunteers (n = 65) with and without a history of AUD (38 AUD, 27 controls) were included and completed a well-validated threat-of-shock task to probe responses to U-threat and predictable threat (P-threat) while startle eyeblink potentiation was collected. Individuals also completed a newly designed, analogous version of the task during functional magnetic resonance imaging (fMRI). Results indicated that individuals with AUD displayed greater startle magnitude during U-threat, but not P-threat, and greater right insula and dorsal anterior cingulate cortex (dACC) activation during both forms of threat compared with controls. Startle magnitude and insula activation during U-threat positively correlated with self-reported problem drinking and coping motives for alcohol use. Findings demonstrate that individuals with AUD display exaggerated sensitivity to U-threat at the behavioral and neural level and that these multimethod biomarkers tap into negative reinforcement processes of alcohol abuse.