RESUMEN
A single dose of psilocybin, a psychedelic that acutely causes distortions of space-time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trials1-4. In animal models, psilocybin induces neuroplasticity in cortex and hippocampus5-8. It remains unclear how human brain network changes relate to subjective and lasting effects of psychedelics. Here we tracked individual-specific brain changes with longitudinal precision functional mapping (roughly 18 magnetic resonance imaging visits per participant). Healthy adults were tracked before, during and for 3 weeks after high-dose psilocybin (25 mg) and methylphenidate (40 mg), and brought back for an additional psilocybin dose 6-12 months later. Psilocybin massively disrupted functional connectivity (FC) in cortex and subcortex, acutely causing more than threefold greater change than methylphenidate. These FC changes were driven by brain desynchronization across spatial scales (areal, global), which dissolved network distinctions by reducing correlations within and anticorrelations between networks. Psilocybin-driven FC changes were strongest in the default mode network, which is connected to the anterior hippocampus and is thought to create our sense of space, time and self. Individual differences in FC changes were strongly linked to the subjective psychedelic experience. Performing a perceptual task reduced psilocybin-driven FC changes. Psilocybin caused persistent decrease in FC between the anterior hippocampus and default mode network, lasting for weeks. Persistent reduction of hippocampal-default mode network connectivity may represent a neuroanatomical and mechanistic correlate of the proplasticity and therapeutic effects of psychedelics.
Asunto(s)
Encéfalo , Alucinógenos , Red Nerviosa , Psilocibina , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Encéfalo/citología , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Mapeo Encefálico , Red en Modo Predeterminado/citología , Red en Modo Predeterminado/diagnóstico por imagen , Red en Modo Predeterminado/efectos de los fármacos , Red en Modo Predeterminado/fisiología , Alucinógenos/farmacología , Alucinógenos/administración & dosificación , Voluntarios Sanos , Hipocampo/citología , Hipocampo/diagnóstico por imagen , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Imagen por Resonancia Magnética , Metilfenidato/farmacología , Metilfenidato/administración & dosificación , Red Nerviosa/citología , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/efectos de los fármacos , Red Nerviosa/fisiología , Psilocibina/farmacología , Psilocibina/administración & dosificación , Percepción Espacial/efectos de los fármacos , Percepción del Tiempo/efectos de los fármacos , EgoRESUMEN
Motor cortex (M1) has been thought to form a continuous somatotopic homunculus extending down the precentral gyrus from foot to face representations1,2, despite evidence for concentric functional zones3 and maps of complex actions4. Here, using precision functional magnetic resonance imaging (fMRI) methods, we find that the classic homunculus is interrupted by regions with distinct connectivity, structure and function, alternating with effector-specific (foot, hand and mouth) areas. These inter-effector regions exhibit decreased cortical thickness and strong functional connectivity to each other, as well as to the cingulo-opercular network (CON), critical for action5 and physiological control6, arousal7, errors8 and pain9. This interdigitation of action control-linked and motor effector regions was verified in the three largest fMRI datasets. Macaque and pediatric (newborn, infant and child) precision fMRI suggested cross-species homologues and developmental precursors of the inter-effector system. A battery of motor and action fMRI tasks documented concentric effector somatotopies, separated by the CON-linked inter-effector regions. The inter-effectors lacked movement specificity and co-activated during action planning (coordination of hands and feet) and axial body movement (such as of the abdomen or eyebrows). These results, together with previous studies demonstrating stimulation-evoked complex actions4 and connectivity to internal organs10 such as the adrenal medulla, suggest that M1 is punctuated by a system for whole-body action planning, the somato-cognitive action network (SCAN). In M1, two parallel systems intertwine, forming an integrate-isolate pattern: effector-specific regions (foot, hand and mouth) for isolating fine motor control and the SCAN for integrating goals, physiology and body movement.
Asunto(s)
Mapeo Encefálico , Cognición , Corteza Motora , Mapeo Encefálico/métodos , Mano/fisiología , Imagen por Resonancia Magnética , Corteza Motora/anatomía & histología , Corteza Motora/fisiología , Humanos , Recién Nacido , Lactante , Niño , Animales , Macaca/anatomía & histología , Macaca/fisiología , Pie/fisiología , Boca/fisiología , Conjuntos de Datos como AsuntoRESUMEN
Major depressive disorder (MDD) is widely hypothesized to result from disordered communication across brain-wide networks. Yet, prior resting-state-functional MRI (rs-fMRI) studies of MDD have studied zero-lag temporal synchrony (functional connectivity) in brain activity absent directional information. We utilize the recent discovery of stereotyped brain-wide directed signaling patterns in humans to investigate the relationship between directed rs-fMRI activity, MDD, and treatment response to FDA-approved neurostimulation paradigm termed Stanford neuromodulation therapy (SNT). We find that SNT over the left dorsolateral prefrontal cortex (DLPFC) induces directed signaling shifts in the left DLPFC and bilateral anterior cingulate cortex (ACC). Directional signaling shifts in the ACC, but not the DLPFC, predict improvement in depression symptoms, and moreover, pretreatment ACC signaling predicts both depression severity and the likelihood of SNT treatment response. Taken together, our findings suggest that ACC-based directed signaling patterns in rs-fMRI are a potential biomarker of MDD.
Asunto(s)
Trastorno Depresivo Mayor , Humanos , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/terapia , Depresión , Imagen por Resonancia Magnética , Encéfalo/diagnóstico por imagen , Giro del Cíngulo/diagnóstico por imagen , Corteza Prefrontal/diagnóstico por imagenRESUMEN
The distribution of brain aerobic glycolysis (AG) in normal young adults correlates spatially with amyloid-beta (Aß) deposition in individuals with symptomatic and preclinical Alzheimer disease (AD). Brain AG decreases with age, but the functional significance of this decrease with regard to the development of AD symptomatology is poorly understood. Using PET measurements of regional blood flow, oxygen consumption, and glucose utilization-from which we derive AG-we find that cognitive impairment is strongly associated with loss of the typical youthful pattern of AG. In contrast, amyloid positivity without cognitive impairment was associated with preservation of youthful brain AG, which was even higher than that seen in cognitively unimpaired, amyloid negative adults. Similar findings were not seen for blood flow nor oxygen consumption. Finally, in cognitively unimpaired adults, white matter hyperintensity burden was found to be specifically associated with decreased youthful brain AG. Our results suggest that AG may have a role in the resilience and/or response to early stages of amyloid pathology and that age-related white matter disease may impair this process.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Adulto Joven , Humanos , Enfermedad de Alzheimer/patología , Tomografía de Emisión de Positrones , Encéfalo/metabolismo , Péptidos beta-Amiloides/metabolismo , Disfunción Cognitiva/patología , Amiloide/metabolismo , Proteínas Amiloidogénicas , GlucólisisRESUMEN
Slow waves (SWs) are globally propagating, low-frequency (0.5- to 4-Hz) oscillations that are prominent during sleep and anesthesia. SWs are essential to neural plasticity and memory. However, much remains unknown about the mechanisms coordinating SW propagation at the macroscale. To assess SWs in the context of macroscale networks, we recorded cortical activity in awake and ketamine/xylazine-anesthetized mice using widefield optical imaging with fluorescent calcium indicator GCaMP6f. We demonstrate that unilateral somatosensory stimulation evokes bilateral waves that travel across the cortex with state-dependent trajectories. Under anesthesia, we observe that rhythmic stimuli elicit globally resonant, front-to-back propagating SWs. Finally, photothrombotic lesions of S1 show that somatosensory-evoked global SWs depend on bilateral recruitment of homotopic primary somatosensory cortices. Specifically, unilateral lesions of S1 disrupt somatosensory-evoked global SW initiation from either hemisphere, while spontaneous SWs are largely unchanged. These results show that evoked SWs may be triggered by bilateral activation of specific, homotopically connected cortical networks.
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Ondas Encefálicas/fisiología , Estimulación Eléctrica , Potenciales Evocados Somatosensoriales , Sueño/fisiología , Corteza Somatosensorial/fisiología , Vigilia/fisiología , Animales , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
The hippocampus is critically important for a diverse range of cognitive processes, such as episodic memory, prospective memory, affective processing, and spatial navigation. Using individual-specific precision functional mapping of resting-state functional MRI data, we found the anterior hippocampus (head and body) to be preferentially functionally connected to the default mode network (DMN), as expected. The hippocampal tail, however, was strongly preferentially functionally connected to the parietal memory network (PMN), which supports goal-oriented cognition and stimulus recognition. This anterior-posterior dichotomy of resting-state functional connectivity was well-matched by differences in task deactivations and anatomical segmentations of the hippocampus. Task deactivations were localized to the hippocampal head and body (DMN), relatively sparing the tail (PMN). The functional dichotomization of the hippocampus into anterior DMN-connected and posterior PMN-connected parcels suggests parallel but distinct circuits between the hippocampus and medial parietal cortex for self- versus goal-oriented processing.
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Mapeo Encefálico , Hipocampo/fisiología , Red Nerviosa/fisiología , Lóbulo Parietal/fisiología , Adulto , Bases de Datos Factuales , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Memoria Episódica , Vías Nerviosas , Análisis y Desempeño de Tareas , Adulto JovenRESUMEN
Whole-brain resting-state functional MRI (rs-fMRI) during 2 wk of upper-limb casting revealed that disused motor regions became more strongly connected to the cingulo-opercular network (CON), an executive control network that includes regions of the dorsal anterior cingulate cortex (dACC) and insula. Disuse-driven increases in functional connectivity (FC) were specific to the CON and somatomotor networks and did not involve any other networks, such as the salience, frontoparietal, or default mode networks. Censoring and modeling analyses showed that FC increases during casting were mediated by large, spontaneous activity pulses that appeared in the disused motor regions and CON control regions. During limb constraint, disused motor circuits appear to enter a standby mode characterized by spontaneous activity pulses and strengthened connectivity to CON executive control regions.
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Giro del Cíngulo/fisiología , Plasticidad Neuronal/fisiología , Descanso/fisiología , Adulto , Mapeo Encefálico , Función Ejecutiva/fisiología , Femenino , Giro del Cíngulo/citología , Giro del Cíngulo/diagnóstico por imagen , Voluntarios Sanos , Humanos , Imagen por Resonancia Magnética , Masculino , Red Nerviosa/fisiologíaRESUMEN
The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its discovery was an unexpected consequence of brain-imaging studies first performed with positron emission tomography in which various novel, attention-demanding, and non-self-referential tasks were compared with quiet repose either with eyes closed or with simple visual fixation. The default mode network consistently decreases its activity when compared with activity during these relaxed nontask states. The discovery of the default mode network reignited a longstanding interest in the significance of the brain's ongoing or intrinsic activity. Presently, studies of the brain's intrinsic activity, popularly referred to as resting-state studies, have come to play a major role in studies of the human brain in health and disease. The brain's default mode network plays a central role in this work.
Asunto(s)
Encéfalo/fisiología , Vías Nerviosas/fisiología , Descanso/fisiología , Animales , HumanosRESUMEN
Multimodal evidence suggests that brain regions accumulate information over timescales that vary according to anatomical hierarchy. Thus, these experimentally defined "temporal receptive windows" are longest in cortical regions that are distant from sensory input. Interestingly, spontaneous activity in these regions also plays out over relatively slow timescales (i.e., exhibits slower temporal autocorrelation decay). These findings raise the possibility that hierarchical timescales represent an intrinsic organizing principle of brain function. Here, using resting-state functional MRI, we show that the timescale of ongoing dynamics follows hierarchical spatial gradients throughout human cerebral cortex. These intrinsic timescale gradients give rise to systematic frequency differences among large-scale cortical networks and predict individual-specific features of functional connectivity. Whole-brain coverage permitted us to further investigate the large-scale organization of subcortical dynamics. We show that cortical timescale gradients are topographically mirrored in striatum, thalamus, and cerebellum. Finally, timescales in the hippocampus followed a posterior-to-anterior gradient, corresponding to the longitudinal axis of increasing representational scale. Thus, hierarchical dynamics emerge as a global organizing principle of mammalian brains.
Asunto(s)
Mapeo Encefálico/métodos , Encéfalo/fisiología , Vías Nerviosas/fisiología , Adulto , Corteza Cerebral/fisiología , Cuerpo Estriado/fisiología , Bases de Datos Factuales , Femenino , Sustancia Gris/fisiología , Hipocampo/fisiología , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Descanso/fisiología , Factores de TiempoRESUMEN
The amygdala is central to the pathophysiology of many psychiatric illnesses. An imprecise understanding of how the amygdala fits into the larger network organization of the human brain, however, limits our ability to create models of dysfunction in individual patients to guide personalized treatment. Therefore, we investigated the position of the amygdala and its functional subdivisions within the network organization of the brain in 10 highly sampled individuals (5 h of fMRI data per person). We characterized three functional subdivisions within the amygdala of each individual. We discovered that one subdivision is preferentially correlated with the default mode network; a second is preferentially correlated with the dorsal attention and fronto-parietal networks; and third subdivision does not have any networks to which it is preferentially correlated relative to the other two subdivisions. All three subdivisions are positively correlated with ventral attention and somatomotor networks and negatively correlated with salience and cingulo-opercular networks. These observations were replicated in an independent group dataset of 120 individuals. We also found substantial across-subject variation in the distribution and magnitude of amygdala functional connectivity with the cerebral cortex that related to individual differences in the stereotactic locations both of amygdala subdivisions and of cortical functional brain networks. Finally, using lag analyses, we found consistent temporal ordering of fMRI signals in the cortex relative to amygdala subdivisions. Altogether, this work provides a detailed framework of amygdala-cortical interactions that can be used as a foundation for models relating aberrations in amygdala connectivity to psychiatric symptoms in individual patients.
Asunto(s)
Amígdala del Cerebelo/fisiología , Adulto , Amígdala del Cerebelo/diagnóstico por imagen , Atención , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Mapeo Encefálico , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/fisiología , Femenino , Humanos , Individualidad , Imagen por Resonancia Magnética , Masculino , Psiquiatría , Adulto JovenRESUMEN
Sex differences influence brain morphology and physiology during both development and aging. Here we apply a machine learning algorithm to a multiparametric brain PET imaging dataset acquired in a cohort of 20- to 82-year-old, cognitively normal adults (n = 205) to define their metabolic brain age. We find that throughout the adult life span the female brain has a persistently lower metabolic brain age-relative to their chronological age-compared with the male brain. The persistence of relatively younger metabolic brain age in females throughout adulthood suggests that development might in part influence sex differences in brain aging. Our results also demonstrate that trajectories of natural brain aging vary significantly among individuals and provide a method to measure this.
Asunto(s)
Envejecimiento/fisiología , Atención/fisiología , Encéfalo/fisiología , Cognición/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Encéfalo/diagnóstico por imagen , Femenino , Humanos , Aprendizaje Automático , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Caracteres Sexuales , Adulto JovenRESUMEN
Spontaneous infra-slow (<0.1 Hz) fluctuations in functional magnetic resonance imaging (fMRI) signals are temporally correlated within large-scale functional brain networks, motivating their use for mapping systems-level brain organization. However, recent electrophysiological and hemodynamic evidence suggest state-dependent propagation of infra-slow fluctuations, implying a functional role for ongoing infra-slow activity. Crucially, the study of infra-slow temporal lag structure has thus far been limited to large groups, as analyzing propagation delays requires extensive data averaging to overcome sampling variability. Here, we use resting-state fMRI data from 11 extensively-sampled individuals to characterize lag structure at the individual level. In addition to stable individual-specific features, we find spatiotemporal topographies in each subject similar to the group average. Notably, we find a set of early regions that are common to all individuals, are preferentially positioned proximal to multiple functional networks, and overlap with brain regions known to respond to diverse behavioral tasks-altogether consistent with a hypothesized ability to broadly influence cortical excitability. Our findings suggest that, like correlation structure, temporal lag structure is a fundamental organizational property of resting-state infra-slow activity.
Asunto(s)
Encéfalo/fisiología , Hemodinámica/fisiología , Red Nerviosa/fisiología , Descanso/fisiología , Mapeo Encefálico/métodos , Electroencefalografía/métodos , Humanos , Imagen por Resonancia Magnética/métodos , Fenómenos Fisiológicos del Sistema NerviosoRESUMEN
Electrophysiological recordings have established that GABAergic interneurons regulate excitability, plasticity, and computational function within local neural circuits. Importantly, GABAergic inhibition is focally disrupted around sites of brain injury. However, it remains unclear whether focal imbalances in inhibition/excitation lead to widespread changes in brain activity. Here, we test the hypothesis that focal perturbations in excitability disrupt large-scale brain network dynamics. We used viral chemogenetics in mice to reversibly manipulate parvalbumin interneuron (PV-IN) activity levels in whisker barrel somatosensory cortex. We then assessed how this imbalance affects cortical network activity in awake mice using wide-field optical neuroimaging of pyramidal neuron GCaMP dynamics as well as local field potential recordings. We report 1) that local changes in excitability can cause remote, network-wide effects, 2) that these effects propagate differentially through intra- and interhemispheric connections, and 3) that chemogenetic constructs can induce plasticity in cortical excitability and functional connectivity. These findings may help to explain how focal activity changes following injury lead to widespread network dysfunction.
Asunto(s)
Excitabilidad Cortical/fisiología , Interneuronas/fisiología , Vías Nerviosas/fisiopatología , Células Piramidales/fisiología , Corteza Somatosensorial/fisiopatología , Animales , Electrocorticografía , Interneuronas/metabolismo , Ratones , Inhibición Neural/fisiología , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/metabolismo , Plasticidad Neuronal/fisiología , Imagen Óptica , Parvalbúminas , Células Piramidales/metabolismo , Procesamiento de Señales Asistido por Computador , Corteza Somatosensorial/diagnóstico por imagen , Corteza Somatosensorial/metabolismo , Vibrisas/inervaciónRESUMEN
fMRI revolutionized neuroscience by allowing in vivo real-time detection of human brain activity. While the nature of the fMRI signal is understood as resulting from variations in the MRI signal due to brain-activity-induced changes in the blood oxygenation level (BOLD effect), these variations constitute a very minor part of a baseline MRI signal. Hence, the fundamental (and not addressed) questions are how underlying brain cellular composition defines this baseline MRI signal and how a baseline MRI signal relates to fMRI. Herein we investigate these questions by using a multimodality approach that includes quantitative gradient recalled echo (qGRE), volumetric and functional connectivity MRI, and gene expression data from the Allen Human Brain Atlas. We demonstrate that in vivo measurement of the major baseline component of a GRE signal decay rate parameter (R2t*) provides a unique genetic perspective into the cellular constituents of the human cortex and serves as a previously unidentified link between cortical tissue composition and fMRI signal. Data show that areas of the brain cortex characterized by higher R2t* have high neuronal density and have stronger functional connections to other brain areas. Interestingly, these areas have a relatively smaller concentration of synapses and glial cells, suggesting that myelinated cortical axons are likely key cortical structures that contribute to functional connectivity. Given these associations, R2t* is expected to be a useful signal in assessing microstructural changes in the human brain during development and aging in health and disease.
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Encéfalo/metabolismo , Redes Reguladoras de Genes , Genoma Humano , Imagen por Resonancia Magnética/métodos , Adulto , Anciano , Encéfalo/irrigación sanguínea , Mapeo Encefálico , Circulación Cerebrovascular , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Patterns of low frequency brain-wide activity have drawn attention across multiple disciplines in neuroscience. Brain-wide activity patterns are often described through correlations, which capture concurrent increases and decreases in neural activity. More recently, several groups have described reproducible temporal sequences across the brain, illustrating precise long-distance control over the timing of low frequency activity. Features of correlation and temporal organization both point to a systems-level structure of brain activity consisting of large-scale networks and their mutual interactions. Yet a unified view for understanding large networks and their interactions remains elusive. Here, we propose a framework for computing probabilistic flow in brain-wide activity. We demonstrate how flow probabilities are modulated across rest and task states and show that the probabilistic perspective captures both intra- and inter-network dynamics. Finally, we suggest that a probabilistic framework may prove fruitful in characterizing low frequency brain-wide activity in health and disease.
Asunto(s)
Mapeo Encefálico/métodos , Encéfalo/fisiología , Imagen por Resonancia Magnética , Adulto , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Masculino , Modelos Estadísticos , Vías Nerviosas/fisiología , Procesamiento de Señales Asistido por Computador , Adulto JovenRESUMEN
Spontaneous infra-slow brain activity (ISA) exhibits a high degree of temporal synchrony, or correlation, between distant brain regions. The spatial organization of ISA synchrony is not explained by anatomical connections alone, suggesting that active neural processes coordinate spontaneous activity. Inhibitory interneurons (IINs) form electrically coupled connections via the gap junction protein connexin 36 (Cx36) and networks of interconnected IINs are known to influence neural synchrony over short distances. However, the role of electrically coupled IIN networks in regulating spontaneous correlation over the entire brain is unknown. In this study, we performed OIS imaging on Cx36-/- mice to examine the role of this gap junction in ISA correlation across the entire cortex. We show that Cx36 deletion increased long-distance intra-hemispheric anti-correlation and inter-hemispheric correlation in spontaneous ISA. This suggests that electrically coupled IIN networks modulate ISA synchrony over long cortical distances.
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Corteza Cerebral/metabolismo , Conexinas/deficiencia , Interneuronas/metabolismo , Red Nerviosa/metabolismo , Inhibición Neural/fisiología , Animales , Corteza Cerebral/citología , Conexinas/genética , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Red Nerviosa/citología , Distribución Aleatoria , Proteína delta-6 de Union ComunicanteRESUMEN
Tauopathy is a hallmark pathology of Alzheimer's disease with a strong relationship with cognitive impairment. As such, understanding tau may be a key to clinical interventions. In vivo tauopathy has been measured using cerebrospinal fluid assays, but these do not provide information about where pathology is in the brain. The introduction of PET ligands that bind to paired helical filaments provides the ability to measure the amount and distribution of tau pathology. The heritability of the age of dementia onset tied to the specific mutations found in autosomal dominant Alzheimer's disease families provides an elegant model to study the spread of tau across the course of the disease as well as the cross-modal relationship between tau and other biomarkers. To better understand the pathobiology of Alzheimer's disease we measured levels of tau PET binding in individuals with dominantly inherited Alzheimer's disease using data from the Dominantly Inherited Alzheimer Network (DIAN). We examined cross-sectional measures of amyloid-ß, tau, glucose metabolism, and grey matter degeneration in 15 cognitively normal mutation non-carriers, 20 asymptomatic carriers, and 15 symptomatic mutation carriers. Linear models examined the association of pathology with group, estimated years to symptom onset, as well as cross-modal relationships. For comparison, tau PET was acquired on 17 older adults with sporadic, late onset Alzheimer disease. Tau PET binding was starkly elevated in symptomatic DIAN individuals throughout the cortex. The brain areas demonstrating elevated tau PET binding overlapped with those seen in sporadic Alzheimer's disease, but with a greater cortical involvement and greater levels of binding despite similar cognitive impairment. Tau PET binding was elevated in the temporal lobe, but the most prominent loci of pathology were in the precuneus and lateral parietal regions. Symptomatic mutation carriers also demonstrated elevated tau PET binding in the basal ganglia, consistent with prior work with amyloid-ß. The degree of tau tracer binding in symptomatic individuals was correlated to other biomarkers, particularly markers of neurodegeneration. In addition to the differences seen with tau, amyloid-ß was increased in both asymptomatic and symptomatic groups relative to non-carriers. Glucose metabolism showed decline primarily in the symptomatic group. MRI indicated structural degeneration in both asymptomatic and symptomatic cohorts. We demonstrate that tau PET binding is elevated in symptomatic individuals with dominantly inherited Alzheimer's disease. Tau PET uptake was tied to the onset of cognitive dysfunction, and there was a higher amount, and different regional pattern of binding compared to late onset, non-familial Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Tauopatías/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/metabolismo , Biomarcadores/metabolismo , Encéfalo/metabolismo , Cognición/fisiología , Disfunción Cognitiva/metabolismo , Demencia/metabolismo , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Ovillos Neurofibrilares/metabolismo , Presenilina-1/genética , Proteínas tau/metabolismoRESUMEN
Decades of work in experimental animals has established the importance of visual experience during critical periods for the development of normal sensory-evoked responses in the visual cortex. However, much less is known concerning the impact of early visual experience on the systems-level organization of spontaneous activity. Human resting-state fMRI has revealed that infraslow fluctuations in spontaneous activity are organized into stereotyped spatiotemporal patterns across the entire brain. Furthermore, the organization of spontaneous infraslow activity (ISA) is plastic in that it can be modulated by learning and experience, suggesting heightened sensitivity to change during critical periods. Here we used wide-field optical intrinsic signal imaging in mice to examine whole-cortex spontaneous ISA patterns. Using monocular or binocular visual deprivation, we examined the effects of critical period visual experience on the development of ISA correlation and latency patterns within and across cortical resting-state networks. Visual modification with monocular lid suturing reduced correlation between left and right cortices (homotopic correlation) within the visual network, but had little effect on internetwork correlation. In contrast, visual deprivation with binocular lid suturing resulted in increased visual homotopic correlation and increased anti-correlation between the visual network and several extravisual networks, suggesting cross-modal plasticity. These network-level changes were markedly attenuated in mice with genetic deletion of Arc, a gene known to be critical for activity-dependent synaptic plasticity. Taken together, our results suggest that critical period visual experience induces global changes in spontaneous ISA relationships, both within the visual network and across networks, through an Arc-dependent mechanism.
Asunto(s)
Proteínas del Citoesqueleto/fisiología , Aprendizaje , Acontecimientos que Cambian la Vida , Proteínas del Tejido Nervioso/fisiología , Plasticidad Neuronal/genética , Plasticidad Neuronal/fisiología , Corteza Visual/fisiología , Animales , Encéfalo/fisiología , Mapeo Encefálico , Corteza Cerebral/fisiología , Proteínas del Citoesqueleto/genética , Femenino , Eliminación de Gen , Perfilación de la Expresión Génica , Genotipo , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Proteínas del Tejido Nervioso/genética , Privación Sensorial/fisiologíaRESUMEN
Resting state functional connectivity is defined in terms of temporal correlations between physiologic signals, most commonly studied using functional magnetic resonance imaging. Major features of functional connectivity correspond to structural (axonal) connectivity. However, this relation is not one-to-one. Interhemispheric functional connectivity in relation to the corpus callosum presents a case in point. Specifically, several reports have documented nearly intact interhemispheric functional connectivity in individuals in whom the corpus callosum (the major commissure between the hemispheres) never develops. To investigate this question, we assessed functional connectivity before and after surgical section of the corpus callosum in 22 patients with medically refractory epilepsy. Section of the corpus callosum markedly reduced interhemispheric functional connectivity. This effect was more profound in multimodal associative areas in the frontal and parietal lobe than primary regions of sensorimotor and visual function. Moreover, no evidence of recovery was observed in a limited sample in which multiyear, longitudinal follow-up was obtained. Comparison of partial vs. complete callosotomy revealed several effects implying the existence of polysynaptic functional connectivity between remote brain regions. Thus, our results demonstrate that callosal as well as extracallosal anatomical connections play a role in the maintenance of interhemispheric functional connectivity.
Asunto(s)
Conectoma , Cuerpo Calloso/fisiología , Lateralidad Funcional , Corteza Sensoriomotora/fisiología , Adolescente , Ondas Encefálicas , Niño , Preescolar , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/cirugía , Femenino , Humanos , Masculino , Corteza Sensoriomotora/diagnóstico por imagenRESUMEN
Accumulating evidence indicates that resting-state functional magnetic resonance imaging (rsfMRI) signals correspond to propagating electrophysiological infra-slow activity (<0.1â¯Hz). Thus, pairwise correlations (zero-lag functional connectivity (FC)) and temporal delays among regional rsfMRI signals provide useful, complementary descriptions of spatiotemporal structure in infra-slow activity. However, the slow nature of fMRI signals implies that practical scan durations cannot provide sufficient independent temporal samples to stabilize either of these measures. Here, we examine factors affecting sampling variability in both time delay estimation (TDE) and FC. Although both TDE and FC accuracy are highly sensitive to data quantity, we use surrogate fMRI time series to study how the former is additionally related to the magnitude of a given pairwise correlation and, to a lesser extent, the temporal sampling rate. These contingencies are further explored in real data comprising 30-min rsfMRI scans, where sampling error (i.e., limited accuracy owing to insufficient data quantity) emerges as a significant but underappreciated challenge to FC and, even more so, to TDE. Exclusion of high-motion epochs exacerbates sampling error; thus, both sides of the bias-variance (or data quality-quantity) tradeoff associated with data exclusion should be considered when analyzing rsfMRI data. Finally, we present strategies for TDE in motion-corrupted data, for characterizing sampling error in TDE and FC, and for mitigating the influence of sampling error on lag-based analyses.