Cerebellar Coordination of Neuronal Communication in Cerebral Cortex

Cognitive processes involve precisely coordinated neuronal communications between multiple cerebral cortical structures in a task specific manner. Rich new evidence now implicates the cerebellum in cognitive functions. There is general agreement that cerebellar cognitive function involves interactions between the cerebellum and cerebral cortical association areas. Traditional views assume reciprocal interactions between one cerebellar and one cerebral cortical site, via closed-loop connections. We offer evidence supporting a new perspective that assigns the cerebellum the role of a coordinator of communication. We propose that the cerebellum participates in cognitive function by modulating the coherence of neuronal oscillations to optimize communications between multiple cortical structures in a task specific manner.

Shifting gradients of macroscale cortical organization mark the transition from childhood to adolescence

The transition from childhood to adolescence is marked by pronounced shifts in brain structure and function that coincide with the development of physical, cognitive, and social abilities. Prior work in adult populations has characterized the topographical organization of the cortex, revealing macroscale functional gradients that extend from unimodal (somatosensory/motor and visual) regions through the cortical association areas that underpin complex cognition in humans. However, the presence of these core functional gradients across development as well as their maturational course have yet to be established. Here, leveraging 378 resting-state functional MRI scans from 190 healthy individuals aged 6 to 17 y old, we demonstrate that the transition from childhood to adolescence is reflected in the gradual maturation of gradient patterns across the cortical sheet. In children, the overarching organizational gradient is anchored within the unimodal cortex, between somatosensory/motor and visual territories. Conversely, in adolescence, the principal gradient of connectivity transitions into an adult-like spatial framework, with the default network at the opposite end of a spectrum from primary sensory and motor regions. The observed gradient transitions are gradually refined with age, reaching a sharp inflection point in 13 and 14 y olds. Functional maturation was nonuniformly distributed across cortical networks. Unimodal networks reached their mature positions early in development, while association regions, in particular the medial prefrontal cortex, reached a later peak during adolescence. These data reveal age-dependent changes in the macroscale organization of the cortex and suggest the scheduled maturation of functional gradient patterns may be critically important for understanding how cognitive and behavioral capabilities are refined across development.

Broad transcriptomic dysregulation across the cerebral cortex in ASD

Classically, psychiatric disorders have been considered to lack defining pathology, but recent work has demonstrated consistent disruption at the molecular level, characterized by transcriptomic and epigenetic alterations.1–3 In ASD, upregulation of microglial, astrocyte, and immune signaling genes, downregulation of specific synaptic genes, and attenuation of regional gene expression differences are observed.1,2,4–6 However, whether these changes are limited to the cortical association areas profiled is unknown. Here, we perform RNA-sequencing (RNA-seq) on 725 brain samples spanning 11 distinct cortical areas in 112 ASD cases and neurotypical controls. We identify substantially more genes and isoforms that differentiate ASD from controls than previously observed. These alterations are pervasive and cortex-wide, but vary in magnitude across regions, roughly showing an anterior to posterior gradient, with the strongest signal in visual cortex, followed by parietal cortex and the temporal lobe. We find a notable enrichment of ASD genetic risk variants among cortex-wide downregulated synaptic plasticity genes and upregulated protein folding gene isoforms. Finally, using snRNA-seq, we determine that regional variation in the magnitude of transcriptomic dysregulation reflects changes in cellular proportion and cell-type-specific gene expression, particularly impacting L3/4 excitatory neurons. These results highlight widespread, genetically-driven neuronal dysfunction as a major component of ASD pathology in the cerebral cortex, extending beyond association cortices to involve primary sensory regions.

Network analysis of mesoscale mouse brain structural connectome yields modular structure that aligns with anatomical regions and sensory pathways

The Allen mesoscale mouse brain structural connectome is analysed using standard network methods combined with 3D visualizations. The full region-to-region connectivity data is used, with a focus on the strongest structural links. The spatial embedding of links and time evolution of signalling is incorporated, with two-step links included. Modular decomposition using the Infomap method produces 8 network modules that correspond approximately to major brain anatomical regions and system functions. These modules align with the anterior and posterior primary sensory systems and association areas. 3D visualization of network links is facilitated by using a set of simplified schematic coordinates that reduces visual complexity. Selection of key nodes and links, such as sensory pathways and cortical association areas together reveal structural features of the mouse structural connectome consistent with biological functions in the sensory-motor systems, and selective roles of the anterior and posterior cortical association areas of the mouse brain. Time progression of signals along sensory pathways reveals that close links are to local cortical association areas and cross modal, while longer links provide anterior-posterior coordination and inputs to non cortical regions. The fabric of weaker links generally are longer range with some having brain-wide reach. Cortical gradients are evident along sensory pathways within the structural network.Author’s SummaryNetwork models incorporating spatial embedding and signalling delays are used to investigate the mouse structural connectome. Network models that include time respecting paths are used to trace signaling pathways and reveal separate roles of shorter vs. longer links. Here computational methods work like experimental probes to uncover biologically relevant features. I use the Infomap method, which follows random walks on the network, to decompose the directed, weighted network into 8 modules that align with classical brain anatomical regions and system functions. Primary sensory pathways and cortical association areas are separated into individual modules. Strong, short range links form the sensory-motor paths while weaker links spread brain-wide, possibly coordinating many regions.

Pathophysiology of Alzheimer Disease

Genetic discoveries coupled with neuropathologic investigations initially established the central role for β-amyloidosis in Alzheimer disease (AD). Three dominantly inherited genes (APP, PSEN1, and PSEN2) and one common allelic variant with lower penetrance (APOE) account for the majority of the genetic basis for AD. PET biomarkers for AD have been developed in the past decade and are fundamentally altering our view of the disease. The availability of PET tracers, first for amyloid and now for tau, has enabled researchers to develop a model of AD that begins long before people become symptomatic. In persons destined to develop dementia due to AD, brain β-amyloid levels begin to rise 10 to 20 years earlier. Other imaging changes that might precede symptomatic disease include (1) reductions in brain metabolic activity in a group of temporal and parietal cortical association areas that can be demonstrated by [18F]fluorodeoxyglucose-PET scanning; (2) losses of hippocampal volume as measured on structural magnetic resonance imaging; and (3) loss of cortical thickness or cortical volume in temporal and parietal cortical association areas. All of these changes are greatly accentuated once people become symptomatic. Although mild elevations in tau PET abnormalities can also be seen in presymptomatic individuals, it is only when persons become symptomatic that marked elevations in these abnormalities begin to occur in those same temporal and parietal cortical association areas. Cerebrospinal fluid (CSF) biomarkers provide a complementary view, with CSF β-amyloid levels falling (presumably due to aggregation within the cortex) even before amyloid PET abnormalities are visible. CSF total tau and phospho-tau levels begin to rise when persons are much closer to being symptomatic. The sum of these observations has allowed researchers to gain a far more insightful antemortem view of the pathophysiology of AD in humans than had previously been available from neuropathologic investigations. Keywords: β-amyloid, cerebrospinal fluid β-amyloid, cerebrospinal fluid phospho-tau, cortical thickness, [18F]fluorodeoxyglucose–positron emission tomography, hippocampal atrophy, preclinical Alzheimer disease, tau protein

Pathophysiology of Alzheimer Disease

Genetic discoveries coupled with neuropathologic investigations initially established the central role for β-amyloidosis in Alzheimer disease (AD). Three dominantly inherited genes (APP, PSEN1, and PSEN2) and one common allelic variant with lower penetrance (APOE) account for the majority of the genetic basis for AD. PET biomarkers for AD have been developed in the past decade and are fundamentally altering our view of the disease. The availability of PET tracers, first for amyloid and now for tau, has enabled researchers to develop a model of AD that begins long before people become symptomatic. In persons destined to develop dementia due to AD, brain β-amyloid levels begin to rise 10 to 20 years earlier. Other imaging changes that might precede symptomatic disease include (1) reductions in brain metabolic activity in a group of temporal and parietal cortical association areas that can be demonstrated by [18F]fluorodeoxyglucose-PET scanning; (2) losses of hippocampal volume as measured on structural magnetic resonance imaging; and (3) loss of cortical thickness or cortical volume in temporal and parietal cortical association areas. All of these changes are greatly accentuated once people become symptomatic. Although mild elevations in tau PET abnormalities can also be seen in presymptomatic individuals, it is only when persons become symptomatic that marked elevations in these abnormalities begin to occur in those same temporal and parietal cortical association areas. Cerebrospinal fluid (CSF) biomarkers provide a complementary view, with CSF β-amyloid levels falling (presumably due to aggregation within the cortex) even before amyloid PET abnormalities are visible. CSF total tau and phospho-tau levels begin to rise when persons are much closer to being symptomatic. The sum of these observations has allowed researchers to gain a far more insightful antemortem view of the pathophysiology of AD in humans than had previously been available from neuropathologic investigations. Keywords: β-amyloid, cerebrospinal fluid β-amyloid, cerebrospinal fluid phospho-tau, cortical thickness, [18F]fluorodeoxyglucose–positron emission tomography, hippocampal atrophy, preclinical Alzheimer disease, tau protein

Evidence of a Novel Somatopic Map in the Human Neocerebellum During Complex Actions

The human neocerebellum has been hypothesized to contribute to many high-level cognitive processes including attention, language, and working memory. Support for these nonmotor hypotheses comes from evidence demonstrating structural and functional connectivity between the lateral cerebellum and cortical association areas as well as a lack of somatotopy in lobules VI and VII, a hallmark of motor representations in other areas of the cerebellum and cerebral cortex. We set out to test whether somatotopy exists in these lobules by using functional magnetic resonance imaging to measure cerebellar activity while participants produced simple or complex movements, using either fingers or toes. We observed a previously undiscovered somatotopic organization in neocerebellar lobules VI and VIIA that was most prominent when participants executed complex movements. In contrast, activation in the anterior lobe showed a similar somatotopic organization for both simple and complex movements. While the anterior somatotopic representation responded selectively during ipsilateral movements, the new cerebellar map responded during both ipsi- and contralateral movements. The presence of a bilateral, task-dependent somatotopic map in the neocerebellum emphasizes an important role for this region in the control of skilled actions.

Role of the Lateral Prefrontal Cortex in Executive Behavioral Control

The lateral prefrontal cortex is critically involved in broad aspects of executive behavioral control. Early studies emphasized its role in the short-term retention of information retrieved from cortical association areas and in the inhibition of prepotent responses. Recent studies of subhuman primates and humans have revealed the role of this area in more general aspects of behavioral planning. Novel findings of neuronal activity have specified how neurons in this area take part in selective attention for action and in selecting an intended action. Furthermore, the involvement of the lateral prefrontal cortex in the implementation of behavioral rules and in setting multiple behavioral goals has been discovered. Recent studies have begun to reveal neuronal mechanisms for strategic behavioral planning and for the development of knowledge that enables the planning of macrostructures of event-action sequences at the conceptual level.

Synaptic Enhancement Induced Through Callosal Pathways in Cat Association Cortex

The corpus callosum plays a major role in synchronizing neocortical activities in the two hemispheres. We investigated the changes in callosally elicited excitatory postsynaptic potentials (EPSPs) of neurons from cortical association areas 5 and 7 of cats under barbiturate or ketamine-xylazine anesthesia. Single pulses to callosal pathway evoked control EPSPs; pulse-trains were subsequently applied at different frequencies to homotopic sites in the contralateral cortex, as conditioning stimulation; thereafter, the single pulses were applied again to test changes in synaptic responsiveness by comparing the amplitudes of control and conditioned EPSPs. In 41 of 42 neurons recorded under barbiturate anesthesia, all frequencies of conditioning callosal stimuli induced short-term (5–30 min) enhancement of test EPSPs elicited by single stimuli. Neurons tested with successive conditioning pulse-trains at different frequencies displayed stronger enhancement with high-frequency (40–100 Hz) than with low-frequency (10–20 Hz) rhythmic pulse-trains; >100 Hz, the potentiation saturated. In a neuronal sample, microdialysis of an N-methyl-d-aspartate (NMDA) receptor blocker in barbiturate-treated cats suppressed this potentiation, and potentiation of callosally evoked EPSPs was not detected in neurons recorded under ketamine-xylazine anesthesia, thus indicating that EPSPs' potentiation implicates, at least partially, NMDA receptors. These data suggest that callosal activities occurring within low-frequency and fast-frequency oscillations play a role in cortical synaptic plasticity.