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Recovery of consciousness after traumatic brain injury (TBI) is heterogeneous and difficult to predict. Structures such as the thalamus and prefrontal cortex are thought to be important in facilitating consciousness. We sought to investigate whether the integrity of thalamo-prefrontal circuits, assessed via diffusion tensor imaging (DTI), was associated with the return of goal-directed behavior after severe TBI. We classified a cohort of severe TBI patients ( N = 25, 20 males) into Early and Late/Never outcome groups based on their ability to follow commands within 30 days post-injury. We assessed connectivity between whole thalamus, and mediodorsal thalamus (MD), to prefrontal cortex (PFC) subregions including dorsolateral PFC (dlPFC), medial PFC (mPFC), anterior cingulate (ACC), and orbitofrontal (OFC) cortices. We found that the integrity of thalamic projections to PFC subregions (L OFC, L and R ACC, and R mPFC) was significantly associated with Early command-following. This association persisted when the analysis was restricted to prefrontal-mediodorsal (MD) thalamus connectivity. In contrast, dlPFC connectivity to thalamus was not significantly associated with command-following. Using the integrity of thalamo-prefrontal connections, we created a linear regression model that demonstrated 72% accuracy in predicting command-following after a leave-one-out analysis. Together, these data support a role for thalamo-prefrontal connectivity in the return of goal-directed behavior following TBI.
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Cerebellar contributions to a brainwide network for flexible behavior in mice
Abstract The cerebellum regulates nonmotor behavior, but the routes of influence are not well characterized. Here we report a necessary role for the posterior cerebellum in guiding a reversal learning task through a network of diencephalic and neocortical structures, and in flexibility of free behavior. After chemogenetic inhibition of lobule VI vermis or hemispheric crus I Purkinje cells, mice could learn a water Y-maze but were impaired in ability to reverse their initial choice. To map targets of perturbation, we imaged c-Fos activation in cleared whole brains using light-sheet microscopy. Reversal learning activated diencephalic and associative neocortical regions. Distinctive subsets of structures were altered by perturbation of lobule VI (including thalamus and habenula) and crus I (including hypothalamus and prelimbic/orbital cortex), and both perturbations influenced anterior cingulate and infralimbic cortex. To identify functional networks, we used correlated variation in c-Fos activation within each group. Lobule VI inactivation weakened within-thalamus correlations, while crus I inactivation divided neocortical activity into sensorimotor and associative subnetworks. In both groups, high-throughput automated analysis of whole-body movement revealed deficiencies in across-day behavioral habituation to an open-field environment. Taken together, these experiments reveal brainwide systems for cerebellar influence that affect multiple flexible responses.
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- Award ID(s):
- 1734030
- PAR ID:
- 10429921
- Date Published:
- Journal Name:
- Communications Biology
- Volume:
- 6
- Issue:
- 1
- ISSN:
- 2399-3642
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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The human brain is sexually dimorphic and these sex differences have shown to affect brain response to trauma. We investigated the sex differences in the tract structures by studying diffusion weighted (DW) images of 594 females and 506 males from the Human-Connectome-Project dataset. All the female and male DW images were reconstructed in the ICBM152 space using Q-Space diffeomorphic reconstruction technique and their mapped orientation distribution function images were averaged to generate the female- and male-DW-templates. The tract streamlines were generated through tractography for female and male templates and normalized to the total brain volume . The distributions of normalized tract lengths were significantly different between female- and male-templates and the female-template showed to have more longer normalized tracts compared to the male template. For the regional analysis, the templates were parcellated into sixteen regions of interests (ROI) including brain-stem, five subregions of corpus-callosum, and right and left hippocampus, thalamus, cerebellum white-matter (WM), cerebral WM, and cerebellum cortex using a FreeSurfer-based segmentation atlas. For all the ROIs, the average fractional anisotropy (0.5-5.7%) and normalized tract lengths (1.1-2.7%) were larger in female template while the average mean diffusion was larger (1.3-5.6%) in male-template. Quantifying brain connectivity by counting number of tracts passing through pairs of ROIs, showed more pairs with a higher connectivity in female-template, and one of the highest percentages of sex differences in right/left cerebellum WM/cortex connections. Our results reinforce the need to continue investigating the sex variations in axonal structure and their effects to brain trauma.more » « less
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BackgroundReading and math constitute important academic skills, and as such, reading disability (RD or developmental dyslexia) and math disability (MD or developmental dyscalculia) can have negative consequences for children’s educational progress. Although RD and MD are different learning disabilities, they frequently co-occur. Separate theories have implicated the cerebellum and its cortical connections in RD and in MD, suggesting that children with combined reading and math disability (RD + MD) may have altered cerebellar function and disrupted functional connectivity between the cerebellum and cortex during reading and during arithmetic processing. MethodsHere we compared Control and RD + MD groups during a reading task as well as during an arithmetic task on (i) activation of the cerebellum, (ii) background functional connectivity, and (iii) task-dependent functional connectivity between the cerebellum and the cortex. ResultsThe two groups (Control, RD + MD) did not differ for either task (reading, arithmetic) on any of the three measures (activation, background functional connectivity, task-dependent functional connectivity). ConclusionThese results do not support theories that children’s deficits in reading and math originate in the cerebellum.more » « less
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Temporally coordinated neural activity is central to nervous system function and purposeful behavior. Still, there is a paucity of evidence demonstrating how this coordinated activity within cortical and subcortical regions governs behavior. We investigated this between the primary motor (M1) and contralateral cerebellar cortex as rats learned a neuroprosthetic/brain-machine interface (BMI) task. In neuroprosthetic task, actuator movements are causally linked to M1 “direct” neurons that drive the decoder for successful task execution. However, it is unknown how task-related M1 activity interacts with the cerebellum. We observed a notable 3 to 6 hertz coherence that emerged between these regions’ local field potentials (LFPs) with learning that also modulated task-related spiking. We identified robust task-related indirect modulation in the cerebellum, which developed a preferential relationship with M1 task–related activity. Inhibiting cerebellar cortical and deep nuclei activity through optogenetics led to performance impairments in M1-driven neuroprosthetic control. Together, these results demonstrate that cerebellar influence is necessary for M1-driven neuroprosthetic control.more » « less
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Background: Coil placement on the cerebellum lacks accuracy in targeting the intended lobules and limits the efficacy of cerebellar transcranial magnetic stimulation (TMS) in treating movement disorders. Objective: Develop a multiscale computational pipeline and method to rapidly predict the cellular response to cerebellar TMS and optimize the coil placement accordingly for lobule-specific activation. Methods: The pipeline integrates 3T T1/T2-weighted MRI scans of the human cerebellum, lobule parcellation, and finite element models of the TMS-induced electric (E-) fields for figure-of-eight coils (MagStim D70) and double-cone coils (Deymed 120BFV). A constrained optimization method is developed to estimate the fiber bundles from cerebellar cortices to deep nuclei and, for both coil types, find the coil placement and orientation that maximize the E-field intensity in a user-selected lobule. Multicompartmental Purkinje cell models with realistic axon geometries and Gaussian process regression are added to predict the recruitment in the Purkinje layer. Results: Our pipeline was tested in five individuals to target the left lobule VIII and resulted in normalized E-field intensities at the target 49.6±25.6% (D70) and 29.3±17.7% (120BFV) higher compared to standard coil positions (i.e., 3 cm left, 1 cm below the inion), mean±S.D. The minimum pulse intensity to recruit Purkinje cells on a 4 mm2-surface in the target decreased by 21.6% (range: 4.7-55.0%) and 10.7% (range: 7.9-18.2%), and the spillover to adjacent lobules decreased by 70.6±16.3% and 71.7±20.8% compared to standard positions (D70 and 120BFV, respectively). Conclusion: Our tools are effective at targeting specific lobules and pave the way toward patient-specific setups.more » « less
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1038/s42003-023-04920-0
