Plasticity in the Brain after a Traumatic Brachial Plexus Injury in Adults

In this chapter, we aim to discuss the neurophysiological basis of the brain reorganization (also called plasticity) that associates with a traumatic brachial plexus injury (TBPI), as well as following the brachial plexus surgical reconstruction and its physical rehabilitation. We start by reviewing core aspects of plasticity following peripheral injuries such as amputation and TBPI as well as those associated with chronic pain conditions. Then, we present recent results collected by our team centered on physiological measurements of plasticity after TBPI. Finally, we discuss that an important limitation in the field is the lack of systematic measurement of TBPI clinical features. We finish by proposing possible future venues in the domain of brain plasticity following a TBPI

Effect of muscle length in a handgrip task on corticomotor excitability of extrinsic and intrinsic hand muscles under resting and submaximal contraction conditions

Funding Information: This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior ‐ Brasil (CAPES) ‐ Finance Code 001. VHS received funding from the Jane and Aatos Erkko Foundation, the Academy of Finland (decision #349985), and the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement #810377). BR was funded by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (grant #2022/00582‐9) and by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (grant #141723/2015‐7). RHM was funded by CNPq (grant #141056/2018‐5) and FAPESP (grant #2022/14526‐3). This research was supported by CNPq (grant #310397/2021), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) (CNE #202.785/2018 and E‐26/010.002418/2019), and Financiadora de Estudos e Projetos (FINEP); PROINFRA HOSPITALAR grant #18.569‐8. This research is also part of the activities of FAPESP's Research, Innovation and Dissemination Center for Neuromathematics‐NeuroMat (FAPESP grant #2013/07699‐0). | openaire: EC/H2020/810377/EU//ConnectToBrainThe neurophysiological mechanisms underlying muscle force control for different wrist postures still need to be better understood. To further elucidate these mechanisms, the present study aimed to investigate the effects of wrist posture on the corticospinal excitability by transcranial magnetic stimulation (TMS) of extrinsic (flexor [FCR] and extensor carpi radialis [ECR]) and intrinsic (flexor pollicis brevis (FPB)) muscles at rest and during a submaximal handgrip strength task. Fourteen subjects (24.06 ± 2.28 years) without neurological or motor disorders were included. We assessed how the wrist posture (neutral: 0°; flexed: +45°; extended: −45°) affects maximal handgrip strength (HGSmax) and the motor evoked potentials (MEP) amplitudes during rest and active muscle contractions. HGSmax was higher at 0° (133%) than at −45° (93.6%; p < 0.001) and +45° (73.9%; p < 0.001). MEP amplitudes were higher for the FCR at +45° (83.6%) than at −45° (45.2%; p = 0.019) and at +45° (156%; p < 0.001) and 0° (146%; p = 0.014) than at −45° (106%) at rest and active condition, respectively. Regarding the ECR, the MEP amplitudes were higher at −45° (113%) than at +45° (60.8%; p < 0.001) and 0° (72.6%; p = 0.008), and at −45° (138%) than +45° (96.7%; p = 0.007) also at rest and active conditions, respectively. In contrast, the FPB did not reveal any difference among wrist postures and conditions. Although extrinsic and intrinsic hand muscles exhibit overlapping cortical representations and partially share the same innervation, they can be modulated differently depending on the biomechanical constraints.Peer reviewe

Retinoic Acid-Treated Pluripotent Stem Cells Undergoing Neurogenesis Present Increased Aneuploidy and Micronuclei Formation

The existence of loss and gain of chromosomes, known as aneuploidy, has been previously described within the central nervous system. During development, at least one-third of neural progenitor cells (NPCs) are aneuploid. Notably, aneuploid NPCs may survive and functionally integrate into the mature neural circuitry. Given the unanswered significance of this phenomenon, we tested the hypothesis that neural differentiation induced by all-trans retinoic acid (RA) in pluripotent stem cells is accompanied by increased levels of aneuploidy, as previously described for cortical NPCs in vivo. In this work we used embryonal carcinoma (EC) cells, embryonic stem (ES) cells and induced pluripotent stem (iPS) cells undergoing differentiation into NPCs. Ploidy analysis revealed a 2-fold increase in the rate of aneuploidy, with the prevalence of chromosome loss in RA primed stem cells when compared to naive cells. In an attempt to understand the basis of neurogenic aneuploidy, micronuclei formation and survivin expression was assessed in pluripotent stem cells exposed to RA. RA increased micronuclei occurrence by almost 2-fold while decreased survivin expression by 50%, indicating possible mechanisms by which stem cells lose their chromosomes during neural differentiation. DNA fragmentation analysis demonstrated no increase in apoptosis on embryoid bodies treated with RA, indicating that cell death is not the mandatory fate of aneuploid NPCs derived from pluripotent cells. In order to exclude that the increase in aneuploidy was a spurious consequence of RA treatment, not related to neurogenesis, mouse embryonic fibroblasts were treated with RA under the same conditions and no alterations in chromosome gain or loss were observed. These findings indicate a correlation amongst neural differentiation, aneuploidy, micronuclei formation and survivin downregulation in pluripotent stem cells exposed to RA, providing evidence that somatically generated chromosomal variation accompanies neurogenesis in vitro.Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ)[E26/111.556/2008]Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ)[E26/103.081/2008]Conselho Nacional para o Desenvolvimento Cientifico e Tecnologico (CNPq)[573.975/2008-6]Conselho Nacional para o Desenvolvimento Cientifico e Tecnologico (CNPq)[573476/08-0]Conselho Nacional para o Desenvolvimento Cientifico e Tecnologico (CNPq)[MCT/CNPq 01/2005 - Institutos do Milenio]Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)[2006/61285-9

Neural differentiation in ES and iPS cells after RA treatment.

<p>(A) Schematic representation of protocol. (B) Immunofluorescence quantification confirmed commitment into neural progenitors (nestin) and young neurons (βIII-tubulin). The images correspond to ES-differentiated cells. The bars indicate mean ± S.E.M. of two independent assays, *p<0.05. ES, embryonic stem cells; iPS, induced pluripotent stem cells; RA, <i>all-trans</i> retinoic acid.</p

Chromosomal instability increases after induction of neural phenotype by RA in EC cells.

<p>(A) The rate of chromosomal instability presented a 2-fold increase. The bars indicate mean ± S.E.M. of two independent assays, *p<0.05. (B) Analysis of relative DNA content demonstrated that neural cells (RA) presented less DNA than cells incubated with vehicle. RA, <i>all-trans</i> retinoic acid.</p

During neurogenesis, stem cells are prone to chromosome loss and micronuclei formation, which correlates with survivin downregulation.

<p>Neural aneuploidy may contribute to cell diversity within the CNS. CNS, central nervous system.</p

RA induces aneuploidy increase in pluripotent stem cells but not in somatic cells.

<p>(A) Metaphase spreads of RA-NPCs derived from ES cells stained with DAPI. After RA-neural differentiation, the aneuploidy level increased in (B) ES and (C) iPS cells, while (D) mouse embryonic fibroblasts (MEF) exposed to RA did not present aneuploidy increase. The data refer to mean ± S.E.M. of three independent experiments, *p<0.05. ES, embryonic stem cells; iPS, induced pluripotent stem cells; NPCs, neural progenitor cells; RA, <i>all-trans</i> retinoic acid.</p

Reduced survivin expression in RA-treated pluripotent stem cells.

<p>(A) Survivin mRNA and (B) survivin protein were significantly reduced after RA treatment. For quantitative PCR, relative mRNA levels represent the amount of survivin mRNA compared to β-actin mRNA; for western blotting, relative survivin levels are compared to α-tubulin. Bars indicate mean ± S.E.M. of three independent assays, * p<0.1. Data were expressed as the ratio of the mean of RA to the mean of vehicle.</p

RA-treated stem cells do not necessarily undergo apoptosis.

<p>No difference in apoptosis between RA-NPCs and cells incubated with vehicle was observed in (A) EC cells or (B) ES cells. The bars indicate mean ± S.E.M. of three independent assays, *p<0.05. RA-NPCs, neural progenitor cells derived from <i>all-trans</i> retinoic acid treatment; EC, embryonal carcinoma cells; ES, embryonic stem cells.</p

Micronuclei formation increase in pluripotent ES and iPS cells after RA exposure.

<p>(A) Photomicrography of two daughter cells nuclei (arrowhead) and a micronucleus (arrow) detected by DAPI staining. (B) RA increased micronuclei formation in ES and iPS cells. Data was expressed as the ratio of the mean of RA to the mean of vehicle. Bars indicate mean ± S.E.M. of three independent assays, *p<0.05, #p<0.1. ES, embryonic stem cells; iPS, induced pluripotent stem cells; RA, <i>all-trans</i> retinoic acid.</p