Search Results (19)

The nucleus accumbens shell (NAcSh) is a major structure associated with distinct aspects of reward and mnemonic information encoding, relying on spatial data to define optimal behavioral strategies. Chronic pain-derived striatal plasticity is considered one underpinning cause of working memory (WM) impairments. However, it is unclear how the NAcSh is involved in these spatial deficits. To address this, we evaluated the impact of unilateral local NAcSh electrical lesions during the execution of a food-reinforced eight-shaped spatial alternation WM task. Behavioral performance was assessed in rats after the onset of the neuropathic pain model—spared nerve injury (SNI). Our findings indicate that the induction of SNI and/or NAcSh lesions did not significantly impact the animals’ performance accuracy or motor activity during the execution of the behavioral task, but altered their response latency patterns. In addition, these manipulations did not induce significant antinociceptive effects. Collectively, these results suggest that the NAcSh may participate in specific aspects of spatial information integration and processing under neuropathic pain conditions. Full article

(1) Background: The literature regarding orthorexia nervosa (ON) has well documented the association with other mental disorders, such as obsessive–compulsive and eating disorders. However, the research has not taken into account stress-related behavior and the conduction of physical activity (PA), both structured and unstructured. (2) Methods: In this cross-sectional study, 165 students of the University of Parma (92 females and 74 males) aged between 18 and 49 years old (mean = 24.62 ± 4.81) were consecutively recruited. The ORTO-15 questionnaire was used to divide the total sample into a group without orthorexia (score > 40) and a group with orthorexia (score < 40). All subjects completed the P Stress Questionnaire, and specific items were extrapolated from the Eating Habits Structured Interview (EHSI) to investigate lifestyle, including structured and unstructured PA. (3) Results: Subjects with orthorexia represented 83% of the total sample and reported higher levels of stress-related risk behaviors (i.e., sense of responsibility (t = −1.99, p = 0.02), precision (t = −1.99, p = 0.03), stress disorders (t = −1.38, p = 0.05), reduced spare time (t = −1.97, p = 0.03), and hyperactivity (t = −1.68, p = 0.04)) and a higher frequency of PA (i.e., hours spent training in structured PA, daily (t = −1.68, p = 0.05), weekly (t = −1.91, p = 0.03), and monthly (t = −1.91, p = 0.03), the tendency to carry out physical exercise even if tired (t = −1.97, p = 0.02), and to adhere to unstructured PA (i.e., moving on foot or by bike rather than using transport (t = 1.27, p = 0.04)). (4) Conclusions: The results confirmed the presence of hyperactivity at a motor and behavioral level in people with orthorexia. Further studies are necessary to highlight the causality between ON, stress, and physical activity but it may be possible to hypothesize that “obsessive” physical exercise may not generate the benefits generally known by the literature. Full article

Brain imaging studies have recently provided some evidence in favor of covert cognitive processes that are ongoing in patients with disorders of consciousness (DoC) (e.g., a minimally conscious state and vegetative state/unresponsive wakefulness syndrome) when engaged in passive sensory stimulation or active tasks such as motor imagery. In this exploratory study, we used transcranial magnetic stimulation (TMS) of the motor cortex to assess modulations of corticospinal excitability induced by action observation in eleven patients with DoC. Action observation is known to facilitate corticospinal excitability in healthy subjects, unveiling how the observer’s motor system maps others’ actions onto her/his motor repertoire. Additional stimuli were non-biological motion and acoustic startle stimuli, considering that sudden and loud acoustic stimulation is known to lower corticospinal excitability in healthy subjects. The results indicate that some form of motor resonance is spared in a subset of patients with DoC, with some significant difference between biological and non-biological motion stimuli. However, there was no covariation between corticospinal excitability and the type of DoC diagnosis (i.e., whether diagnosed with VS/UWS or MCS). Similarly, no covariation was detected with clinical changes between admission and discharge in clinical outcome measures. Both motor resonance and the difference between the resonance with biological/non-biological motion discrimination correlated with the amplitude of the N20 somatosensory evoked potentials, following the stimulation of the median nerve at the wrist (i.e., the temporal marker signaling the activation of the contralateral primary somatosensory cortex). Moreover, the startle-evoking stimulus produced an anomalous increase in corticospinal excitability, suggesting a functional dissociation between cortical and subcortical circuits in patients with DoC. Further work is needed to better comprehend the conditions in which corticospinal facilitation occurs and whether and how they may relate to individual clinical parameters. Full article

To date, there is no cure for Parkinson’s disease (PD). There is a pressing need for anti-neurodegenerative therapeutics that can slow or halt PD progression by targeting underlying disease mechanisms. Specifically, preventing the build-up of alpha-synuclein (αSyn) and its aggregated and mutated forms is a key therapeutic target. In this study, an adeno-associated viral vector loaded with the A53T gene mutation was used to induce rapid αSyn-associated PD pathogenesis in C57BL/6 mice. We tested the ability of a novel therapeutic, a single chain fragment variable (scFv) antibody with specificity only for pathologic forms of αSyn, to protect against αSyn-induced neurodegeneration, after unilateral viral vector injection in the substantia nigra. Additionally, polyanhydride nanoparticles, which provide sustained release of therapeutics with dose-sparing properties, were used as a delivery platform for the scFv. Through bi-weekly behavioral assessments and across multiple post-mortem immunochemical analyses, we found that the scFv-based therapies allowed the mice to recover motor activity and reduce overall αSyn expression in the substantia nigra. In summary, these novel scFv-based therapies, which are specific exclusively for pathological aggregates of αSyn, show early promise in blocking PD progression in a surrogate mouse PD model. Full article

Parkinson’s disease (PD) is a neurodegenerative disorder with typical motor symptoms. Recent studies have suggested that excessive GABA from reactive astrocytes tonically inhibits dopaminergic neurons and reduces the expression of tyrosine hydroxylase (TH), the key dopamine-synthesizing enzyme, in the substantia nigra pars compacta (SNpc). However, the expression of DOPA decarboxylase (DDC), another dopamine-synthesizing enzyme, is relatively spared, raising a possibility that the live but non-functional TH-negative/DDC-positive neurons could be the therapeutic target for rescuing PD motor symptoms. However, due to the absence of a validated DDC-specific promoter, manipulating DDC-positive neuronal activity has not been tested as a therapeutic strategy for PD. Here, we developed an AAV vector expressing mCherry under rat DDC promoter (AAV-rDDC-mCherry) and validated the specificity in the rat SNpc. Modifying this vector, we expressed hM3Dq (Gq-DREADD) under DDC promoter in the SNpc and ex vivo electrophysiologically validated the functionality. In the A53T-mutated alpha-synuclein overexpression model of PD, the chemogenetic activation of DDC-positive neurons in the SNpc significantly alleviated the parkinsonian motor symptoms and rescued the nigrostriatal TH expression. Altogether, our DDC-promoter will allow dopaminergic neuron-specific gene delivery in rodents. Furthermore, we propose that the activation of dormant dopaminergic neurons could be a potential therapeutic strategy for PD. Full article

Objective: Discrepancies in the definition of adductor canal block (ACB) lead to inconsistent results. To investigate the actual analgesic and motor-sparing effects of ACB by anatomically defining femoral triangle block (FTB), proximal ACB (p-ACB), and distal ACB (d-ACB), we re-classified the previously claimed ACB approaches according to the ultrasound findings or descriptions in the corresponding published articles. A meta-analysis with subsequent subgroup analyses based on these corrected results was performed to examine the true impact of ACB on its analgesic effect and motor function (quadriceps muscle strength or mobilization ability). An optimal ACB technique was also suggested based on an updated review of evidence and ultrasound anatomy. Materials and Methods: We systematically searched studies describing the use of ACB for knee surgery. Cochrane Library, PubMed, Web of Science, and Embase were searched with the exclusion of non-English articles from inception to 28 February 2022. The motor-sparing and analgesic aspects in true ACB were evaluated using meta-analyses with subsequent subgroup analyses according to the corrected classification system. Results: The meta-analysis includes 19 randomized controlled trials. Compared with the femoral nerve block group, the quadriceps muscle strength (standardized mean difference (SMD) = 0.33, 95%-CI [0.01; 0.65]) and mobilization ability (SMD = −22.44, 95%-CI [−35.37; −9.51]) are more preserved in the mixed ACB group at 24 h after knee surgery. Compared with the true ACB group, the FTB group (SMD = 5.59, 95%-CI [3.44; 8.46]) has a significantly decreased mobilization ability at 24 h after knee surgery. Conclusion: By using the corrected classification system, we proved the motor-sparing effect of true ACB compared to FTB. According to the updated ultrasound anatomy, we suggested proximal ACB to be the analgesic technique of choice for knee surgery. Although a single-shot ACB is limited in duration, it remains the candidate of the analgesic standard for knee surgery on postoperative day 1 or 2 because it induces analgesia with less motor involvement in the era of multimodal analgesia. Furthermore, data from the corrected classification system may provide the basis for future research. Full article

Objective. Clavicle fracture fixation is commonly performed under general anesthesia due to the complex sensory innervation in this region which poses a challenge for anesthesiologists applying regional anesthetic (RA) techniques. In part 1 of this two-part study, we summarized the current literature describing various RA approaches in clavicle fractures and surgery. In our earlier scoping review, we surmised that a superficial or intermediate cervical plexus block (CPB) may provide analgesia for this procedure and, when combined with an interscalene brachial plexus block (ISB), can provide anesthesia to the clavicular region for surgical fixation. We performed a retrospective study, consolidating assumptions that were based on the results of our earlier scoping review. Methods. A retrospective study was conducted on 168 consecutive patients who underwent clavicle fixation surgery at a tertiary healthcare system in Singapore. We used a standardized pro forma to collate perioperative data from the electronic health records of both hospitals, including anesthetic technique, analgesic requirements, pain scores, and adverse events, up to the second postoperative day or up until discharge. Results. In our study, patients who received RA had significantly reduced pain scores and opioid requirements, compared to general anesthesia (GA) alone. Through subgroup analysis, differences were found in postoperative pain scores and opioid requirements in the following order: GA alone > GA with local infiltration analgesia > CPB > CPB plus ISB. All patients who received combined CPB and ISB had upper limb weakness in recovery, compared to none with CPB alone (p < 0.001). Of those who received an ISB either in isolation or combined with a CPB, four (9.3%) were reported to have dyspnea (within 24 h) and motor weakness that persisted beyond 12 h, compared to none for patients that received CPB alone. Conclusions. Addition of a CPB to GA for clavicle fracture fixation surgery is associated with reduced pain scores in the early postoperative period, with a lower opioid requirement compared to GA alone. In patients undergoing GA, the combination of a CPB with an ISB was associated with a small, although statistically significant, reduction in pain scores and opioid requirements compared to a CPB alone. Full article

Mitochondria are central in the pathogenesis of Parkinson’s disease (PD), as they are involved in oxidative stress, synaptopathy, and other immunometabolic pathways. Accordingly, they are emerging as a potential neuroprotection target, although further human-based evidence is needed for therapeutic advancements. This study aims to shape the pattern of mitochondrial respiration in the blood leukocytes of PD patients in relation to both clinical features and the profile of cerebrospinal fluid (CSF) biomarkers of neurodegeneration. Mitochondrial respirometry on the peripheral blood mononucleate cells (PBMCs) of 16 PD patients and 14 controls was conducted using Seahorse Bioscience technology. Bioenergetic parameters were correlated either with standard clinical scores for motor and non-motor disturbances or with CSF levels of α-synuclein, amyloid-β peptides, and tau proteins. In PD, PBMC mitochondrial basal respiration was normal; maximal and spare respiratory capacities were both increased; and ATP production was higher, although not significantly. Maximal and spare respiratory capacity was directly correlated with disease duration, MDS-UPDRS part III and Hoehn and Yahr motor scores; spare respiratory capacity was correlated with the CSF amyloid-β-42 to amyloid-β-42/40 ratio. We provided preliminary evidence showing that mitochondrial respiratory activity increases in the PBMCs of PD patients, probably following the compensatory adaptations to disease progression, in contrast to the bases of the neuropathological substrate. Full article

Objective. Clavicle fractures are common injuries potentially associated with significant perioperative pain. However, this region’s complex sensory innervation poses a challenge for regional anesthetic or analgesic (RA) techniques. We conducted this scoping review to summarize the current literature, particularly with regards to motor-sparing techniques. Methods. A scoping review was carried out in accordance with the Joanna Briggs Institute’s framework. All articles describing the use of RA for clavicle fractures or surgery were included. PubMed^®, Ovid MEDLINE^®, EMBASE^®, Scopus^®, CINAHL^®, and the Cochrane database were searched without language restrictions. Results. Database searches identified 845 articles, 44 of which were included in this review, with a combined patient total of 3161. We included all peer-reviewed publications containing clinical data and summarized the findings. Conclusions. Current evidence of RA techniques in clavicle surgery is heterogeneous, with different approaches used to overcome the overlapping sensory innervation. The literature largely comprises case reports/series, with several randomized controlled trials. Intermediate cervical plexus block is the regional technique of choice for clavicle surgery, and can provide reliable surgical anesthesia when combined with an interscalene block. Cervical plexus block can provide motor-sparing analgesia following clavicle surgery. Promising alternatives include the clavipectoral block, which is a novel motor-sparing regional technique. Further studies are required to determine the efficacy and safety of various techniques. Full article

Background: Traumatic spinal cord injury (SCI) is a devastating condition commonly originating from motor vehicle accidents or falls. Trauma care after SCI is challenging; after decompression surgery and spine stabilization, the first step is to assess the location and severity of the traumatic lesion. For this, clinical outcome measures are used to quantify the residual sensation and volitional control of muscles below the level of injury. These clinical assessments are important for decision-making, including the prediction of the recovery potential of individuals after the SCI. In clinical care, this quantification is usually performed using sensation and motor scores, a semi-quantitative measurement, alongside the binary classification of the sacral sparing (yes/no). Objective: In this perspective article, I review the use of surface EMG (sEMG) as a quantitative outcome measurement in subacute and chronic trauma care after SCI. Methods: Here, I revisit the main findings of two comprehensive scoping reviews recently published by our team on this topic. I offer a perspective on the combined findings of these scoping reviews, which integrate the changes in sEMG with SCI and the use of sEMG in neurorehabilitation after SCI. Results: sEMG provides a complimentary assessment to quantify the residual control of muscles with great sensitivity and detail compared to the traditional clinical assessments. Our scoping reviews unveiled the ability of the sEMG assessment to detect discomplete lesions (muscles with absent motor scores but present sEMG). Moreover, sEMG is able to measure the spontaneous activity of motor units at rest, and during passive maneuvers, the evoked responses with sensory or motor stimulation, and the integrity of the spinal cord and descending tracts with motor evoked potentials. This greatly complements the diagnostics of the SCI in the subacute phase of trauma care and deepens our understanding of neurorehabilitation strategies during the chronic phase of the traumatic injury. Conclusions: sEMG offers important insights into the neurophysiological factors underlying sensorimotor impairment and recovery after SCIs. Although several qualitative or semi-quantitative outcome measures determine the level of injury and the natural recovery after SCIs, using quantitative measures such as sEMG is promising. Nonetheless, there are still several barriers limiting the use of sEMG in the clinical environment and a need to advance high-density sEMG technology. Full article

Spinal cord injury is associated with damage in descending and ascending pathways between brainstem/cortex and spinal neurons, leading to loss in sensory-motor functions. This leads not only to locomotor reduction but also to important respiratory impairments, both reducing cardiorespiratory engagement, and increasing cardiovascular risk and mortality. Moreover, individuals with high-level injuries suffer from sleep-disordered breathing in a greater proportion than the general population. Although no current treatments exist to restore motor function in spinal cord injury (SCI), serotoninergic (5-HT) 1A receptor agonists appear as pharmacologic neuromodulators that could be important players in inducing functional improvements by increasing the activation of spared motoneurons. Indeed, single therapies of serotoninergic 1A (5-HT_1A) agonists allow for acute and temporary recovery of locomotor function. Moreover, the 5-HT_1A agonist could be even more promising when combined with other pharmacotherapies, exercise training, and/or spinal stimulation, rather than administered alone. In this review, we discuss previous and emerging evidence showing the value of the 5HT_1A receptor agonist therapies for motor and respiratory limitations in SCI. Moreover, we provide mechanistic hypotheses and clinical impact for the potential benefit of 5-HT_1A agonist pharmacology in inducing neuroplasticity and improving locomotor and respiratory functions in SCI. Full article

High spinal cord injuries (SCIs) lead to permanent diaphragmatic paralysis. The search for therapeutics to induce functional motor recovery is essential. One promising noninvasive therapeutic tool that could harness plasticity in a spared descending respiratory circuit is repetitive transcranial magnetic stimulation (rTMS). Here, we tested the effect of chronic high-frequency (10 Hz) rTMS above the cortical areas in C2 hemisected rats when applied for 7 days, 1 month, or 2 months. An increase in intact hemidiaphragm electromyogram (EMG) activity and excitability (diaphragm motor evoked potentials) was observed after 1 month of rTMS application. Interestingly, despite no real functional effects of rTMS treatment on the injured hemidiaphragm activity during eupnea, 2 months of rTMS treatment strengthened the existing crossed phrenic pathways, allowing the injured hemidiaphragm to increase its activity during the respiratory challenge (i.e., asphyxia). This effect could be explained by a strengthening of respiratory descending fibers in the ventrolateral funiculi (an increase in GAP-43 positive fibers), sustained by a reduction in inflammation in the C1–C3 spinal cord (reduction in CD68 and Iba1 labeling), and acceleration of intracellular plasticity processes in phrenic motoneurons after chronic rTMS treatment. These results suggest that chronic high-frequency rTMS can ameliorate respiratory dysfunction and elicit neuronal plasticity with a reduction in deleterious post-traumatic inflammatory processes in the cervical spinal cord post-SCI. Thus, this therapeutic tool could be adopted and/or combined with other therapeutic interventions in order to further enhance beneficial outcomes. Full article

Mitochondrial defects in motor neurons are pathological hallmarks of ALS, a neuromuscular disease with no effective treatment. Studies have shown that butyrate, a natural gut-bacteria product, alleviates the disease progression of ALS mice overexpressing a human ALS-associated mutation, hSOD1^G93A. In the current study, we examined the potential molecular mechanisms underlying the effect of butyrate on mitochondrial function in cultured motor-neuron-like NSC34 with overexpression of hSOD1^G93A (NSC34-G93A). The live cell confocal imaging study demonstrated that 1mM butyrate in the culture medium improved the mitochondrial network with reduced fragmentation in NSC34-G93A cells. Seahorse analysis revealed that NSC34-G93A cells treated with butyrate showed an increase of ~5-fold in mitochondrial Spare Respiratory Capacity with elevated Maximal Respiration. The time-dependent changes in the mRNA level of PGC1α, a master regulator of mitochondrial biogenesis, revealed a burst induction with an early increase (~5-fold) at 4 h, a peak at 24 h (~19-fold), and maintenance at 48 h (8-fold) post-treatment. In line with the transcriptional induction of PGC1α, both the mRNA and protein levels of the key molecules (MTCO1, MTCO2, and COX4) related to the mitochondrial electron transport chain were increased following the butyrate treatment. Our data indicate that activation of the PGC1α signaling axis could be one of the molecular mechanisms underlying the beneficial effects of butyrate treatment in improving mitochondrial bioenergetics in NSC34-G93A cells. Full article

Human mitochondrial disease exhibits large variation of clinical phenotypes, even in patients with the same causative gene defect. We illustrate this heterogeneity by confronting clinical and biochemical data of two patients with the uncommon pathogenic homoplasmic NC_012920.1(MT-ATP6):m.9035T>C variant in MT-ATP6. Patient 1 presented as a toddler with severe motor and speech delay and spastic ataxia without extra-neurologic involvement. Patient 2 presented in adolescence with ataxia and ophthalmoplegia without cognitive or motor impairment. Respiratory chain complex activities were normal in cultured skin fibroblasts from both patients when calculated as ratios over citrate synthase activity. Native gels found presence of subcomplexes of complex V in fibroblast and/or skeletal muscle. Bioenergetic measurements in fibroblasts from both patients detected reduced spare respiratory capacities and altered extracellular acidification rates, revealing a switch from mitochondrial respiration to glycolysis to uphold ATP production. Thus, in contrast to the differing disease presentation, biochemical evidence of mitochondrial deficiency turned out quite similar. We conclude that biochemical analysis remains a valuable tool to confirm the genetic diagnosis of mitochondrial disease, especially in patients with new gene variants or atypical clinical presentation. Full article

Transcutaneous (TSS) and epidural spinal stimulation (ESS) are electrophysiological techniques that have been used to investigate the interactions between exogenous electrical stimuli and spinal sensorimotor networks that integrate descending motor signals with afferent inputs from the periphery during motor tasks such as standing and stepping. Recently, pilot-phase clinical trials using ESS and TSS have demonstrated restoration of motor functions that were previously lost due to spinal cord injury (SCI). However, the spinal network interactions that occur in response to TSS or ESS pulses with spared descending connections across the site of SCI have yet to be characterized. Therefore, we examined the effects of delivering TSS or ESS pulses to the lumbosacral spinal cord in nine individuals with chronic SCI. During low-frequency stimulation, participants were instructed to relax or attempt maximum voluntary contraction to perform full leg flexion while supine. We observed similar lower-extremity neuromusculature activation during TSS and ESS when performed in the same participants while instructed to relax. Interestingly, when participants were instructed to attempt lower-extremity muscle contractions, both TSS- and ESS-evoked motor responses were significantly inhibited across all muscles. Participants with clinically complete SCI tested with ESS and participants with clinically incomplete SCI tested with TSS demonstrated greater ability to modulate evoked responses than participants with motor complete SCI tested with TSS, although this was not statistically significant due to a low number of subjects in each subgroup. These results suggest that descending commands combined with spinal stimulation may increase activity of inhibitory interneuronal circuitry within spinal sensorimotor networks in individuals with SCI, which may be relevant in the context of regaining functional motor outcomes. Full article