Noninvasive modulation of human corticostriatal activity.

Corticostriatal activity is an appealing target for nonpharmacological treatments of brain disorders. In humans, corticostriatal activity may be modulated with noninvasive brain stimulation (NIBS). However, a NIBS protocol with a sound neuroimaging measure demonstrating a change in corticostriatal activity is currently lacking. Here, we combine transcranial static magnetic field stimulation (tSMS) with resting-state functional MRI (fMRI). We first present and validate the ISAAC analysis, a well-principled framework that disambiguates functional connectivity between regions from local activity within regions. All measures of the framework suggested that the region along the medial cortex displaying greater functional connectivity with the striatum is the supplementary motor area (SMA), where we applied tSMS. We then use a data-driven version of the framework to show that tSMS of the SMA modulates the local activity in the SMA proper, in the adjacent sensorimotor cortex, and in the motor striatum. We finally use a model-driven version of the framework to clarify that the tSMS-induced modulation of striatal activity can be primarily explained by a change in the shared activity between the modulated motor cortical areas and the motor striatum. These results suggest that corticostriatal activity can be targeted, monitored, and modulated noninvasively in humans.

Randomised, double-blind, placebo-controlled, parallel-group, multicentric, phase IIA clinical trial for evaluating the safety, tolerability, and therapeutic efficacy of daily oral administration of NFX88 to treat neuropathic pain in individuals with spinal cord injury.

STUDY DESIGN: Double-blind, randomized, placebo-controlled, parallel-group multicentric phase IIA clinical trial. OBJECTIVE: To assess the safety and tolerability of oral administration of NFX-88 in subjects with chronic spinal cord injury (SCI) and explore its efficacy in pain control. SETTING: A total of 7 spinal cord injury rehabilitation units in Spain. METHODS: A total of 61 adult with traumatic complete or incomplete spinal cord injury (C4-T12 level), were randomised 1:1:1:1 to a placebo, NFX88 1.05 g, 2.1 g, 4.2 g/day for up to 12 weeks. The placebo or NFX-88 was administered as add-on therapy to pre-existing pregabalin (150-300 mg per day). Safety and tolerability were evaluated, and the Visual Analogue Scale (VAS) was the primary measure to explore the efficacy of NFX-88 in pain control. RESULTS: No severe treatment-related adverse effects were reported for any of the four study groups. 44 SCI individuals completed the study and were analysed. The data obtained from the VAS analysis and the PainDETECT Questionnaire (PD-Q) suggested that the combination of NFX88 with pregabalin is more effective than pregabalin with placebo at reducing neuropathic pain (NP) in individuals with SCI and that the dose 2.10 g/day causes the most dramatic pain relief. CONCLUSIONS: NFX88 treatment was found to be highly safe and well tolerated, with the dose of 2.10 g/day being the most effective at causing pain relief. Thus, the promising efficacy of this first-in-class lipid mediator deserves further consideration in future clinical trials.

Factors Associated With Fatigue in People With Spinal Cord Injury: A Systematic Review and Meta-analysis.

OBJECTIVE: To investigate the association between fatigue and clinical and demographic variables in people with spinal cord injury (SCI). DATA SOURCES: Five databases (MEDLINE, Physiotherapy Evidence Database, Cochrane, Google Scholar, Cumulative Index to Nursing and Allied Health) were searched up to November 2021. STUDY SELECTION: Observational studies that reported the association between fatigue and clinical and demographic variables in English or Spanish were eligible. Reviews, qualitative research studies, and nonoriginal articles were excluded. Twenty-three of the 782 identified studies met the inclusion criteria for the meta-analysis. DATA EXTRACTION: Two researchers independently extracted the data. The strength of the association between each factor and fatigue was determined by the effect size. When the results of the effect size were expressed with different statistics, the correlation coefficient was the preferred estimation. The risk of bias was assessed using the Appraisal Tool for Cross-Sectional Studies and the Newcastle-Ottawa Scale. DATA SUMMARY: A pooled analysis of the associations between fatigue and 17 factors was performed. A direct association was found between fatigue and 9 factors (sorted by effect size): anxiety (r=0.57; 95% CI, 0.29-0.75), stress (r=0.54; 95% confidence interval [CI], 0.26-0.74), depression (r=0.47; 95% CI, 0.44-0.50), pain (r=0.34; 95% CI, 0.16-0.50), analgesic medication (r=0.32; 95% CI, 0.28-0.36), assistive devices (r=0.23; 95% CI, 0.17-0.29), lesion level (r=0.15; 95% CI, 0.07-0.23), incomplete SCI (r=0.13; 95% CI, 0.05-0.22), and medication (r=0.12; 95% CI, 0.01-0.23). An inverse association was found with 3 factors (sorted by effect size): self-efficacy (r=-0.63; 95% CI, -0.81 to -0.35), participation (r=-0.32; 95% CI, -0.58 to -0.001), and physical activity (r=-0.17; 95% CI, -0.28 to -0.05). No association was found with age, sex, educational level, time since injury, and spasticity. CONCLUSIONS: Several factors were associated with fatigue in people with SCI, with those related to mental health showing the strongest associations. These results should be interpreted with caution because of the high heterogeneity observed in some factors.

Small interfering RNAs in the management of human rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) has unclear pathogenesis, but the molecules that feed its inflammatory state are known. Small interfering RNAs (siRNAs) are useful to identify molecular targets and evaluate the efficacy of specific drugs, and can themselves be used for therapeutic purposes. SOURCES OF DATA: A systematic search of different databases to March 2022 was performed to define the role of siRNAs in RA therapy. Twenty suitable studies were identified. AREAS OF AGREEMENT: Small interfering RNAs can be useful in the study of inflammatory processes in RA, and identify possible therapeutic targets and drug therapies. AREAS OF CONTROVERSY: Many genes and cytokines participate in the inflammatory process of RA and can be regulated with siRNA. However, it is difficult to determine whether the responses to siRNAs and other drugs studied in human cells in vitro are similar to the responses in vivo. GROWING POINTS: Inflammatory processes can be affected by the gene dysregulation of siRNAs on inflammatory cytokines. AREAS TIMELY FOR DEVELOPING RESEARCH: To date, it is not possible to determine whether the pharmacological response of siRNAs on cells in vitro would be similar to what takes place in vivo for the diseases studied so far.

Altered motor cortex physiology and dysexecutive syndrome in patients with fatigue and cognitive difficulties after mild COVID-19.

BACKGROUND AND PURPOSE: Fatigue and cognitive difficulties are reported as the most frequently persistent symptoms in patients after mild SARS-CoV-2 infection. An extensive neurophysiological and neuropsychological assessment of such patients was performed focusing on motor cortex physiology and executive cognitive functions. METHODS: Sixty-seven patients complaining of fatigue and/or cognitive difficulties after resolution of mild SARS-CoV-2 infection were enrolled together with 22 healthy controls (HCs). Persistent clinical symptoms were investigated by means of a 16-item questionnaire. Fatigue, exertion, cognitive difficulties, mood and 'well-being' were evaluated through self-administered tools. Utilizing transcranial magnetic stimulation of the primary motor cortex (M1) resting motor threshold, motor evoked potential amplitude, cortical silent period duration, short-interval intracortical inhibition, intracortical facilitation, long-interval intracortical inhibition and short-latency afferent inhibition were evaluated. Global cognition and executive functions were assessed with screening tests. Attention was measured with computerized tasks. RESULTS: Post COVID-19 patients reported a mean of 4.9 persistent symptoms, high levels of fatigue, exertion, cognitive difficulties, low levels of well-being and reduced mental well-being. Compared to HCs, patients presented higher resting motor thresholds, lower motor evoked potential amplitudes and longer cortical silent periods, concurring with reduced M1 excitability. Long-interval intracortical inhibition and short-latency afferent inhibition were also impaired, indicating altered GABAB -ergic and cholinergic neurotransmission. Short-interval intracortical inhibition and intracortical facilitation were not affected. Patients also showed poorer global cognition and executive functions compared to HCs and a clear impairment in sustained and executive attention. CONCLUSIONS: Patients with fatigue and cognitive difficulties following mild COVID-19 present altered excitability and neurotransmission within M1 and deficits in executive functions and attention.

Nucleus Accumbens Stimulation Modulates Inhibitory Control by Right Prefrontal Cortex Activation in Obsessive-Compulsive Disorder.

Inhibitory control is considered a compromised cognitive function in obsessive-compulsive (OCD) patients and likely linked to corticostriatal circuitry disturbances. Here, 9 refractory OCD patients treated with deep brain stimulation (DBS) were evaluated to address the dynamic modulations of large-scale cortical network activity involved in inhibitory control after nucleus accumbens (NAc) stimulation and their relationship with cortical thickness. A comparison of DBS "On/Off" states showed that patients committed fewer errors and exhibited increased intraindividual reaction time variability, resulting in improved goal maintenance abilities and proactive inhibitory control. Visual P3 event-related potentials showed increased amplitudes during Go/NoGo performance. Go and NoGo responses increased cortical activation mainly over the right inferior frontal gyrus and medial frontal gyrus, respectively. Moreover, increased cortical activation in these areas was equally associated with a higher cortical thickness within the prefrontal cortex. These results highlight the critical role of NAc DBS for preferentially modulating the neuronal activity underlying sustained speed responses and inhibitory control in OCD patients and show that it is triggered by reorganizing brain functions to the right prefrontal regions, which may depend on the underlying cortical thinning. Our findings provide updated structural and functional evidence that supports critical dopaminergic-mediated frontal-striatal network interactions in OCD.

Pregnancy and parturition after hip arthroplasty.

BACKGROUND: The indications for total hip arthroplasty (THA) have become more widespread. Of the patients receiving a THA, some will be women with child-bearing potential. There has been little research into the effects of pregnancy and parturition on THA, and the effect of THA on pregnancy and parturition. METHODS: A systematic search in different database, to December 2020, was performed to define the effects of pregnancy and parturition on THA, and the effect of THA on pregnancy and parturition. Seven suitable studies were identified. RESULTS: Following a THA, there appear to be no harmful effects on subsequent pregnancies with regards to either the health of the mother or baby. There is no increase in pregnancy complications, or difficulties in labour arising from the THA. Some women and their obstetricians may opt for a pre-emptive Caesarian section, but there is no scientific basis for this line of action. The state of pregnancy in turn appears to have no harmful effects on the THA. CONCLUSION: Further research will be useful to better understand which materials and which types of prostheses to use in young women of childbearing age to ensure maximum safety for pregnancy and childbirth.

Cortical layer-specific modulation of neuronal activity after sensory deprivation due to spinal cord injury.

Cortical areas have the capacity of large-scale reorganization following sensory deafferentation. However, it remains unclear whether this phenomenon is a unique process that homogeneously affects the entire deprived cortical region or whether it is susceptible to changes depending on neuronal networks across distinct cortical layers. Here, we studied how the local circuitry within each layer of the deafferented cortex forms the basis for neuroplastic changes after immediate thoracic spinal cord injury (SCI) in anaesthetized rats. In vivo electrophysiological recordings from deafferented hindlimb somatosensory cortex showed that SCI induces layer-specific changes mediating evoked and spontaneous activity. In supragranular layer 2/3, SCI increased gamma oscillations and the ability of these neurons to initiate up-states during spontaneous activity, suggesting an altered corticocortical network and/or intrinsic properties that may serve to maintain the excitability of the cortical column after deafferentation. On the other hand, SCI enhanced the infragranular layers' ability to integrate evoked sensory inputs leading to increased and faster neuronal responses. Delayed evoked response onsets were also observed in layer 5/6, suggesting alterations in thalamocortical connectivity. Altogether, our data indicate that SCI immediately modifies the local circuitry within the deafferented cortex allowing supragranular layers to better integrate spontaneous corticocortical information, thus modifying column excitability, and infragranular layers to better integrate evoked sensory inputs to preserve subcortical outputs. These layer-specific neuronal changes may guide the long-term alterations in neuronal excitability and plasticity associated with the rearrangements of somatosensory networks and the appearance of central sensory pathologies usually associated with spinal cord injury. KEY POINTS: Sensory stimulation of forelimb produces cortical evoked responses in the somatosensory hindlimb cortex in a layer-dependent manner. Spinal cord injury favours the input statistics of corticocortical connections between intact and deafferented cortices. After spinal cord injury supragranular layers exhibit better integration of spontaneous corticocortical information while infragranular layers exhibit better integration of evoked sensory stimulation. Cortical reorganization is a layer-specific phenomenon.

Small interfering RNAs in tendon homeostasis.

BACKGROUND: Tenogenesis and tendon homeostasis are guided by genes encoding for the structural molecules of tendon fibres. Small interfering RNAs (siRNAs), acting on gene regulation, can therefore participate in the process of tendon healing. SOURCES OF DATA: A systematic search of different databases to October 2020 identified 17 suitable studies. AREAS OF AGREEMENT: SiRNAs can be useful to study reparative processes of tendons and identify possible therapeutic targets in tendon healing. AREAS OF CONTROVERSY: Many genes and growth factors involved in the processes of tendinopathy and tendon healing can be regulated by siRNAs. It is however unclear which gene silencing determines the expected effect. GROWING POINTS: Gene dysregulation of growth factors and tendon structural proteins can be influenced by siRNA. AREAS TIMELY FOR DEVELOPING RESEARCH: It is not clear whether there is a direct action of the siRNAs that can be used to facilitate the repair processes of tendons.

Cortical disinhibition in Parkinson's disease.

In Parkinson's disease, striatal dopamine depletion produces profound alterations in the neural activity of the cortico-basal ganglia motor loop, leading to dysfunctional motor output and parkinsonism. A key regulator of motor output is the balance between excitation and inhibition in the primary motor cortex, which can be assessed in humans with transcranial magnetic stimulation techniques. Despite decades of research, the functional state of cortical inhibition in Parkinson's disease remains uncertain. Towards resolving this issue, we applied paired-pulse transcranial magnetic stimulation protocols in 166 patients with Parkinson's disease (57 levodopa-naïve, 50 non-dyskinetic, 59 dyskinetic) and 40 healthy controls (age-matched with the levodopa-naïve group). All patients were studied OFF medication. All analyses were performed with fully automatic procedures to avoid confirmation bias, and we systematically considered and excluded several potential confounding factors such as age, gender, resting motor threshold, EMG background activity and amplitude of the motor evoked potential elicited by the single-pulse test stimuli. Our results show that short-interval intracortical inhibition is decreased in Parkinson's disease compared to controls. This reduction of intracortical inhibition was obtained with relatively low-intensity conditioning stimuli (80% of the resting motor threshold) and was not associated with any significant increase in short-interval intracortical facilitation or intracortical facilitation with the same low-intensity conditioning stimuli, supporting the involvement of cortical inhibitory circuits. Short-interval intracortical inhibition was similarly reduced in levodopa-naïve, non-dyskinetic and dyskinetic patients. Importantly, intracortical inhibition was reduced compared to control subjects also on the less affected side (n = 145), even in de novo drug-naïve patients in whom the less affected side was minimally symptomatic (lateralized Unified Parkinson's Disease Rating Scale part III = 0 or 1, n = 23). These results suggest that cortical disinhibition is a very early, possibly prodromal feature of Parkinson's disease.

Phase II/III placebo-controlled randomized trial of safety and efficacy of growth hormone treatment in incomplete chronic traumatic spinal cord injury.

STUDY DESIGN: This is a double blind phase II/III placebo-controlled randomized trial of the safety and efficacy of GH treatment in incomplete chronic traumatic spinal cord injury. OBJECTIVE: The aim of this study was to investigate the possibility to use exogenous GH administration for motor recovery in chronic traumatic incomplete human SCI. The objectives were to establish safety and efficacy of a combined treatment of subcutaneous GH (or placebo) and rehabilitation in this population. SETTING: Hospital Nacional de Parapléjicos METHODS: The pharmacological treatment was a subcutaneous daily dose of growth hormone (GH, Genotonorm 0.4 mg, Pfizer Pharmaceuticals) or placebo for one year. The pharmacological treatment was performed, during the first six months under hospitalization and supervised rehabilitation. RESULTS: The main findings were that the combined treatment of GH plus rehabilitation treatment is feasible and safe, and that GH but not placebo increases the ISNCSCI motor score. On the other hand, the motor-score increment was marginal (after one-year combined treatment, the mean increment of the motor-score was around 2.5 points). Moreover, we found that intensive and long-lasting rehabilitation program per se increases the functional outcome of SCI individuals (measured using SCIM III and WISCI II). CONCLUSIONS: It is important to highlight that our aim was to propose GH as a possible treatment to improve motor functions in incomplete SCI individuals. At least with the doses we used, we think that the therapeutic effects of this approach are not clinically relevant in most subjects with SCI.

The temporal effect of intra-articular ozone injections on pain in knee osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is a most common orthopaedic condition, often complicated by inflammatory features. SOURCES OF DATA: A systematic search in PubMed, Embase, Google Scholar and Scopus databases (to January 2019) was performed to define the effect obtained in patients with OA of the knee by injections of ozone, on pain and physical function. Six RCTs and 353 patients were included. AREAS OF AGREEMENT: Recently, an increasing number of physicians have used ozone therapy to alleviate the symptoms of acute and chronic OA of the knee. Ozone can allow greater mobility of the knee joint, pain relief and decrease in effusion. AREAS OF CONTROVERSY: The volume and concentration of ozone injected are different in the various treatment protocols published. GROWING POINTS: The action of ozone is unclear, but it is a promising therapeutic modality capable of impacting, favourably, function and quality of life. AREAS TIMELY FOR DEVELOPING RESEARCH: The lack of a clear protocol of use is a major limitation, and to date there is no clear evidence of long-term efficacy.

The presence of residents during orthopedic operation exerts no negative influence on outcome.

BACKGROUND: Operative procedural training is a key component of orthopedic surgery residency. It is unclear how and whether residents participation in orthopedic surgical procedures impacts on post-operative outcomes. SOURCES OF DATA: A systematic search was performed to identify articles in which the presence of a resident in the operating room was certified, and was compared with interventions without the presence of residents. AREAS OF AGREEMENT: There is a likely beneficial role of residents in the operating room, and there is only a weak association between the presence of a resident and a worse outcome for orthopedic surgical patients. AREAS OF CONTROVERSY: Most of the studies were undertaken in USA, and this represents a limit from the point of view of comparison with other academic and clinical realities. GROWING POINT: The data provide support for continued and perhaps increased involvement of resident in orthopedic surgery. AREAS OF RESEARCH: To clarify the role of residents on clinically relevant outcomes in orthopedic patients, appropriately powered randomized control trials should be planned.

MicroRNA in osteoarthritis: physiopathology, diagnosis and therapeutic challenge.

BACKGROUND: Osteoarthritis (OA) is the most orthopedic condition. The pattern of gene expression and the transcription factors that exert control of chondrogenesis have been extensively studied. SOURCES OF DATA: A systematic search (up to July 2018) of articles assessing the role of microRNA (miRNA) in physiopathology, diagnosis and therapy of OA was performed, with the purpose of giving a critical perspective of the possibilities for diagnostic and therapeutic use of miRNA in the management of OA. AREAS OF AGREEMENT: miRNAs are small noncoding RNAs that can regulate gene expression in human cells. miRNAs can be expressed in a different fashion in osteoarthritic compared to nonosteoarthritic cartilage. AREAS OF CONTROVERSY: The mechanisms that produce alteration of gene expression in OA are still not completely understood. miRNAs may be involved in the diagnosis of OA as well as in its treatment. GROWING POINTS: There are complex interactions between miRNAs and their multiple target genes. These interactions may be important in gene regulation and the control of homeostatic pathways in OA. AREAS TIMELY FOR DEVELOPING RESEARCH: miRNA could be useful for diagnostic or management purposes, but the issue of delivery of miRNA targeting agents needs to be overcome before miRNA can be applied in clinical practice.

Development of chronic pain in males with traumatic spinal cord injury: role of circulating levels of the chemokines CCL2 and CXCL10 in subacute stage.

STUDY DESIGN: Longitudinal study. OBJECTIVES: To assess the impact of spinal cord injury (SCI) on circulating levels of chemokines (CCL2 and CXCL10) and its relation with pain development. SETTING: National Hospital for SCI patients. METHODS: We longitudinally studied changes in the circulating levels of CCL2 and CXCL10 in 27 male patients with complete SCI who were evaluated in the early subacute phase and indeed 3 and 6 months after injury measuring at each time-point serum levels of CCL2 and CXCL10. Patients were telephonically interviewed about pain 1 year after SCI. RESULTS: In the early subacute phase, patients with pain showed higher CXCL10 and similar CCL2 levels as opposed to those without pain. Moreover, CCL2 concentrations were positively associated with pain intensity. The results obtained by analysing the temporal profile of the chemokines suggested that CXCL10 was inclined to decrease over time, while CCL2 increased over time. CONCLUSION: The results of this preliminary study, the first performed in humans with traumatic SCI, suggest a link between changes in the circulating chemokine profile and pain development in subacute SCI stage as well as with severity in a more chronic stage. Large series studies will evaluate whether the circulating chemokine status can be useful as a biomarker for assessing the patients' risk for pain development.

Static Magnetic Field Stimulation over Parietal Cortex Enhances Somatosensory Detection in Humans.

The role of neuronal oscillations in human somatosensory perception is currently unclear. To address this, here we use noninvasive brain stimulation to artificially modulate cortical network dynamics in the context of neurophysiological and behavioral recordings. We demonstrate that transcranial static magnetic field stimulation (tSMS) over the somatosensory parietal cortex increases oscillatory power specifically in the alpha range, without significantly affecting bottom-up thalamocortical inputs indexed by the early cortical component of somatosensory evoked potentials. Critically, we next show that parietal tSMS enhances the detection of near-threshold somatosensory stimuli. Interestingly, this behavioral improvement reflects a decrease of habituation to somatosensation. Our data therefore provide causal evidence that somatosensory perception depends on parietal alpha activity.SIGNIFICANCE STATEMENT Artificially increasing alpha power by placing a powerful magnetic field over the somatosensory cortex overcomes the natural decline in detection probability of a repeated near-threshold sensory stimulus.

Transcranial static magnetic field stimulation (tSMS) of the visual cortex decreases experimental photophobia.

Background Transcranial static magnetic field stimulation (tSMS) reduces cortical excitability in humans. Methods The objective of this study was to determine whether tSMS over the occipital cortex is effective in reducing experimental photophobia. In a sham-controlled double-blind crossover study, tSMS (or sham) was applied for 10 minutes with a cylindrical magnet on the occiput of 20 healthy subjects. We assessed subjective discomfort induced by low-intensity and high-intensity visual stimuli presented in a dark room before, during and after tSMS (or sham). Results Compared to sham, tSMS significantly reduced the discomfort induced by high-intensity light stimuli. Conclusions The visual cortex may contribute to visual discomfort in experimental photophobia, providing a rationale for investigating tSMS as a possible treatment for photophobia in migraine.

Static Magnetic Field Stimulation over the Visual Cortex Increases Alpha Oscillations and Slows Visual Search in Humans.

Transcranial static magnetic field stimulation (tSMS) was recently introduced as a promising tool to modulate human cerebral excitability in a noninvasive and portable way. However, a demonstration that static magnetic fields can influence human brain activity and behavior is currently lacking, despite evidence that static magnetic fields interfere with neuronal function in animals. Here we show that transcranial application of a static magnetic field (120-200 mT at 2-3 cm from the magnet surface) over the human occiput produces a focal increase in the power of alpha oscillations in underlying cortex. Critically, this neurophysiological effect of tSMS is paralleled by slowed performance in a visual search task, selectively for the most difficult target detection trials. The typical relationship between prestimulus alpha power over posterior cortical areas and reaction time (RT) to targets during tSMS is altered such that tSMS-dependent increases in alpha power are associated with longer RTs for difficult, but not easy, target detection trials. Our results directly demonstrate that a powerful magnet placed on the scalp modulates normal brain activity and induces behavioral changes in humans.