Altered Motor Function Research Articles

The bivalent ligand MCC22 potently attenuates hyperalgesia in a mouse model of cisplatin-evoked neuropathic pain without tolerance or reward

Cisplatin and other widely employed platinum-based anticancer agents produce chemotherapy-induced peripheral neuropathy (CIPN) that often results in pain and hyperalgesia that are difficult to manage. We investigated the efficacy of a novel bivalent ligand, MCC22, for the treatment of pain arising from CIPN. MCC22 consists of mu opioid receptor (MOR) agonist and chemokine receptor 5 (CCR5) antagonist pharmacophores connected through a 22-atom spacer and was designed to target a putative MOR-CCR5 heteromer localized in pain processing areas. Mice received once daily intraperitoneal (i.p.) injections of cisplatin (1 mg/kg) for seven days and behavior testing began 7 days later. Cisplatin produced mechanical hyperalgesia that was decreased dose-dependently by MCC22 given by intrathecal (ED50 = 0.004 pmol) or i.p. (3.07 mg/kg) routes. The decrease in hyperalgesia was associated with decreased inflammatory response by microglia in the spinal cord. Unlike morphine, MCC22 given daily for nine days did not exhibit tolerance to its analgesic effect and its characteristic antihyperalgesic activity was fully retained in morphine-tolerant mice. Furthermore, MCC22 did not alter motor function and did not exhibit rewarding properties. Given the exceptional potency of MCC22 without tolerance or reward, MCC22 has the potential to vastly improve management of chronic pain due to CIPN.This article is part of the Special Issue entitled ‘New Vistas in Opioid Pharmacology’.

A Targeted Mutation Disrupting Mitochondrial Complex IV Function in Primary Afferent Neurons Leads to Pain Hypersensitivity Through P2Y1 Receptor Activation.

As mitochondrial dysfunction is evident in neurodegenerative disorders that are accompanied by pain, we generated inducible mutant mice with disruption of mitochondrial respiratory chain complex IV, by COX10 deletion limited to sensory afferent neurons through the use of an Advillin Cre-reporter. COX10 deletion results in a selective energy-deficiency phenotype with minimal production of reactive oxygen species. Mutant mice showed reduced activity of mitochondrial respiratory chain complex IV in many sensory neurons, increased ADP/ATP ratios in dorsal root ganglia and dorsal spinal cord synaptoneurosomes, as well as impaired mitochondrial membrane potential, in these synaptoneurosome preparations. These changes were accompanied by marked pain hypersensitivity in mechanical and thermal (hot and cold) tests without altered motor function. To address the underlying basis, we measured Ca2+ fluorescence responses of dorsal spinal cord synaptoneurosomes to activation of the GluK1 (kainate) receptor, which we showed to be widely expressed in small but not large nociceptive afferents, and is minimally expressed elsewhere in the spinal cord. Synaptoneurosomes from mutant mice showed greatly increased responses to GluK1 agonist. To explore whether altered nucleotide levels may play a part in this hypersensitivity, we pharmacologically interrogated potential roles of AMP-kinase and ADP-sensitive purinergic receptors. The ADP-sensitive P2Y1 receptor was clearly implicated. Its expression in small nociceptive afferents was increased in mutants, whose in vivo pain hypersensitivity, in mechanical, thermal and cold tests, was reversed by a selective P2Y1 antagonist. Energy depletion and ADP elevation in sensory afferents, due to mitochondrial respiratory chain complex IV deficiency, appear sufficient to induce pain hypersensitivity, by ADP activation of P2Y1 receptors.

Brainstem morphology and movement disorders

The control of movement involves complex neural circuits that span several brain regions. One brain region that is important for movement is a brainstem structure called the substantia nigra. The importance of this brain region is evidenced by the motor signs that accompany Parkinson's disease, a movement disorder characterised by degeneration of neurons in the substantia nigra. Substantia nigra morphology is difficult to assess in humans with standard clinical MRI but it can be readily viewed with transcranial sonography. Use of this technique has shown that the substantia nigra is abnormally bright and enlarged in patients with Parkinson's disease, and the abnormality (hyperechogencity) is present in 78–90% of patients. Because of this, the technique is now being used in some countries as a diagnostic aid for Parkinson's disease. Substantia nigra hyperechogenicity has also been observed in ∼9% of healthy adults. The presence of this abnormality in healthy older adults is a significant risk factor for Parkinson's disease. Healthy older adults with this abnormality are 17 times more likely to be diagnosed with Parkinson's disease over a 3-year period than people without the abnormality (Berg et al 2011 Arch Neurol 68:932-7). Our research team has demonstrated that substantia nigra hyperechogenicity in healthy older adults is associated with altered neuronal circuitry in a functionally connected brain region (motor cortex) and altered fine motor function. The changes share similarities with de novo patients diagnosed with Parkinson's disease. Our results support use of transcranial ultrasound as a diagnostic aid and early disease marker for Parkinson's disease. Our research has also identified a young-adult population that has a high prevalence of substantia nigra hyperechogenicity – individuals that have used the drug methamphetamine or ‘ice’. Methamphetamine is toxic to the same neurons that undergo neurodegeneration in Parkinson's disease. Our research shows that two thirds of young adults that have used methamphetamine, as little as five times, have substantia nigra hyperechogenicity and use of the drug is associated with clinical signs of parkinsonism. This observation is alarming because methamphetamine is a significant health problem in many countries and there are no reports of the substantia nigra abnormality returning to normal in the literature (in any population), despite tens of thousands of people having undergone the procedure world-wide. Our research suggests that substantia nigra hyperechogenicity in healthy adults is associated with changes characteristic of Parkinson's disease and supports its role as a marker of vulnerability for this disorder.

From emotion processing to metacognition

Functional neurological disorder (FND) is the term used (DSM-5) to refer to a disabling neuropsychiatric condition that is frequently encountered in medical practice. It was previously known as conversion disorder (CD) and formerly described as hysteria. It is characterised by neuro­logical symptoms (e.g., weakness, numbness, tremor…) without evidence of any brain lesion. Early neurobiological accounts of this disorder were part of the foundation of psychiatry and neurology, but were then dominated by a purely psychodynamic perspective. The advent of neuroimaging in the past two decades has stimulated renewed interest in the “functional” brain underpinnings of these symptoms, with growing interest and ­increasing attempts to investigate them in a neuroscience perspective. In this brief review, I discuss recent evidence pointing to how top-down mechanisms may alter motor function in patients with motor FND/CD, through coupling with neural systems associated with internal self-monitoring, emotion regulation and memory, and thus lead to the emergence of functional symptoms. More research, however, is still needed to elucidate the causes of FND/CD (why they occur), in addition to their neuro­anatomical substrates (how they occur).

Inclusion Cysts after Fetal Spina Bifida Repair: A Third Hit?

Introduction: Fetal spina bifida repair (fSBR) has proven effective in the reversibility of hindbrain herniation, lower rate of shunt-dependent hydrocephalus, and independent ambulation. Besides distinct advantages, there are also concerns related to fSBR. One of these is the postnatal occurrence of inclusion cysts (IC). Methods: In a prospective study, 48 children who underwent fSBR were followed up. Postnatal assessment included clinical examination, cystometry, and spinal MRI. Indication for IC resection was the evidence of a spinal mass on MRI in the presence of deteriorating motor or bladder function, pain, or considerable growth of the IC. Results: Fourteen children (30%) developed IC, all within the first 2 years of life. Six children underwent IC resection; 4 children due to deteriorating function, 2 children due to doubling of the mass on MRI within 1 year. Following IC resection, 4/6 children (67%) demonstrated altered motor function and 6 children (100%) were diagnosed with neurogenic bladder dysfunction. Conclusions: Systematic follow-up of patients with a history of fSBR revealed a high incidence of IC. Whether these are of dysembryogenic or iatrogenic origin, remains unclear. Since both IC per se and IC resection may lead to loss of neurologic function, IC can be considered a “third hit”.

Neurobehavioral Alterations in Zebrafish Due to Long-Term Exposure to Low Doses of Inorganic Arsenic.

Inorganic arsenic (As) is one of the most ubiquitous and toxic substances with widespread health effects on human populations and biodiversity. Although arsenic is a frequent surface water pollutant, there is scant evidence about neurotoxicity in aquatic species in different stages of development. In the present study, we investigated the neurobehavioral effects of chronic exposure to environmentally relevant doses of arsenic. We exposed zebrafish to 50 and 500 ppb during the larval, juvenile, and adult stage (from 4 h to 150 days postfertilization). We then used broad behavioral screening to evaluate motor function, social behavior, learning and memory, and anxiety-like behaviors. Our results show that arsenic exposure to 500 ppb alters motor function from the embryo to the adult stage. Furthermore, during the adult phase, associative learning and the sensorimotor response are affected with both high and low doses of As, respectively. Notably, exposure to 500 ppb of As induces behaviors associated with anxiety, during the juvenile and adult phase but not the larval stage, without changes in whole-body cortisol levels. These results indicate that chronic exposure to arsenic during their lifespan is capable of producing alterations in different behavioral markers in aquatic vertebrates.

Maternal thyroid disorder in pregnancy and risk of cerebral palsy in the child: A population-based cohort study

Introduction Cerebral palsy is the most common severe motor disability in childhood, but its etiology is incompletely understood. Studies have suggested that prenatal thyroid hormone disturbances affect child neurodevelopment and may alter motor function. Objective To investigate the association between maternal thyroid disorder in pregnancy and risk of cerebral palsy in the child in two large study populations in Denmark and Norway. Method We conducted a population-based cohort study using two study populations. (1) 1,270,079 children born in Denmark 1979–2007 identified in nationwide registers, and (2) 192,918 children born 1996–2009 recruited into the Danish National Birth Cohort and The Norwegian Mother and Child Cohort study, combined in the MOthers and BAbies in Norway and Denmark (MOBAND) collaboration cohort. Register based and self-reported information on maternal thyroid disorder were studied in relation to risk of cerebral palsy and its unilateral and bilateral spastic subtypes using multiple logistic regression. Information on CP was derived from the Danish and Norwegian National Cerebral Palsy Registries, and all CP cases registered from age one to age six years, which were verified by neuro-pediatricians, were included. Results In register data, hypothyroidism was recognized in 12,929 (1.0%), hyperthyroidism in 9943 (0.8%), and unclassifiable thyroid disorder in 753 ( Conclusion Maternal thyroid disorder was not related in this study to bilateral spastic CP, which is the predominant CP subtype, but we do find a higher risk of unilateral spastic CP in children of mothers whose thyroid disorders were identified in pregnancy. The offspring of such women are more likely to have been exposed to abnormal thyroid hormone levels in utero than the offspring of women whose thyroid disorders were diagnosed and treated prior to conception. A useful extension of our findings would be to see whether they can be replicated in studies making use of maternal blood samples.

Chronic Traumatic Encephalopathy in Professional American Football Players: Where Are We Now?

Repetitive head trauma provides a favorable milieu for the onset of inflammatory and neurodegenerative processes. The result of long-lasting head trauma is chronic traumatic encephalopathy (CTE), a disease process well-recognized in boxers, military personnel, and more recently, in American football players. CTE is a chronic neurodegenerative disease with hallmarks of hyperphosphorylated tau (p-tau) aggregates and intercellular lesions of neurofibrillary tangles. The criteria for CTE diagnosis requires at least 1–2 focal perivascular lesions of p-tau in the cerebral cortex, at the depth of the sulci. These pathognomonic lesions aggregate within neurons and glial cells such as astrocytes, and cell processes within the vicinity of small blood vessels. CTE presents in a distinct topographical distribution pattern compared to other tauopathies such as AD and other age-related astrogliopathies. CTE also has an insidious onset, years after repetitive head trauma. The disease course of CTE is characterized by cognitive dysfunction, behavioral changes, and can progress to altered motor function with parkinsonian-like manifestations in later stages. This short review aims to summarize CTE in professional football, epidemiology, diagnosis based on neuroanatomical abnormalities, cognitive degeneration, and adverse mental health effects, as well as gaps in the literature and future directions in diagnostics, therapeutics, and preventive measures.

Developmental nicotine exposure alters glycinergic neurotransmission to hypoglossal motoneurons in neonatal rats.

We tested the hypothesis that nicotine exposure in utero and after birth [developmental nicotine exposure (DNE)] disrupts development of glycinergic synaptic transmission to hypoglossal motoneurons (XIIMNs). Glycinergic spontaneous and miniature inhibitory postsynaptic currents (sIPSC/mIPSC) were recorded from XIIMNs in brain stem slices from 1- to 5-day-old rat pups of either sex, under baseline conditions and following stimulation of nicotinic acetylcholine (ACh) receptors with nicotine (i.e., an acute nicotine challenge). Under baseline conditions, there were no significant effects of DNE on the amplitude or frequency of either sIPSCs or mIPSCs. In addition, DNE did not alter the magnitude of the whole cell current evoked by bath application of glycine, consistent with an absence of change in postsynaptic glycine-mediated conductance. An acute nicotine challenge (bath application of 0.5 μM nicotine) increased sIPSC frequency in the DNE cells, but not control cells. In contrast, nicotine challenge did not change mIPSC frequency in either control or DNE cells. In addition, there were no significant changes in the amplitude of either sIPSCs or mIPSCs in response to nicotine challenge. The increased frequency of sIPSCs in response to an acute nicotine challenge in DNE cells reflects an enhancement of action potential-mediated input from glycinergic interneurons to hypoglossal motoneurons. This could lead to more intense inhibition of hypoglossal motoneurons in response to exogenous nicotine or endogenous ACh. The former would occur with smoking or e-cigarette use while the latter occurs with changes in sleep state and with hypercapnia. NEW & NOTEWORTHY Here we show that perinatal nicotine exposure does not impact baseline glycinergic neurotransmission to hypoglossal motoneurons but enhances glycinergic inputs to hypoglossal motoneurons in response to activation of nicotinic acetylcholine (ACh) receptors with acute nicotine. Given that ACh is the endogenous ligand for nicotinic ACh receptors, the latter reveals a potential mechanism whereby perinatal nicotine exposure alters motor function under conditions where ACh release increases, such as the transition from non-rapid-eye movement to rapid-eye movement sleep, and during hypercapnia.

Cortical thickness and gyrification patterns in patients with psychogenic non-epileptic seizures

Psychogenic non-epileptic seizures (PNES) are often viewed as manifestations of altered motor and sensory function resulting from psychological responses to adverse experiences. Yet many patients and non-expert healthcare professionals find it difficult to understand how severe disturbances in normal neurological functioning can solely result from underlying psychological mechanisms to the exclusion of other physical causes. Perhaps importantly, recent advances using neuroimaging techniques point to possible structural and functional correlates in PNES. In an attempt to further our understanding of the neurobiological correlates of this condition, we compared the brain scans of 20 patients with PNES (14 females, mean age 41.05, range 19–62) and 20 age- and gender-matched healthy controls (14 females, mean age 40.65, range 21–61) to investigate group differences for cortical thickness and gyrification patterns using FreeSurfer. Compared to controls, patients with PNES showed cortical thickness increases in motor, sensory and occipital areas as well as cortical thickness decreases in temporal and frontal brain regions. In addition, we observed age-related changes in cortical thickness in the right lateral occipital area in PNES. However, contrary to our prediction that atypical gyrification may be present, we did not find any evidence of abnormalities on a measure thought to reflect prenatal and early childhood cortical development and organization. Nor did we find significant correlations between cortical thickness results and clinical features. These findings partly corroborate, but also differ from previous morphometric studies in PNES. These inconsistencies likely reflect the aetiology and phenomenological heterogeneity of PNES.

Effects of localized vibration on knee joint position sense in individuals with anterior cruciate ligament reconstruction

BackgroundAnterior cruciate ligament injury can disrupt one's mechanoreceptors and result in decreased proprioception such as joint position sense and ultimately altered motor function. The application of localized vibration has been used to investigate the integrity of the sensorimotor system and the mechanisms of quadriceps function after anterior cruciate ligament injury and reconstruction. The purpose of the study is to evaluate joint position sense with and without vibration and compare among anterior cruciate ligament reconstructed, contralateral, and control limbs. MethodsFourteen subjects with anterior cruciate ligament reconstruction (8 males and 6 females) and fourteen control subjects (7 males and 7 females) participated in the study. Subjects sat on an isokinetic dynamometer chair with localized vibration strapped on the quadriceps tendon while visual and auditory cues were removed. Subjects were asked to remember an active target position and replicate that position actively. The absolute difference between the target and replicated trial was used as joint position sense. There were three trials at three target positions (15, 45, and 75 degrees of knee flexion) with and without vibration. The order of testing conditions was randomized. One-way analysis of variance or non-parametric equivalent (Kruskal-Wallis test) was used to compare among limbs. Significance was set at P < 0.05 a priori. FindingsThere were no significant joint position sense differences among anterior cruciate ligament reconstructed, contralateral, and control limbs with or without vibration (P = 0.207–0.914). InterpretationThere are several potential reasons for the current findings: vibration-induced post effect, locations of vibration, types of vibration, and rehabilitation status. Future studies should expand the current investigation and explore both sensory and motor functions in anterior cruciate ligament reconstructed subjects.

Face sensorimotor cortex undergoes neuroplastic changes in a rat model of trigeminal neuropathic pain.

Trigeminal nerve injury can result in neuropathic pain behavior and alterations in motor function, but it is unclear if such injury produces neuroplastic alterations in face sensorimotor cortex that could contribute to the alterations in motor function. Therefore, this study aimed to determine if trigeminal nerve injury in a rat neuropathic pain model induces neuroplastic changes in jaw and tongue motor representations in face sensorimotor cortex in association with facial nociceptive behavior. Right infraorbital nerve transection was performed in adult male Sprague-Dawley rats; sham-operated rats served as controls. Nociceptive behavior was assessed by testing facial mechanical sensitivity pre-operatively and post-operatively (1-28 days). Intracortical microstimulation was also applied post-operatively in a series of microelectrode penetrations to map jaw and tongue motor representations in the face sensorimotor cortex by analyzing anterior digastric and genioglossus electromyographic activities evoked by microstimulation at histologically verified sites in face primary somatosensory cortex (face-SI) as well as face primary motor cortex (face-MI). Compared to sham, infraorbital nerve injury induced a significant (2-way repeated-measures analysis of variance, P < 0.001) bilateral decrease in facial mechanical threshold that lasted up to 28 days post-operatively. Nerve injury also induced a significant bilateral decrease compared to sham (P < 0.05) in the number of anterior digastric and/or genioglossus sites in face-MI and in face-SI. These findings indicate that trigeminal nerve injury induces neuroplastic alterations in jaw and tongue motor representations in face sensorimotor cortex that are associated with facial nociceptive behavior and that may contribute to sensorimotor changes following trigeminal nerve injury.

Developmental plasticity of GABAergic neurotransmission to brainstem motoneurons.

Critical homeostatic behaviours such as suckling, swallowing and breathing depend on the precise control of tongue muscle activity. Perinatal nicotine exposure has multiple effects on baseline inhibitory GABAergic neurotransmission to hypoglossal motoneurons (XIIMNs), consistent with homeostatic compensations directed at maintaining normal motoneuron output. Developmental nicotine exposure (DNE) alters how GABAergic neurotransmission is modulated by acute activation of nicotinic acetylcholine receptors, which may provide insight into mechanisms by which nicotine exposure alters motor function under conditions that result in increased release of GABA, such as hypoxia, or endogenous acetylcholine, as occurs in the transition from NREM to REM sleep, or in response to exogenous nicotine. Nicotinic acetylcholine receptor (nAChR) signalling regulates neuronal differentiation and synaptogenesis. Here we test the hypothesis that developmental nicotine exposure (DNE) disrupts the development of GABAergic synaptic transmission to hypoglossal motoneurons (XIIMNs). GABAergic spontaneous and miniature inhibitory postsynaptic currents (sIPSCs/mIPSCs) were recorded from XIIMNs in brainstem slices from control and DNE rat pups of either sex, 1-5days old, at baseline and following acute stimulation of nAChRs with nicotine. At baseline, sIPSCs were less frequent and smaller in DNE cells (consistent with decreased action potential-mediated GABA release), and mIPSCs were more frequent (consistent with increased vesicular GABA release from presynaptic terminals). Acute nicotine challenge increased sIPSC frequency in both groups, though the increase was greater in DNE cells. Acute nicotine challenge did not change the frequency of mIPSCs in either group, though mIPSC amplitude increased significantly in DNE cells, but not control cells. Stimulation of postsynaptic GABAA receptors with muscimol caused a significantly greater chloride current in DNE cells than in control cells. The increased quantal release of GABA, coupled with the rise in the strength of postsynaptic inhibition may be homeostatic adjustments to the decreased action-potential-mediated input from GABAergic interneurons. However, this will exaggerate synaptic inhibition under conditions where the release of GABA (e.g. hypoxia) or ACh (sleep-wake transitions) is increased. These findings reveal a mechanism that may explain why DNE is associated with deficits in the ability to respond appropriately to chemosensory stimuli or to changes in neuromodulation secondary to changes in central nervous system state.

Inertial Sensor Technology Can Capture Changes in Dynamic Balance Control during the Y Balance Test

Introduction: The Y Balance Test (YBT) is one of the most commonly utilised clinical dynamic balance assessments. Research has demonstrated the utility of the YBT in identifying balance deficits in individuals following lower limb injury. However, quantifying dynamic balance based on reach distances alone fails to provide potentially important information related to the quality of movement control and choice of movement strategy during the reaching action. The addition of an inertial sensor to capture more detailed motion data may allow for the inexpensive, accessible quantification of dynamic balance control during the YBT reach excursions. As such, the aim of this study was to compare baseline and fatigued dynamic balance control, using reach distances and 95EV (95% ellipsoid volume), and evaluate the ability of 95EV to capture alterations in dynamic balance control, which are not detected by YBT reach distances. Methods: As part of this descriptive laboratory study, 15 healthy participants completed repeated YBTs at 20, 10, and 0 min prior to and following a modified 60-s Wingate test that was used to introduce a short-term reduction in dynamic balance capability. Dynamic balance was assessed using the standard normalised reach distance method, while dynamic balance control during the reach attempts was simultaneously measured by means of the 95EV derived from an inertial sensor, worn at the level of the 4th lumbar vertebra. Results: Intraclass correlation coefficients for the inertial sensor-derived measures ranged from 0.76 to 0.92, demonstrating strong intrasession test-retest reliability. Statistically significant alterations (p < 0.05) in both reach distance and the inertial sensor-derived 95EV measure were observed immediately post-fatigue. However, reach distance deficits returned to baseline levels within 10 min, while 95EV remained significantly increased (p < 0.05) beyond 20 min for all 3 reach distances. Conclusion: These findings demonstrate the ability of an inertial sensor-derived measure to quantify alterations in dynamic balance control, which are not captured by traditional reach distances alone. This suggests that the addition of an inertial sensor to the YBT may provide clinicians and researchers with an accessible means to capture subtle alterations in motor function in the clinical setting.

Peripheral Corticotropin Releasing Factor Signaling Inhibits Gastric Emptying: Mechanisms of Action and Role in Stress-related Gastric Alterations of Motor Function.

The activation of Corticotrophin Releasing-Factor (CRF) receptors in the brain is well established to coordinate the endocrine, behavioral, autonomic and visceral responses to stress. In addition, CRF receptors are also expressed within the gut where they exert biological actions and play a role in modulating stress-related gastrointestinal function. In particular, peripheral injection of CRF and related peptides, urocortin 1, 2 or 3 inhibit Gastric Emptying (GE) and alters fasted and fed pattern of gastroduodenal motility in several experimental species. Urocortin 1 interacts synergistically with cholecystokin-8 to inhibit gastric emptying in lean mice which is no longer observed in diet-induced obese rats. In in vitro circular or longitudinal muscle preparation of rat antrum, CRF and urocortin 1 and 2 suppressed spontaneous contractile activity. CRF and urocortins interact with the CRF receptor 2 (CRF-R2) to inhibit gastric motor function monitored both in vivo and in vitro. The CRF-R2 mediated inhibition of antral and corpus contractility involves a direct action on gastric myenteric neurons where CRF-R2 is expressed and may also involve the activation of serotonin acting on 5-HT3 receptor. The involvement of peripheral CRF receptors in gastric motor alterations occurring under stress conditions are stressors specific with CRF-R2 mediating the early phase of gastric ileus induced by abdominal surgery and the delayed emptying elicited by acute restraint stress. However gastric stasis elicited by endotoxin is not mediated by CRF-R2 and CRF receptors are not involved in the basal regulation of fed or fasted pattern of gastric motility.

Genetic induction of hypometabolism by ablation of MC4R does not suppress ALS-like phenotypes in the G93A mutant SOD1 mouse model

Dysfunction and death of motor neurons leads to progressive paralysis in amyotrophic lateral sclerosis (ALS). Recent studies have reported organism-level metabolic dysfunction as a prominent but poorly understood feature of the disease. ALS patients are hypermetabolic with increased resting energy expenditure, but if and how hypermetabolism contributes to disease pathology is unknown. We asked if decreasing metabolism in the mutant superoxide dismutase 1 (SOD1) mouse model of ALS (G93A SOD1) would alter motor function and survival. To address this, we generated mice with the G93A SOD1 mutation that also lacked the melanocortin-4 receptor (MC4R). MC4R is a critical regulator of energy homeostasis and food intake in the hypothalamus. Loss of MC4R is known to induce hyperphagia and hypometabolism in mice. In the MC4R null background, G93A SOD1 mice become markedly hypometabolic, overweight and less active. Decreased metabolic rate, however, did not reverse any ALS-related disease phenotypes such as motor dysfunction or decreased lifespan. While hypermetabolism remains an intriguing target for intervention in ALS patients and disease models, our data indicate that the melanocortin system is not a good target for manipulation. Investigating other pathways may reveal optimal targets for addressing metabolic dysfunction in ALS.

Neuron-Glia Crosstalk and Neuropathic Pain: Involvement in the Modulation of Motor Activity in the Orofacial Region.

Neuropathic orofacial pain (NOP) is a debilitating condition. Although the pathophysiology remains unclear, accumulating evidence suggests the involvement of multiple mechanisms in the development of neuropathic pain. Recently, glial cells have been shown to play a key pathogenetic role. Nerve injury leads to an immune response near the site of injury. Satellite glial cells are activated in the peripheral ganglia. Various neural and immune mediators, released at the central terminals of primary afferents, lead to the sensitization of postsynaptic neurons and the activation of glia. The activated glia, in turn, release pro-inflammatory factors, further sensitizing the neurons, and resulting in central sensitization. Recently, we observed the involvement of glia in the alteration of orofacial motor activity in NOP. Microglia and astroglia were activated in the trigeminal sensory and motor nuclei, in parallel with altered motor functions and a decreased pain threshold. A microglial blocker attenuated the reduction in pain threshold, reduced the number of activated microglia, and restored motor activity. We also found an involvement of the astroglial glutamate–glutamine shuttle in the trigeminal motor nucleus in the alteration of the jaw reflex. Neuron–glia crosstalk thus plays an important role in the development of pain and altered motor activity in NOP.

ERK/MAPK Signaling Is Required for Pathway-Specific Striatal Motor Functions.

The ERK/MAPK intracellular signaling pathway is hypothesized to be a key regulator of striatal activity via modulation of synaptic plasticity and gene transcription. However, prior investigations into striatal ERK/MAPK functions have yielded conflicting results. Further, these studies have not delineated the cell-type-specific roles of ERK/MAPK signaling due to the reliance on globally administered pharmacological ERK/MAPK inhibitors and the use of genetic models that only partially reduce total ERK/MAPK activity. Here, we generated mouse models in which ERK/MAPK signaling was completely abolished in each of the two distinct classes of medium spiny neurons (MSNs). ERK/MAPK deletion in D1R-MSNs (direct pathway) resulted in decreased locomotor behavior, reduced weight gain, and early postnatal lethality. In contrast, loss of ERK/MAPK signaling in D2R-MSNs (indirect pathway) resulted in a profound hyperlocomotor phenotype. ERK/MAPK-deficient D2R-MSNs exhibited a significant reduction in dendritic spine density, markedly suppressed electrical excitability, and suppression of activity-associated gene expression even after pharmacological stimulation. Our results demonstrate the importance of ERK/MAPK signaling in governing the motor functions of the striatal direct and indirect pathways. Our data further show a critical role for ERK in maintaining the excitability and plasticity of D2R-MSNs.SIGNIFICANCE STATEMENT Alterations in ERK/MAPK activity are associated with drug abuse, as well as neuropsychiatric and movement disorders. However, genetic evidence defining the functions of ERK/MAPK signaling in striatum-related neurophysiology and behavior is lacking. We show that loss of ERK/MAPK signaling leads to pathway-specific alterations in motor function, reduced neuronal excitability, and the inability of medium spiny neurons to regulate activity-induced gene expression. Our results underscore the potential importance of the ERK/MAPK pathway in human movement disorders.

Investigating the effects of maximal anaerobic fatigue on dynamic postural control using the Y-Balance Test.

The Y Balance Test is one of the most commonly used dynamic balance assessments, providing an insight into the integration of the sensorimotor subsystems. In recent times, there has been an increase in interest surrounding it's use in various clinical populations demonstrating alterations in motor function. Therefore, it is important to examine the effect physiological influences such as fatigue play in dynamic postural control, and establish a timeframe for its recovery. Descriptive laboratory study. Twenty male and female (age 23.75±4.79years, height 174.12±8.45cm, mass 69.32±8.76kg) partaking in competitive sport, completed the Y Balance Test protocol at 0, 10 and 20min, prior to a modified 60s Wingate fatiguing protocol. Post-fatigue assessments were then completed at 0, 10 and 20 min post-fatiguing intervention. Intraclass correlation coefficients demonstrated excellent intra-session reliability (0.976-0.982) across the three pre-fatigue YBT tests. Post-hoc paired sample t-tests demonstrated that all three reach directions demonstrated statistically significant differences between pre-fatigue and the first post-fatigue measurement (anterior; p=0.019, posteromedial; p=0.019 & posterolateral; p=0.003). The anterior reach direction returned to pre-fatigue levels within 10min (p=0.632). The posteromedial reach direction returned to pre-fatigue levels within 20min (p=0.236), while the posterolateral direction maintained a statistically significant difference at 20min (p=0.023). Maximal anaerobic fatigue has a negative effect on normalised Y balance test scores in all three directions. Following the fatiguing protocol, dynamic postural control returns to pre-fatigue levels for the anterior (<10min), posteromedial (<20min) and posterolateral (>20min).

Conversion disorder: Unexplained symptoms of silenced emotions?

IntroductionConversion disorder is a condition defined by the presence of symptoms of altered voluntary motor or sensory function, not intentionally produced or feigned, presumed to be the expression of a psychological conflict or stressor, but mimicking neurological diseases or other medical conditions, that must be excluded before this diagnosis is made. The suspicion of conversion disorder arises when clinical findings are incompatible with the suggested neurological or medical conditions and there is a temporal relation between the onset of the symptoms and a psychological stressor. However, when these hints are absent, diagnosis may not be clear and require wider workup.Objectives/aimsTo make a brief review on conversion disorder and present an illustrative clinical-vignette.MethodsWe collected information from medical records and interview with the patient and made a research on PubMed with the MeSH terms “conversion disorder”.ResultsWe present a 51-years-old female outpatient with episodes of paralysis of left upper and lower limbs. Some months before the onset of these symptoms, her daughter came to live with her. Their relationship became very conflictual. Electroencephalogram, laboratory and imaging studies were normal. She did not tolerate the antidepressants tried (SSRI, SNRI and trazodone), but reported to feel better with amisulpride and alprazolam.ConclusionsWidely discussed in the past as “hysteria”, conversion disorder is still intriguing, because little is known about the link between body and mind, making the management of patients with this disorder challenging and highlighting the need for more studies on the topic.Disclosure of interestThe authors have not supplied their declaration of competing interest.