In vivo assessment of HCN channel current (I(h)) in human motor axons

The "Trond" protocol of nerve excitability tests has been used widely to assess axonal function in peripheral nerve. In this study, the routine Trond protocol was expanded to refine assessment of cAMP-dependent, hyperpolarization-activated current (I(h)) activity. I(h) activity is generated by hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels in response to hyperpolarization. It limits activity-dependent hyperpolarization, contributes to neuronal automaticity, and is implicated in chronic pain states. Published data regarding I(h) activity in motor nerve are scant. We used additional strong, prolonged hyperpolarizing conditioning stimuli in the threshold electrotonus component of the Trond protocol to demonstrate the time-course of activation of I(h) in motor axons. Fifteen healthy volunteers were tested on four occasions during 1 week. I(h) action was revealed in the threshold electrotonus by the limiting and often reversal, after about 100 ms, of the threshold increase caused by strong hyperpolarizing currents. Statistical analysis by repeated-measures analysis of variance enabled confidence limits to be established for variation between subjects and within subjects. The results demonstrate that, of all the excitability parameters, those dependent on I(h) were the most characteristic of an individual, because variance between subjects was more than four times the variance within subjects. This study demonstrates a reliable method for in vivo assessment of I(h,) and also serves to document the normal variability in nerve excitability properties within subjects.

Brain activation during anticipation of sound sequences

Music consists of sound sequences that require integration over time. As we become familiar with music, associations between notes, melodies, and entire symphonic movements become stronger and more complex. These associations can become so tight that, for example, hearing the end of one album track can elicit a robust image of the upcoming track while anticipating it in total silence. Here, we study this predictive “anticipatory imagery” at various stages throughout learning and investigate activity changes in corresponding neural structures using functional magnetic resonance imaging. Anticipatory imagery (in silence) for highly familiar naturalistic music was accompanied by pronounced activity in rostral prefrontal cortex (PFC) and premotor areas. Examining changes in the neural bases of anticipatory imagery during two stages of learning conditional associations between simple melodies, however, demonstrates the importance of fronto-striatal connections, consistent with a role of the basal ganglia in “training” frontal cortex (Pasupathy and Miller, 2005). Another striking change in neural resources during learning was a shift between caudal PFC earlier to rostral PFC later in learning. Our findings regarding musical anticipation and sound sequence learning are highly compatible with studies of motor sequence learning, suggesting common predictive mechanisms in both domains.

In situ melanoma of the nail unit in children: report of two cases in fair-skinned Caucasian children

Nail melanoma in children is rarely reported in the literature, and all of the published cases were diagnosed in dark-skinned phototypes or in Asians. We report two cases of in situ nail matrix melanoma presenting as longitudinal melanonychia (LM) in fair-skinned children of Italian origin. Nail plate dermatoscopy revealed a brown background with lines of irregular color, spacing, and thickness in both cases. Histopathology of the excised lesions showed melanoma in situ. Clinical, dermatoscopic, and pathological criteria that permit clear differentiation of benign melanocytic activation or proliferation from nail matrix melanoma are not established for children. The presence of a pigmented band of a single nail in a child usually represents a problem for clinicians, because the clinical and dermatoscopic features that are considered possible indicators of nail unit melanoma in adults are frequently observed in benign melanocytic hyperplasia and nevi in children. There is therefore the need to find parameters useful for clinical and dermatoscopic diagnosis in childhood nail pigmentation and to reach a consensus on management of children with a band of LM.

Brain activation during string playing

This chapter attempts to integrate data from both functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) to elucidate the activation of the cortical areas in musical performance for both execution and imagination of music during string playing. In both fMRI and EEG experiments, playing the music was compared with imagining the music. This allowed separation of the areas mainly involved in motor execution from those involved in imagining, planning, and working memory, thus differentiating musical from purely motor areas.

Effects of rivastigmine on actigraphically monitored motor activity in severe agitation related to Alzheimer's disease: a placebo-controlled pilot study

Acetylcholinesterase inhibitors (AChEIs) are effective in the treatment of cognitive symptoms in Alzheimer's disease (AD). Because the behavioral and psychological symptoms of dementia (BPSD) have also been attributed to central cholinergic deficits, we examined whether the AChEI rivastigmine can reduce motor activity as measured in a rater-independent manner by wrist actigraphy in agitated AD patients. A total of 20 consecutive AD inpatients (13 females, 7 males, 80.4+/-9.1 years, S.D.) were included from our geriatric psychiatry unit, all of whom were exhibiting agitated behavior not attributable to delirium. Patients were assigned randomly and in a single-blinded fashion to rivastigmine 3mg or placebo for 14 days. Motor activity levels were monitored using an actigraph worn continuously on the wrist of the non-dominant hand. At the beginning and end of the study, patients were assessed using the Neuropsychiatric Inventory (NPI) and Nurses' Observation Scale for Geriatric Patients (NOSGER). Patients in the rivastigmine group exhibited less agitation than placebo recipients on the NPI-agitation subscale, but not on NOSGER. Actigraphic measurements showed a tendency towards reduced motor activity in the rivastigmine group. Because rivastigmine usually exerts its main effects after a longer period of time, the short-term effects seen in our study justify further controlled clinical trials examining the use of rivastigmine in BPSD by means of actigraphy.

Concurrent activation of dopamine D1 and D2 receptors is required to evoke neural and behavioral phenotypes of cocaine sensitization

Repeated exposure to psychomotor stimulants produces a striking behavioral syndrome involving repetitive, stereotypic behaviors that occur if an additional exposure to the stimulant is experienced. The same stimulant exposure produces specific alterations in gene expression patterns in the striatum. To identify the dopamine receptor subtypes required for the parallel expression of these acquired neural and behavioral responses, we treated rats with different D1-class and D2-class dopamine receptor agonists and compared the responses of drug-naive rats with those of rats given previous intermittent treatment with cocaine. In rats exposed to repeated cocaine treatment, the effects of a subsequent challenge treatment with either a D1-class agonist (SKF 81297) or a D2-class agonist (quinpirole) were not significantly different from those observed in drug-naive animals: the drugs administered singly did not induce robust stereotyped motor behaviors nor produce significantly striosome-predominant expression of early genes in the striatum. In contrast, challenge treatment with the D1-class and D2-class agonists in combination led to marked and correlated increases in stereotypy and striosome-predominant gene expression in the striatum. Thus, immediately after repeated psychomotor stimulant exposure, only the concurrent activation of D1 and D2 receptor subclasses evoked expression of the neural and behavioral phenotypes acquired through repeated cocaine exposure. These findings suggest that D1-D2 dopamine receptor synergisms underlie the coordinate expression of both network-level changes in basal ganglia activation patterns and the repetitive and stereotypic motor response patterns characteristic of psychomotor stimulant sensitization.

Significance of coil orientation for motor evoked potentials from nasalis muscle elicited by transcranial magnetic stimulation

OBJECTIVE: In transcranial magnetic stimulation (TMS) of the motor cortex, the optimal orientation of the coil on the scalp is dependent on the muscle under investigation, but not yet known for facial muscles. METHODS: Using a figure-of-eight coil, we compared TMS induced motor evoked potentials (MEPs) from eight different coil orientations when recording from ipsi- and contralateral nasalis muscle. RESULTS: The MEPs from nasalis muscle revealed three components: The major ipsi- and contra-lateral middle latency responses of approximately 10 ms onset latency proved entirely dependent on voluntary pre-innervation. They were most easily obtained from a coil orientation with posterior inducing current direction, and in this respect resembled the intrinsic hand rather than the masseter muscles. Early short duration responses of around 6 ms onset latency were best elicited with an antero-lateral current direction and not pre-innervation dependent, and therefore most probably due to stimulation of the nerve roots. Late responses (>18 ms) could inconsistently be elicited with posterior coil orientations in pre-innervated condition. CONCLUSIONS: By using the appropriate coil orientation and both conditions relaxed and pre-innervated, cortically evoked MEP responses from nasalis muscle can reliably be separated from peripheral and reflex components and also from cross talk of masseter muscle activation.

Mapping of direction and muscle representation in the human primary motor cortex controlling thumb movements

Larger body parts are somatotopically represented in the primary motor cortex (M1), while smaller body parts, such as the fingers, have partially overlapping representations. The principles that govern the overlapping organization of M1 remain unclear. We used transcranial magnetic stimulation (TMS) to examine the cortical encoding of thumb movements in M1 of healthy humans. We performed M1 mapping of the probability of inducing a thumb movement in a particular direction and used low intensity TMS to disturb a voluntary thumb movement in the same direction during a reaction time task. With both techniques we found spatially segregated representations of the direction of TMS-induced thumb movements, thumb flexion and extension being best separated. Furthermore, the cortical regions corresponding to activation of a thumb muscle differ, depending on whether the muscle functions as agonist or as antagonist for flexion or extension. In addition, we found in the reaction time experiment that the direction of a movement is processed in M1 before the muscles participating in it are activated. It thus appears that one of the organizing principles for the human corticospinal motor system is based on a spatially segregated representation of movement directions and that the representation of individual somatic structures, such as the hand muscles, overlap.

BRAIN ACTIVATION AND CONNECTIVITY IN NON-DISABLED MULTIPLE SCLEROSIS PATIENTS

Multiple sclerosis (MS) is the most common demyelinating disease affecting the central nervous system. There is no cure for MS and current therapies have limited efficacy. While the majority of individuals with MS develop significant clinical disability, a subset experiences a disease course with minimal impairment even in the presence of significant apparent tissue damage on magnetic resonance imaging (MRI). The current studies combined functional MRI and diffusion tensor imaging (DTI) to elucidate brain mechanisms associated with lack of clinical disability in patients with MS. Recent evidence has implicated cortical reorganization as a mechanism to limit the clinical manifestation of the disease. Functional MRI was used to test the hypothesis that non-disabled MS patients (Expanded Disability Status Scale ≤ 1.5) show increased recruitment of cognitive control regions (dorsolateral prefrontal and anterior cingulate cortex) while performing sensory, motor and cognitive tasks. Compared to matched healthy controls, patients increased activation of cognitive control brain regions when performing non-dominant hand movements and the 2-back working memory task. Using dynamic causal modeling, we tested whether increased cognitive control recruitment is associated with alterations in connectivity in the working memory functional network. Patients exhibited similar network connectivity to that of control subjects when performing working memory tasks. We subsequently investigated the integrity of major white matter tracts to assess structural connectivity and its relation to activation and functional integration of the cognitive control system. Patients showed substantial alterations in callosal, inferior and posterior white matter tracts and less pronounced involvement of the corticospinal tracts and superior longitudinal fasciculi (SLF). Decreased structural integrity within the right SLF in patients was associated with decreased performance, and decreased activation and connectivity of the cognitive control system when performing working memory tasks. These studies suggest that patient with MS without clinical disability increase cognitive control system recruitment across functional domains and rely on preserved functional and structural connectivity of brain regions associated with this network. Moreover, the current studies show the usefulness of combining brain activation data from functional MRI and structural connectivity data from DTI to improve our understanding of brain adaptation mechanisms to neurological disease.

The human vestibular cortex revealed by coordinate-based activation likelihood estimation meta-analysis.

The vestibular system contributes to the control of posture and eye movements and is also involved in various cognitive functions including spatial navigation and memory. These functions are subtended by projections to a vestibular cortex, whose exact location in the human brain is still a matter of debate (Lopez and Blanke, 2011). The vestibular cortex can be defined as the network of all cortical areas receiving inputs from the vestibular system, including areas where vestibular signals influence the processing of other sensory (e.g. somatosensory and visual) and motor signals. Previous neuroimaging studies used caloric vestibular stimulation (CVS), galvanic vestibular stimulation (GVS), and auditory stimulation (clicks and short-tone bursts) to activate the vestibular receptors and localize the vestibular cortex. However, these three methods differ regarding the receptors stimulated (otoliths, semicircular canals) and the concurrent activation of the tactile, thermal, nociceptive and auditory systems. To evaluate the convergence between these methods and provide a statistical analysis of the localization of the human vestibular cortex, we performed an activation likelihood estimation (ALE) meta-analysis of neuroimaging studies using CVS, GVS, and auditory stimuli. We analyzed a total of 352 activation foci reported in 16 studies carried out in a total of 192 healthy participants. The results reveal that the main regions activated by CVS, GVS, or auditory stimuli were located in the Sylvian fissure, insula, retroinsular cortex, fronto-parietal operculum, superior temporal gyrus, and cingulate cortex. Conjunction analysis indicated that regions showing convergence between two stimulation methods were located in the median (short gyrus III) and posterior (long gyrus IV) insula, parietal operculum and retroinsular cortex (Ri). The only area of convergence between all three methods of stimulation was located in Ri. The data indicate that Ri, parietal operculum and posterior insula are vestibular regions where afferents converge from otoliths and semicircular canals, and may thus be involved in the processing of signals informing about body rotations, translations and tilts. Results from the meta-analysis are in agreement with electrophysiological recordings in monkeys showing main vestibular projections in the transitional zone between Ri, the insular granular field (Ig), and SII.

Is mental practice an effective adjunct therapeutic strategy for upper limb motor restoration after stroke?

Stroke is one of the most common conditions requiring rehabilitation, and its motor impairments are a major cause of permanent disability. Hemiparesis is observed by 80% of the patients after acute stroke. Neuroimaging studies showed that real and imagined movements have similarities regarding brain activation, supplying evidence that those similarities are based on the same process. Within this context, the combination of MP with physical and occupational therapy appears to be a natural complement based on neurorehabilitation concepts. Our study seeks to investigate if MP for stroke rehabilitation of upper limbs is an effective adjunct therapy. PubMed (Medline), ISI knowledge (Institute for Scientific Information) and SciELO (Scientific Electronic Library) were terminated on 20 February 2015. Data were collected on variables as follows: sample size, type of supervision, configuration of mental practice, setting the physical practice (intensity, number of sets and repetitions, duration of contractions, rest interval between sets, weekly and total duration), measures of sensorimotor deficits used in the main studies and significant results. Random effects models were used that take into account the variance within and between studies. Seven articles were selected. As there was no statistically significant difference between the two groups (MP vs Control), showed a – 0.6 (95% CI: –1.27 to 0.04), for upper limb motor restoration after stroke. The present meta-analysis concluded that MP is not effective as adjunct therapeutic strategy for upper limb motor restoration after stroke.

Trends in utilization of computer tomography (CT) scans for victims of motor vehicle collision (MVCs) in a level I trauma center from 1996 to 2006

Purpose. To evaluate trends in the utilization of head, abdominal, thoracic and other body regions CTs in the management of victims of MVC at a level I trauma center from 1996 to 2006.^ Method. From the trauma registry, I identified patients involved in MVC's in a level I trauma center and categorized them into three age groups of 13-18, 19-55 and ≥56. I used International Classification of Disease (ICD-9-CM) codes to find the type and number of CTs examinations performed for each patient. I plotted the mean number of CTs per patient against year of admission to find the crude estimate of change in utilization pattern for each type of CT. I used logistic regression to assess whether repetitive CTs (≥ 2) for head, abdomen, thorax and other body regions were associated with age group and year of admission for MVC patients. I adjusted the estimates for gender, ethnicity, insurance status, mechanism and severity of injury, intensive care unit admission status, patient disposition (dead or alive) and year of admission.^ Results. Utilization of head, abdominal, thoracic and other body regions CTs significantly increased over 11-year period. Utilization of head CT was greatest in the 13-18 age group, and increased from 0.58 CT/patient in 1996 to 1.37 CT/patient in 2006. Abdominal CTs were more common in the ≥56+ age group, and increased from 0.33 CT/patient in 1996 to 0.72 CT/patient in 2006. Utilization of thoracic CTs was higher in the 56+ age group, and increased from 0.01 CT/patient in 1996 to 0.42 CT/patient in 2006. Utilization of other CTs did not change materially during the study period for adolescents, adults or older adults. In the multivariable analysis, after adjustment for potential confounders, repetitive head CTs significantly increased in the 13-18 age group (95% CI: 1.29-1.87, p=<0.001) relative to the 19-55 age group. Repetitive thoracic CT use was lower in adolescents (95% CI: 0.22-0.70, p=<0.001) relative to the 19-55 age group.^ Conclusion. There has been a substantial increase in the utilization of head, abdominal, thoracic and other CTs in the management of MVC patients. Future studies need to identify if increased utilization of CTs have resulted in better health outcome for these patients. ^

αvβ8 Integrin Interacts with RhoGDI1 to Regulate Rac1 and Cdc42 Activation and Drive Glioblastoma Cell Invasion

As an interface between the circulatory and central nervous systems, the neurovascular unit is vital to the development and survival of tumors. The malignant brain cancer glioblastoma multiforme (GBM) displays invasive growth behaviors that are major impediments to surgical resection and targeted therapies. Adhesion and signaling pathways that drive GBM cell invasion remain largely uncharacterized. Here we have utilized human GBM cell lines, primary patient samples, and pre-clinical mouse models to demonstrate that integrin αvβ8 is a major driver of GBM cell invasion. β8 integrin is overexpressed in many human GBM cells, with higher integrin expression correlating with increased invasion and diminished patient survival. Silencing β8 integrin in human GBM cells leads to impaired tumor cell invasion due to hyperactivation of the Rho GTPases Rac1 and Cdc42. β8 integrin associates with Rho GDP Dissociation Inhibitor 1 (RhoGDI1), an intracellular signaling effector that sequesters Rho GTPases in their inactive GDP-bound states. Silencing RhoGDI1 expression or uncoupling αvβ8 integrin-RhoGDI1 protein interactions blocks GBM cell invasion due to Rho GTPase hyperactivation. These data reveal for the first time that αvβ8 integrin, via interactions with RhoGDI1, suppresses activation of Rho proteins to promote GBM cell invasiveness. Hence, targeting the αvβ8 integrin-RhoGDI1 signaling axis may be an effective strategy for blocking GBM cell invasion.

Evidence for the role of agonist binding frequency in receptor -mediated activation of adenylate cyclase

$\beta$-adrenergic receptor-mediated activation of adenylate cyclase exhibits an agonist-specific separation between the dose/response curve (characterized by the EC$\sb{50}$) and the dose/binding curve (characterized by the K$\sb{\rm d}$). Cyclase activity can be near-maximal when receptor occupancy is quite low (EC$\sb{50}$ $\ll$ K$\sb{\rm d}$). This separation between the binding and response curves can be explained by the assumption that the rate of cyclase activation is proportional to the concentration of agonist-bound receptors, since the receptor is mobile and can activate more than one cyclase (the Collision Coupling Model of Tolkovsky and Levitzki). Here it is established that agonist binding frequency plays an additional role in adenylate cyclase activation in S49 murine lymphoma cells. Using epinephrine (EC$\sb{50}$ = 10 nM, K$\sb{\rm d}$ = 2 $\mu$M), the rate of cyclase activation decreased by 80% when a small (1.5%) receptor occupancy was restricted (by addition of the antagonist propranolol) to a small number (1.5%) of receptors rather than being proportionally distributed among the cell's entire population of receptors. Thus adenylate cyclase activity is not proportional to receptor occupancy in all circumstances. Collisions between receptor and cyclase pairs apparently occur a number of times in rapid sequence (an encounter); the high binding frequency of epinephrine ensures that discontiguous regions of the cell surface experience some period of agonist-bound receptor activity per small unit time minimizing "wasted" collisions between activated cyclase and bound receptor within an encounter. A contribution of agonist binding frequency to activation is thus possible when: (1) the mean lifetime of the agonist-receptor complex is shorter than the mean encounter time, and (2) the absolute efficiency (intrinsic ability to promote cyclase activation per collision) of the agonist-receptor complex is high. These conclusions are supported by experiments using agonists of different efficiencies and binding frequencies. These results are formalized in the Encounter Coupling Model of adenylate cyclase activation, which takes into explicit account the agonist binding frequency, agonist affinity for the $\beta$-adrenergic receptor, agonist efficiency, encounter frequency and the encounter time between receptor and cyclase. ^