Spine radiography in the evaluation of back and neck pain in an orthopaedic emergency clinic

BACKGROUND AND OBJECTIVES Despite the recommendations of national and international societies for the treatment of patients with acute neck and back pain, still too many radiologic examinations were performed. The purpose of this study was to analyze and optimize diagnostics and treatment of patients with acute back pain. METHODS The medical records of 484 patients presented to the emergency clinic with acute neck or back pain were analyzed for clinical history, physical examination, radiographic findings and therapy. RESULTS Radiographs of the lumbar, cervical, or thoracic spine were performed in 338 cases (70%). Radiographs were normal in 142 patients (42%) and degenerative changes were identified in 123 patients (36%). Only 2 patients (0.4%) had radiographic findings that had direct therapeutic relevance: 1 patient with metastatic disease and 1 patient with posttraumatic C1-C2 instability. For most patients without sensorimotor deficits and absent specific indications for radiography (“red flags”), therapy was not affected by the results of radiography. CONCLUSIONS Plain radiography of the spine was unnecessary in most patients initially evaluated with non-specific acute back pain and does not improve the clinical outcome. The implementation of national and international guidelines is a slow process, but helps to reduce costs and to protect patients from unnecessary ionizing radiation exposure.

DTI and VBM reveal white matter changes without associated gray matter changes in patients with idiopathic restless legs syndrome

BACKGROUND AND PURPOSE We evaluated cerebral white and gray matter changes in patients with iRLS in order to shed light on the pathophysiology of this disease. METHODS Twelve patients with iRLS were compared to 12 age- and sex-matched controls using whole-head diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) techniques. Evaluation of the DTI scans included the voxelwise analysis of the fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD). RESULTS Diffusion tensor imaging revealed areas of altered FA in subcortical white matter bilaterally, mainly in temporal regions as well as in the right internal capsule, the pons, and the right cerebellum. These changes overlapped with changes in RD. Voxel-based morphometry did not reveal any gray matter alterations. CONCLUSIONS We showed altered diffusion properties in several white matter regions in patients with iRLS. White matter changes could mainly be attributed to changes in RD, a parameter thought to reflect altered myelination. Areas with altered white matter microstructure included areas in the internal capsule which include the corticospinal tract to the lower limbs, thereby supporting studies that suggest changes in sensorimotor pathways associated with RLS.

Mechanisms of TGF-beta1-induced neuronal plasticity in Aplysia

Transforming growth factor beta-1 (TGF-β1) is a cytokine and neurotrophic factor whose neuromodulatory effects in Aplysia californica were recently described. Previous results demonstrated that TGF-β1 induces long-term increases in the efficacy of sensorimotor synapses, a neural correlate of sensitization of the defensive tail withdrawal reflex. These results provided the first evidence that a neurotrophic factor regulates neuronal plasticity associated with a simple form of learning in Aplysia, and raised many questions regarding the nature of the modulation. No homologs of TGF-β had previously been identified in Aplysia, and thus, it was not known whether components of TGF-β1 signaling pathways were present in Aplysia. Furthermore, the signaling mechanisms engaged by TGF-β1 had not been identified, and it was not known whether TGF-β1 regulated other aspects of neuronal function.^ The present investigation into the actions of TGF-β1 was initiated by examining the distribution of the type II TGF-β1 receptor, the ligand binding receptor. The receptor was widely distributed in the CNS and most neurons exhibited somatic and neuritic immunoreactivity. In addition, the ability of TGF-β1 to activate the cAMP/PKA and MAPK pathways, known to regulate several important aspects of neuronal function, was examined. TGF-β1 acutely decreased cAMP levels in sensory neurons, activated MAPK and triggered translocation of MAPK to the nucleus. MAPK activation was critical for both short- and long-term regulation of neuronal function by TGF-β1. TGF-β1 acutely decreased synaptic depression induced by low frequency stimuli in a MAPK-dependent manner. This regulation may result, at least in part, from the modulation of synapsin, a major peripheral synaptic vesicle protein. TGF-β1 stimulated MAPK-dependent phosphorylation of synapsin, a process believed to regulate synaptic vesicle mobilization from reserve to readily-releasable pools of neurotransmitter. In addition to its acute effect on synaptic efficacy, TGF-β1 also induced long-term increases in sensory neuron excitability. Whereas transient exposure to TGF-β1 was not sufficient to drive short-or long-term changes in excitability, prolonged exposure to TGF-β1 induced long-term changes in excitability that depended on MAPK. The results of these studies represent significant progress toward an understanding of the role of TGF-β1 in neuronal plasticity. ^

The role of sensory neuron outgrowth in long-term sensitization of the tail-elicited tail-siphon withdrawal reflex of Aplysia

Neuronal outgrowth has been proposed in many systems as a mechanism underlying memory storage. For example, sensory neuron outgrowth is widely accepted as an underlying mechanism of long-term sensitization of defensive withdrawal reflexes in Aplysia. The hypothesis is that learning leads to outgrowth and consequently to the formation of new synapses, which in turn strengthen the neural circuit underlying the behavior. However, key experiments to test this hypothesis have never been performed. ^ Four days of sensitization training leads to outgrowth of siphon sensory neurons mediating the siphon-gill withdrawal response in Aplysia . We found that a similar training protocol produced robust outgrowth in tail sensory neurons mediating the tail siphon withdrawal reflex. In contrast, 1 day of training, which effectively induces long-term behavioral sensitization and synaptic facilitation, was not associated with neuronal outgrowth. Further examination of the effect of behavioral training protocols on sensory neuron outgrowth indicated that this structural modification is associated only with the most persistent forms of sensitization, and that the induction of these changes is dependent on the spacing of the training trials over multiple days. Therefore, we suggest that neuronal outgrowth is not a universal mechanism underlying long-term sensitization, but is involved only in the most persistent forms of the memory. ^ Sensory neuron outgrowth presumably contributes to long-term sensitization through formation of new synapses with follower motor neurons, but this hypothesis has never been directly tested. The contribution of outgrowth to long-term sensitization was assessed using confocal microscopy to examine sites of contact between physiologically connected pairs of sensory and motor neurons. Following 4 days of training, the strength of both the behavior and sensorimotor synapse and the number of appositions with follower neurons was enhanced only on the trained side of the animal. In contrast, outgrowth was induced on both sides of the animal, indicating that although sensory neuron outgrowth does appear to contribute to sensitization through the formation of new synapses, outgrowth alone is not sufficient to account for the effects of sensitization. This indicates that key regulatory steps are downstream from outgrowth, possibly in the targeting of new processes and activation of new synapses. ^

Mechanisms of heterosynaptic modulation of transmission in Aplysia

Heterosynaptic plasticity has received considerable attention as a means to induce and maintain cell-wide, as opposed to synapse-specific, learning-related modifications. Modulatory neurotransmitters are thought to provide the attentional and motivational state for memory formation. However, the cellular and molecular mechanisms mediating the effects of most of these modulators on synaptic plasticity and learning remain unclear. A well established system for the study of heterosynaptic plasticity is the Aplysia sensorimotor synapse, which is subject regulation by at least two neuromodulators, serotonin (5-HT) and FMRFa. ^ 5-HT engages multiple second messenger cascades to induce short- and long-term facilitation (STF and LTF, respectively) of synaptic transmission. One mechanism proposed to be involved in STF is mobilization of synaptic vesicles from a storage pool to a releasable pool. To investigate this hypothesis, we examined the involvement of the protein synapsin, a central element in the regulation of the storage pool of vesicles in nerve terminals, in STF. 5-HT induced phosphorylation of synapsin and modified its subcellular distribution via PKA and p42/44 MAPK. Electrophysiological experiments and computer simulations suggested that synapsin can support heterosynaptic plasticity by regulating vesicle mobilization. ^ FMRFa induce short- and long-term synaptic depression in Aplysia . Long-term depression (LTD) correlates with morphological changes, the mechanisms of which remain elusive. LTD is also transcription- and translation-dependent, but little is known about the genes expressed and their regulation. We investigated the role of protein degradation via the ubiquitin-proteasome system and the regulation of one of its components, ubiquitin C-terminal hydrolase (ap-uch), in LTD. LTD was sensitive to inhibition of the proteasome and was associated with upregulation of ap-uch mRNA and protein. This upregulation appeared to be mediated by the transcription factor CREB2, which is generally regarded as a transcription repressor. These results suggest that proteasome-mediated protein degradation is engaged in LTD and that CREB2 may act as a transcription activator under certain conditions. ^ These and additional studies on the interaction of the 5-HT and FMRFa-activated pathways suggest that different neuromodulators, by activating several and sometimes overlapping signaling cascades, can exercise bidirectional control on synaptic gain and information processing.^

A Model of Emotion as Patterned Metacontrol

Adaptive systems use feedback as a key strategy to cope with uncertainty and change in their environments. The information fed back from the sensorimotor loop into the control architecture can be used to change different elements of the controller at four different levels: parameters of the control model, the control model itself, the functional organization of the agent and the functional components of the agent. The complexity of such a space of potential configurations is daunting. The only viable alternative for the agent ?in practical, economical, evolutionary terms? is the reduction of the dimensionality of the configuration space. This reduction is achieved both by functionalisation —or, to be more precise, by interface minimization— and by patterning, i.e. the selection among a predefined set of organisational configurations. This last analysis let us state the central problem of how autonomy emerges from the integration of the cognitive, emotional and autonomic systems in strict functional terms: autonomy is achieved by the closure of functional dependency. In this paper we will show a general model of how the emotional biological systems operate following this theoretical analysis and how this model is also of applicability to a wide spectrum of artificial systems.

A Model of Emotion as Patterned Metacontrol

Adaptive agents use feedback as a key strategy to cope with un- certainty and change in their environments. The information fed back from the sensorimotor loop into the control subsystem can be used to change four different elements of the controller: parameters associated to the control model, the control model itself, the functional organization of the agent and the functional realization of the agent. There are many change alternatives and hence the complexity of the agent’s space of potential configurations is daunting. The only viable alternative for space- and time-constrained agents —in practical, economical, evolutionary terms— is to achieve a reduction of the dimensionality of this configuration space. Emotions play a critical role in this reduction. The reduction is achieved by func- tionalization, interface minimization and by patterning, i.e. by selection among a predefined set of organizational configurations. This analysis lets us state how autonomy emerges from the integration of cognitive, emotional and autonomic systems in strict functional terms: autonomy is achieved by the closure of functional dependency. Emotion-based morphofunctional systems are able to exhibit complex adaptation patterns at a reduced cognitive cost. In this article we show a general model of how emotion supports functional adaptation and how the emotional biological systems operate following this theoretical model. We will also show how this model is also of applicability to the construction of a wide spectrum of artificial systems1.

Modulation of cognition-specific cortical activity by gonadal steroids: A positron-emission tomography study in women

There is considerable evidence from animal studies that gonadal steroid hormones modulate neuronal activity and affect behavior. To study this in humans directly, we used H215O positron-emission tomography to measure regional cerebral blood flow (rCBF) in young women during three pharmacologically controlled hormonal conditions spanning 4–5 months: ovarian suppression induced by the gonadotropin-releasing hormone agonist leuprolide acetate (Lupron), Lupron plus estradiol replacement, and Lupron plus progesterone replacement. Estradiol and progesterone were administered in a double-blind cross-over design. On each occasion positron-emission tomography scans were performed during (i) the Wisconsin Card Sorting Test, a neuropsychological test that physiologically activates prefrontal cortex (PFC) and an associated cortical network including inferior parietal lobule and posterior inferolateral temporal gyrus, and (ii) a no-delay matching-to-sample sensorimotor control task. During treatment with Lupron alone (i.e., with virtual absence of gonadal steroid hormones), there was marked attenuation of the typical Wisconsin Card Sorting Test activation pattern even though task performance did not change. Most strikingly, there was no rCBF increase in PFC. When either progesterone or estrogen was added to the Lupron regimen, there was normalization of the rCBF activation pattern with augmentation of the parietal and temporal foci and return of the dorsolateral PFC activation. These data directly demonstrate that the hormonal milieu modulates cognition-related neural activity in humans.

Inosine stimulates extensive axon collateral growth in the rat corticospinal tract after injury

The purine nucleoside inosine has been shown to induce axon outgrowth from primary neurons in culture through a direct intracellular mechanism. For this study, we investigated the effects of inosine in vivo by examining whether it would stimulate axon growth after a unilateral transection of the corticospinal tract. Inosine applied with a minipump to the rat sensorimotor cortex stimulated intact pyramidal cells to undergo extensive sprouting of their axons into the denervated spinal cord white matter and adjacent neuropil. Axon growth was visualized by anterograde tracing with biotinylated dextran amine and by immunohistochemistry with antibodies to GAP-43. Thus, inosine, a naturally occurring metabolite without known side effects, might help to restore essential circuitry after injury to the central nervous system.

Orphanin FQ acts as an anxiolytic to attenuate behavioral responses to stress

Orphanin FQ (OFQ, Nociceptin) is a recently discovered 17-amino acid neuropeptide that is structurally related to the opioid peptides but does not bind opioid receptors. OFQ has been proposed to act as an anti-opioid peptide, but its widespread sites of action in the brain suggest that it may have more general functions. Here we show that OFQ plays an important role in higher brain functions because it can act as an anxiolytic to attenuate the behavioral inhibition of animals acutely exposed to stressful/anxiogenic environmental conditions. OFQ anxiolytic-like effects were consistent across several behavioral paradigms generating different types of anxiety states in animals (light-dark preference, elevated plus-maze, exploratory behavior of an unfamiliar environment, pharmacological anxiogenesis, operant conflict) and were observed at low nonsedating doses (0.1–3 nmol, intracerebroventricular). Like conventional anxiolytics, OFQ interfered with regular sensorimotor function at high doses (>3 nmol). Our results show that an important role of OFQ is to act as an endogenous regulator of acute anxiety responses. OFQ, probably in concert with other major neuropeptides, exerts a modulatory role on the central integration of stressful stimuli and, thereby, may modulate anxiety states generated by acute stress.

Discovery of genes involved with learning and memory: An experimental synthesis of Hirschian and Benzerian perspectives

The biological bases of learning and memory are being revealed today with a wide array of molecular approaches, most of which entail the analysis of dysfunction produced by gene disruptions. This perspective derives both from early “genetic dissections” of learning in mutant Drosophila by Seymour Benzer and colleagues and from earlier behavior-genetic analyses of learning and in Diptera by Jerry Hirsch and coworkers. Three quantitative-genetic insights derived from these latter studies serve as guiding principles for the former. First, interacting polygenes underlie complex traits. Consequently, learning/memory defects associated with single-gene mutants can be quantified accurately only in equilibrated, heterogeneous genetic backgrounds. Second, complex behavioral responses will be composed of genetically distinct functional components. Thus, genetic dissection of complex traits into specific biobehavioral properties is likely. Finally, disruptions of genes involved with learning/memory are likely to have pleiotropic effects. As a result, task-relevant sensorimotor responses required for normal learning must be assessed carefully to interpret performance in learning/memory experiments. In addition, more specific conclusions will be obtained from reverse-genetic experiments, in which gene disruptions are restricted in time and/or space.

Benzodiazepine-insensitive mice generated by targeted disruption of the gamma 2 subunit gene of gamma-aminobutyric acid type A receptors.

Vigilance, anxiety, epileptic activity, and muscle tone can be modulated by drugs acting at the benzodiazepine (BZ) site of gamma-aminobutyric acid type A (GABAA) receptors. In vivo, BZ sites are potential targets for endogenous ligands regulating the corresponding central nervous system states. To assess the physiological relevance of BZ sites, mice were generated containing GABAA receptors devoid of BZ sites. Following targeted disruption of the gamma 2 subunit gene, 94% of the BZ sites were absent in brain of neonatal mice, while the number of GABA sites was only slightly reduced. Except for the gamma 2 subunit, the level of expression and the regional and cellular distribution of the major GABAA receptor subunits were unaltered. The single channel main conductance level and the Hill coefficient were reduced to values consistent with recombinant GABAA receptors composed of alpha and beta subunits. The GABA response was potentiated by pentobarbital but not by flunitrazepam. Diazepam was inactive behaviorally. Thus, the gamma 2 subunit is dispensable for the assembly of functional GABAA receptors but is required for normal channel conductance and the formation of BZ sites in vivo. BZ sites are not essential for embryonic development, as suggested by the normal body weight and histology of newborn mice. Postnatally, however, the reduced GABAA receptor function is associated with retarded growth, sensorimotor dysfunction, and drastically reduced life-span. The lack of postnatal GABAA receptor regulation by endogenous ligands of BZ sites might contribute to this phenotype.

Functional activation of the human ventrolateral frontal cortex during mnemonic retrieval of verbal information.

Regional cerebral blood flow was measured with positron emission tomography during the performance of a verbal free recall task, a verbal paired associate task, and tasks that required the production of verbal responses either by speaking or writing. Examination of the differences in regional cerebral blood flow between these conditions demonstrated that the left ventrolateral frontal cortical area 45 is involved in the recall of verbal information from long-term memory, in addition to its contribution to speech. The act of writing activated a network of areas involving posterior parietal cortex and sensorimotor areas but not ventrolateral frontal cortex.

Neural basis of lexical-semantic processing and integration of symbolic gestures with words

Three studies investigated the relation between symbolic gestures and words, aiming at discover the neural basis and behavioural features of the lexical semantic processing and integration of the two communicative signals. The first study aimed at determining whether elaboration of communicative signals (symbolic gestures and words) is always accompanied by integration with each other and, if present, this integration can be considered in support of the existence of a same control mechanism. Experiment 1 aimed at determining whether and how gesture is integrated with word. Participants were administered with a semantic priming paradigm with a lexical decision task and pronounced a target word, which was preceded by a meaningful or meaningless prime gesture. When meaningful, the gesture could be either congruent or incongruent with word meaning. Duration of prime presentation (100, 250, 400 ms) randomly varied. Voice spectra, lip kinematics, and time to response were recorded and analyzed. Formant 1 of voice spectra, and mean velocity in lip kinematics increased when the prime was meaningful and congruent with the word, as compared to meaningless gesture. In other words, parameters of voice and movement were magnified by congruence, but this occurred only when prime duration was 250 ms. Time to response to meaningful gesture was shorter in the condition of congruence compared to incongruence. Experiment 2 aimed at determining whether the mechanism of integration of a prime word with a target word is similar to that of a prime gesture with a target word. Formant 1 of the target word increased when word prime was meaningful and congruent, as compared to meaningless congruent prime. Increase was, however, present for whatever prime word duration. In the second study, experiment 3 aimed at determining whether symbolic prime gesture comprehension makes use of motor simulation. Transcranial Magnetic Stimulation was delivered to left primary motor cortex 100, 250, 500 ms after prime gesture presentation. Motor Evoked Potential of First Dorsal Interosseus increased when stimulation occurred 100 ms post-stimulus. Thus, gesture was understood within 100ms and integrated with the target word within 250 ms. Experiment 4 excluded any hand motor simulation in order to comprehend prime word. The effect of the prior presentation of a symbolic gesture on congruent target word processing was investigated in study 3. In experiment 5, symbolic gestures were presented as primes, followed by semantically congruent target word or pseudowords. In this case, lexical-semantic decision was accompanied by a motor simulation at 100ms after the onset of the verbal stimuli. Summing up, the same type of integration with a word was present for both prime gesture and word. It was probably subsequent to understanding of the signal, which used motor simulation for gesture and direct access to semantics for words. However, gesture and words could be understood at the same motor level through simulation if words were preceded by an adequate gestural context. Results are discussed in the prospective of a continuum between transitive actions and emblems, in parallelism with language; the grounded/symbolic content of the different signals evidences relation between sensorimotor and linguistic systems, which could interact at different levels.

Proactive and reactive inhibition during overt and covert actions. An electrical neuroimaging study.

Response inhibition is the ability to suppress inadequate but automatically activated, prepotent or ongoing response tendencies. In the framework of motor inhibition, two distinct operating strategies have been described: “proactive” and “reactive” control modes. In the proactive modality, inhibition is recruited in advance by predictive signals, and actively maintained before its enactment. Conversely, in the reactive control mode, inhibition is phasically enacted after the detection of the inhibitory signal. To date, ample evidence points to a core cerebral network for reactive inhibition comprising the right inferior frontal gyrus (rIFG), the presupplementary motor area (pre-SMA) and the basal ganglia (BG). Moreover, fMRI studies showed that cerebral activations during proactive and reactive inhibition largely overlap. These findings suggest that at least part of the neural network for reactive inhibition is recruited in advance, priming cortical regions in preparation for the upcoming inhibition. So far, proactive and reactive inhibitory mechanisms have been investigated during tasks in which the requested response to be stopped or withheld was an “overt” action execution (AE) (i.e., a movement effectively performed). Nevertheless, inhibitory mechanisms are also relevant for motor control during “covert actions” (i.e., potential motor acts not overtly performed), such as motor imagery (MI). MI is the conscious, voluntary mental rehearsal of action representations without any overt movement. Previous studies revealed a substantial overlap of activated motor-related brain networks in premotor, parietal and subcortical regions during overtly executed and imagined movements. Notwithstanding this evidence for a shared set of cerebral regions involved in encoding actions, whether or not those actions are effectively executed, the neural bases of motor inhibition during MI, preventing covert action from being overtly performed, in spite of the activation of the motor system, remain to be fully clarified. Taking into account this background, we performed a high density EEG study evaluating cerebral mechanisms and their related sources elicited during two types of cued Go/NoGo task, requiring the execution or withholding of an overt (Go) or a covert (MI) action, respectively. The EEG analyses were performed in two steps, with different aims: 1) Analysis of the “response phase” of the cued overt and covert Go/NoGo tasks, for the evaluation of reactive inhibitory control of overt and covert actions. 2) Analysis of the “preparatory phase” of the cued overt and covert Go/NoGo EEG datasets, focusing on cerebral activities time-locked to the preparatory signals, for the evaluation of proactive inhibitory mechanisms and their related neural sources. For these purposes, a spatiotemporal analysis of the scalp electric fields was applied on the EEG data recorded during the overt and covert Go/NoGo tasks. The spatiotemporal approach provide an objective definition of time windows for source analysis, relying on the statistical proof that the electric fields are different and thus generated by different neural sources. The analysis of the “response phase” revealed that key nodes of the inhibitory circuit, underpinning inhibition of the overt movement during the NoGo response, were also activated during the MI enactment. In both cases, inhibition relied on the activation of pre-SMA and rIFG, but with different temporal patterns of activation in accord with the intended “covert” or “overt” modality of motor performance. During the NoGo condition, the pre-SMA and rIFG were sequentially activated, pointing to an early decisional role of pre-SMA and to a later role of rIFG in the enactment of inhibitory control of the overt action. Conversely, a concomitant activation of pre-SMA and rIFG emerged during the imagined motor response. This latter finding suggested that an inhibitory mechanism (likely underpinned by the rIFG), could be prewired into a prepared “covert modality” of motor response, as an intrinsic component of the MI enactment. This mechanism would allow the rehearsal of the imagined motor representations, without any overt movement. The analyses of the “preparatory phase”, confirmed in both overt and covert Go/NoGo tasks the priming of cerebral regions pertaining to putative inhibitory network, reactively triggered in the following response phase. Nonetheless, differences in the preparatory strategies between the two tasks emerged, depending on the intended “overt” or “covert” modality of the possible incoming motor response. During the preparation of the overt Go/NoGo task, the cue primed the possible overt response programs in motor and premotor cortex. At the same time, through preactivation of a pre-SMA-related decisional mechanism, it triggered a parallel preparation for the successful response selection and/or inhibition during the subsequent response phase. Conversely, the preparatory strategy for the covert Go/NoGo task was centred on the goal-oriented priming of an inhibitory mechanism related to the rIFG that, being tuned to the instructed covert modality of the motor performance and instantiated during the subsequent MI enactment, allowed the imagined response to remain a potential motor act. Taken together, the results of the present study demonstrate a substantial overlap of cerebral networks activated during proactive recruitment and subsequent reactive enactment of motor inhibition in both overt and covert actions. At the same time, our data show that preparatory cues predisposed ab initio a different organization of the cerebral areas (in particular of the pre-SMA and rIFG) involved with sensorimotor transformations and motor inhibitory control for executed and imagined actions. During the preparatory phases of our cued overt and covert Go/NoGo tasks, the different adopted strategies were tuned to the “how” of the motor performance, reflecting the intended overt and covert modality of the possible incoming action.