Conscious perception of sensory signals depends in part on stimulus salience, relevance and topography. Letting aside differences at skin receptor level and afferent fibres, it is the CNS that makes a contextual selection of relevant sensory inputs. We hypothesized that subjective awareness (AW) of the time at which a sensory stimulus is perceived, a cortical function, may be differently modified by cortical stimulation, according to site and type of the stimulus. In 24 healthy volunteers, we examined the effects of transcranial direct current stimulation (tDCS) on the assessment of AW to heat pain or weak electrical stimuli applied to either the hand palm or dorsum. We also recorded the vertex-evoked potentials to the same stimuli. The assessment was done before, during and after cathodal or anodal tDCS over the parietal cortex contralateral to the hand receiving the stimuli. At baseline, AW to thermal stimuli was significantly longer for palm than for dorsum (P < 0.01), while no differences between stimulation sites were observed for the electrical stimuli. Both cathodal and anodal tDCS caused a significant shortening of AW to thermal stimuli in the palm but not in the dorsum, and no effects on AW to electrical stimuli. Longer AW in the palm than in the dorsum may be attributable to differences in skin thickness. However, the selectivity of the effects of tDCS on AW to thermal stimulation of the glabrous skin reflects the specificity of CNS processing for site and type of sensory inputs.
A group of European experts was commissioned to establish guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) from evidence published up until March 2014, regarding pain, movement disorders, stroke, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consciousness disorders, tinnitus, depression, anxiety disorders, obsessive-compulsive disorder, schizophrenia, craving/addiction, and conversion. Despite unavoidable inhomogeneities, there is a sufficient body of evidence to accept with level A (definite efficacy) the analgesic effect of high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the pain and the antidepressant effect of HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC). A Level B recommendation (probable efficacy) is proposed for the antidepressant effect of low-frequency (LF) rTMS of the right DLPFC, HF-rTMS of the left DLPFC for the negative symptoms of schizophrenia, and LF-rTMS of contralesional M1 in chronic motor stroke. The effects of rTMS in a number of indications reach level C (possible efficacy), including LF-rTMS of the left temporoparietal cortex in tinnitus and auditory hallucinations. It remains to determine how to optimize rTMS protocols and techniques to give them relevance in routine clinical practice. In addition, professionals carrying out rTMS protocols should undergo rigorous training to ensure the quality of the technical realization, guarantee the proper care of patients, and maximize the chances of success. Under these conditions, the therapeutic use of rTMS should be able to develop in the coming years.
The cutaneous silent period (CSP) is a spinal inhibitory reflex mediated by small-diameter afferents (A-delta fibers) and large-diameter efferents (alpha motoneurons). The effect of limb temperature on CSPs has so far not been assessed.
Brain lesions in patients with multiple sclerosis may lead to abnormal excitability of brainstem reflex circuits because of impairment of descending control pathways. We hypothesized that such abnormality should show in the analysis of blink reflex responses in the form of asymmetries in response size. The study was done in 20 patients with relapsing-remitting multiple sclerosis and 12 matched healthy subjects. We identified first patients with latency abnormalities (AbLat). Then, we analyzed response size by calculating the R2c/R2 ratio to stimulation of either side and the mean area of the R2 responses obtained in the same side. Patients with significantly larger response size with respect to healthy subjects in at least one side were considered to have abnormal response excitability (AbEx). We also examined the blink reflex excitability recovery (BRER) and prepulse inhibition (BRIP) of either side in search for additional indices of asymmetry in response excitability. Neurophysiological data were correlated with MRI-determined brain lesion-load and volume. Eight patients were identified as AbLat (median Expanded Disability Status Scale-EDSS?=?2.75) and 7 of them had ponto-medullary lesions. Nine patients were identified as AbEx (EDSS?=?1.5) and only 2 of them, who also were AbLat, had ponto-medullary lesions. In AbEx patients, the abnormalities in response size were confined to one side, with a similar tendency in most variables (significantly asymmetric R1 amplitude, BRER index and BRIP percentage). AbEx patients had asymmetric distribution of hemispheral lesions, in contrast with the symmetric pattern observed in AbLat. The brainstem lesion load was significantly lower in AbEx than in AbLat patients (p?=?0.04). Asymmetric abnormalities in blink reflex response excitability in patients with multiple sclerosis are associated with lesser disability and lower tissue loss than abnormalities in response latency. Testing response excitability could provide a reliable neurophysiological index of dysfunction in early stages of multiple sclerosis.
Facial nerve lesions are usually benign conditions even though patients may present with emotional distress. Facial palsy usually resolves in 3-6 weeks, but if axonal degeneration takes place, it is likely that the patient will end up with a postparalytic facial syndrome featuring synkinesis, myokymic discharges, and hemifacial mass contractions after abnormal reinnervation. Essential hemifacial spasm is one form of facial hyperactivity that must be distinguished from synkinesis after facial palsy and also from other forms of facial dyskinesias. In this condition, there can be ectopic discharges, ephaptic transmission, and lateral spread of excitation among nerve fibers, giving rise to involuntary muscle twitching and spasms. Electrodiagnostic assessment is of relevance for the diagnosis and prognosis of peripheral facial palsy and hemifacial spasm. In this chapter the most relevant clinical and electrodiagnostic aspects of the two disorders are reviewed, with emphasis on the various stages of facial palsy after axonal degeneration, the pathophysiological mechanisms underlying the various features of hemifacial spasm, and the cues for differential diagnosis between the two entities.
Startle stimuli lead to shorter reaction times in control subjects and Parkinsons disease (PD) patients. However, non-startle stimuli also enhance movement initiation in PD. We wanted to examine whether a startle-triggered movement would retain similar kinematic and EMG-related characteristics compared to one induced by a non-startle external cue in PD patients. In this study we investigated the electromyography pattern and the reaction time during a wrist flexion movement in response to three different stimuli: a visual imperative stimulus; visual stimulus simultaneous with a non-startle auditory stimulus and with a startle auditory stimulus. Ten PD patients and ten aged matched controls participated in this study. The reaction times were faster for startle and non-startle stimuli in comparison with the visual imperative stimulus, in both patients and control subjects. The startle cue induced a faster reaction than the non-startle cue. The electromyography pattern remained unchanged across the conditions. The results suggest that the startle reaction effect for upper limb movements are unimpaired in PD patients and has different characteristics than the effect of non-startle stimuli.
The assessment of functional deficits in small fibre neuropathies (SFN) requires using ancillary tests other than conventional neurophysiological techniques. One of the tests with most widespread use is thermal threshold determination, as part of quantitative sensory testing. Thermal thresholds typically reflect one point in the whole subjective experience elicited by a thermal stimulus. We reasoned that more information could be obtained by analyzing the subjective description of the ongoing sensation elicited by slow temperature changes (dynamic thermal testing, DTT). Twenty SFN patients and 20 healthy subjects were requested to describe, by using an electronic visual analog scale system, the sensation perceived when the temperature of a thermode was made to slowly change according to a predetermined pattern. The thermode was attached to the left ventral forearm or the distal third of the left leg and the stimulus was either a monophasic heat or cold stimuli that reached 120% of pain threshold and reversed to get back to baseline at a rate of 0.5 °C/s. Abnormalities seen in patients in comparison to healthy subjects were: (1) delayed perception of temperature changes, both at onset and at reversal, (2) longer duration of pain perception at peak temperature, and (3) absence of an overshoot sensation after reversal, ie, a transient perception of the opposite sensation before the temperature reached again baseline. The use of DTT increases the yield of thermal testing for clinical and physiological studies. It adds information that can be discriminant between healthy subjects and SFN patients and shows physiological details about the process of activation and inactivation of temperature receptors that may be abnormal in SFN.
Incomplete spinal cord injury (SCI) patients have the potential to regain some ambulatory function, and optimal reorganization of remaining circuits can contribute to this recovery. We hypothesized that repetitive transcranial magnetic stimulation (rTMS) may promote active recovery of motor function during gait rehabilitation.
Paralytic poliomyelitis (pPM) is clinically suspected in individuals experiencing a non-progressive syndrome of flaccid paralysis and atrophy as a sequel of an acute infection. Despite normal sensory perception, patients with pPM complain of pain more than matched siblings. Here, we studied the characteristics of evoked pain in a cohort of pPM patients using contact heat evoked potentials and psychophysical tests.
An efficient way to investigate the neural basis of nociceptive responses is the event-related brain potentials (ERPs). One component belonging to this family of ERPs is the mismatch negativity (MMN). It reflects pre-attentive detection of changes in the incoming stimulus by comparing the new stimulus with sensory memory traces. In this work, single trials of ERP taken from EEG signal recorded under thermal and electric stimulation were analyzed with time-frequency representation (TFR). The main objective of this work was to characterize responses to frequent and infrequent stimuli with TFR functions. Variables defined on instantaneous frequency and instantaneous power presented a statistical significance (p-value<0.0001) differentiating these two kind of responses. Furthermore, differences between the averaged instantaneous power and instantaneous frequency were also analyzed. It was found that instantaneous power and instantaneous frequency were able to better isolate the MMN components from EEG noise in certain frequency bands.
Intraneural injection during nerve-stimulator-guided sciatic block at the popliteal fossa may be a common occurrence. Although intraneural injections have not resulted in clinically detectable neurologic injury in small studies in human subjects, intraneural injections result in postinjection inflammation in animal models. This study used clinical, imaging, and electrophysiologic measures to evaluate the occurrence of any subclinical neurologic injury in patients with intraneural injection during sciatic popliteal block.
Brain areas interact mutually to perform particular complex brain functions such as memory or language. Furthermore, under resting-state conditions several spatial patterns have been identified that resemble functional systems involved in cognitive functions. Among these, the default-mode network (DMN), which is consistently deactivated during task periods and is related to a variety of cognitive functions, has attracted most attention. In addition, in resting-state conditions some brain areas engaged in focused attention (such as the anticorrelated network, AN) show a strong negative correlation with DMN; as task demand increases, AN activity rises, and DMN activity falls.
We present a novel approach to quantify skin innervation by measuring the PGP 9.5 immunoreactive (PGP-ir) fluorescence corresponding to axons within the epidermis and dermis. The skin biopsies from 35 controls and 45 small fiber neuropathy (SFN) patients were included. In 50-?m free-floating sections, we determined the intraepidermal nerve fiber density (IENFD) by direct fluorescence visualization and captured 2-?m thick individual optical sections using the same confocal microscope and magnification. We measured the fluorescence of the PGP-ir axons in both, epidermal and dermal area by using the ImageJ software. There was good interobserver and intraobserver reliability of PGP-ir measures, similar than for IENFD. The PGP-ir axons were found decreased in patients with SFN (1.1‰ and 9.0‰ respectively for epidermal and dermal area in contrast to 2.2‰ and 16.0‰, respectively to controls). The area under the ROC curve was 0.90 for the IENFD, 0.84 for epidermal PGP-ir axons and 0.70 for dermal PGP-ir axons. There was a positive correlation between the IENFD and the PGP-ir axons at epidermis (Spearman Rho=0.66, p<0.001) as well as for the dermal nerve length and the PGP-ir axons at dermis (Spearman Rho=0.45, p<0.05). This method is also particularly adequate for the quantitation of dermal nerve fibers. We conclude that quantifying the fluorescent PGP-ir axons could help to assess skin innervation (dermal and epidermal nerve fibers) in patients with SFN.
Neuropathic pain (NP) is a common symptom following spinal cord injury (SCI). NP may be associated with altered processing of somatosensory pathways in dermatomes rostral to the injury level. To explore this possibility, the characteristics of contact heat evoked potentials (CHEPs) and quantitative thermal testing (QTT) were studied at and above the lesion level in SCI patients with NP. The goal was to determine processing abnormalities correlated with data from clinical evaluations.
Over the past two decades, the H reflex has been used as a neural tool to assess the effect on the motoneuronal pool of conditioning volleys in supraspinal descending tracts elicited by transcranial magnetic stimulation (TMS) or auditory stimuli. However, mechanisms mediating such modulation are unclear. These hypothesized neural pathways are likely to be affected by single electrical stimulus applied through the electrodes implanted in the subthalamic nucleus for deep brain stimulation (sSTNDBS). To improve our knowledge on such mechanisms, we examined in 11 Parkinsons disease patients the effects of conditioning sSTNDBS applied contralateral and ipsilateral to the H reflex recording on the amplitude of the soleus H reflex, at interstimulus intervals (ISIs) between 0 and 110 ms. There was a significant main effect of the ISI (P<0.001) and of the sSTNDBS stimulation side (P=0.019) on the percentage change in the soleus H-reflex amplitude. Contralateral sSTNDBS modulation of the soleus H reflex resembles that of TMS in healthy subjects with two facilitation phases (at 5-20 ms and at 60 ms), while after ipsilateral sSTNDBS, there is only a single facilitation phase peaking up at 5 ms later than the first facilitation period observed with contralateral stimulation. These findings contribute to the discussion of the mechanisms underlying the excitability of the spinal alpha motoneuron pool and the modulation of the H reflex by supraspinal stimuli.
The procyanidin-rich extract from grape seeds and skins (GSSE) has antioxidant properties which may have cardioprotective effects. Since it might be interesting to incorporate this extract into a functional food, toxicological tests need to be made to determine how safe it is. In this study we carried out a limit test to determine the acute oral toxicity and the lethal dose 50 (LD50) and some genotoxicity tests of the extract in rats. The LD50 was higher than 5000 mg/kg. Doses of up to 2000 mg/kg showed no increase in micronucleated erythrocytes 72 h after treatment. The bacterial reverse mutation test showed that the extract was weakly mutagenic to the dose of 5 mg/plate and 19.5 and 9.7 ?g/ml of GSSE did not show significant differences in the frequency of aberrant metaphases in relation to negative controls. Our results indicated slight mutagenicity under the study conditions, so further studies should be conducted at lower doses to demonstrate that this extract is not toxic.
Excitability is probably the concept that fits better with the definition of the role of neurophysiology in the study of brainstem functions and circuits. Neurophysiological techniques are likely the best suited of all paraclinical tests for documenting the eventual excitability changes that may occur in certain physiological states and in many neurological disorders. The best known test of brainstem excitability is the blink reflex. While a single stimulus can already indicate the readiness of the interneuronal path and the facial motoneurons to fire, pairs of stimuli (conditioning and test) are suited to analyze the degree of excitability recovery after a single discharge. Another brainstem reflex circuit, which excitability testing can be of interest for physiological and clinical exams is the one involved in the startle reaction. The size of the responses and their habituation are the typical measures of excitability of the startle reflex circuit. Prepulse inhibition is a method to modulate both, the blink reflex and the startle reaction. It is defined as the inhibitory effect caused by a stimulus of an intensity low enough not to induce a response by itself on the response elicited by a subsequent stimulus. The circuits of the blink reflex, startle reaction and prepulse inhibition share some commonalities but they are different enough for the three techniques to provide unique, clinically relevant, information in certain conditions. The role of neurophysiology is not limited to testing those functions. It is important also for the assessment of many other circuits, such as those implicated in eye movements, vestibular reflexes, arousal, sleep, breathing, or autonomic reactions, which are not considered in this review.
The brainstem pathways that mediate the somatosensory blink reflex (SBR) are not completely understood. We hypothesized that the circuits of the SBR might be affected separately from those of the trigeminal blink reflex (TBR). We examined 7 patients with mesencephalic lesions and 8 patients with medullary lesions. The SBR was elicited by median nerve stimulation. The TBR was elicited by supraorbital nerve stimulation. In patients with upper brainstem lesions, the TBR was normal, whereas the SBR was generally abnormal. The SBR was either absent or small and was significantly delayed with respect to control subjects. The opposite was the rule in patients with lower brainstem lesions who had delayed or absent TBR and no abnormal findings in the SBR. The SBR is mediated through circuits in the upper brainstem. Study of the SBR can be helpful in the neurophysiological assessment of patients with mesencephalic lesions.
Repetitive, paired peripheral and transcranial stimulation targeting the cerebral cortex can increase cortical excitability, outlasting the stimulation period. It is unknown whether paired stimulation specifically targeting the spinal cord can modulate spinal excitability. We tested whether the H-reflex facilitation from a sub-threshold conditioning TMS pulse could modulate spinal excitability if delivered repetitively.
Uncertainty exists on whether Parkinsons disease (PD) and essential tremor (ET) patients have similar degree of impairment during motor tasks. We investigated this problem by analyzing nonlinear dynamics of repetitive movements in 21 control subjects, 33 mild-moderate PD patients, and 18 ET patients. Accelerometer signals were recorded during finger tapping and unbounded forearm movements between two points, and processed with moving average filtering to generate a new signal consisting of the temporal distance between consecutive cycles. We calculated: mean interpeak interval (slowness), interpeak interval variability (irregularity), and beat decay (BD) of the auto mutual information (AMI) value, which estimates signal predictability by measuring the loss of signal information over a timescale. Both PD and ET had longer interpeak interval (except for finger tapping), higher interpeak interval variability, and higher BD-AMI values than controls (P ? 0.007, all comparisons). ET patients had higher BD-AMI values than PD (P = 0.003). BD-AMI was the parameter that discriminated better between subjects (diagnosis accuracies about 80%). No differences existed between PD patients with and without tremor or between PD or ET patients with different disease stages, for any parameter. Evaluation of nonlinear dynamics of oscillatory repetitive movements is a feasible and promising tool for studying movement physiology. Movement performance is more predictable in PD and ET than in controls, even in early disease stages. Slowness and irregularity of movement in PD and ET cannot be fully explained by tremor. Some common pathogenic mechanisms leading to bradykinesia may contribute to this impairment.
Unexpected support-surface movements delivered during stance elicit "first trial" postural reactions, which are larger and cause greater instability compared with habituated responses. The nature of this first trial reaction remains unknown. We hypothesized that first trial postural reactions consist of a generalized startle reaction, with a similar muscle synergy as the acoustic startle response, combined with an automatic postural reaction. Therefore we compared acoustic startle responses to first trial postural reactions. Eight healthy subjects stood on a support surface that unexpectedly rotated backwards 10 times, followed by 10 startling acoustic stimuli, or vice versa. Outcome measures included full body kinematics and surface EMG from muscles involved in startle reactions or postural control. Postural perturbations and startling acoustic stimuli both elicited a clear first trial reaction, as reflected by larger kinematic and EMG responses. The ensuing habituation rate to repeated identical stimuli was comparable for neck and trunk muscles in both conditions. Onset latencies in neck muscles occurred significantly later for first trial perturbations compared with startle responses, but earlier in trunk muscles. Our results show that platform tilting initially induces reactions larger than needed to maintain equilibrium. For neck and trunk muscles, these first trial postural reactions resembled acoustic startle reflexes. First trial postural reactions may be triggered by interaction of afferent volleys formed by somatosensory and vestibular inputs. Acoustic startle reactions may also be partially triggered by vestibular inputs. Similar muscle activation driven by vestibular inputs may be the common element of first trial postural responses and acoustic startle reactions.
In the analysis of biological samples, such as plasma or serum, the quantity of sample available is a critical parameter in most cases. A good approach is the use of the microelution SPE (?SPE) plates as sample pre-treatment technique in which the loaded sample volume is low. An off-line ?SPE and ultra-performance LC-ESI-MS/MS (UPLC-ESI-MS/MS) method was developed and validated to determine procyanidins and anthocyanins in spiked plasma samples. The sample pre-treatment ?SPE allowed the simultaneous determination of procyanidins and anthocyanins from plasma by using a small sample volume (350 ?L) and without an evaporation step previous to the chromatographic analysis. Moreover, the use of UPLC technique allowed to determine the studied compounds at low concentration levels in a short analysis time (12.5 min approximately). Then, the developed method was applied to determine the studied compounds, procyanidins and anthocyanins, and their metabolites in rat plasma samples. Previously, the rats had consumed 5000 mg/kg of a grape pomace extract and the plasma was extracted 4 h after administration. The procyanidins catechin and epicatechin glucuronide, methyl catechin and epicatechin glucuronide, and methyl catechin and epicatechin sulphate were detected at ?M concentration level, and the parent anthocyanins at nM.
The authors examined the effects of thermal stimulation on electrodermal activity (EDA) in patients with primary palmar hyperhidrosis (PPH). The authors hypothesised that temperature changes may induce abnormal sudomotor reactions because of simultaneous activation of sudomotor centres through thermal and emotional pathways, and compared patients before and after thoracoscopic sympathectomy.
Motor preparation for execution of both simple and choice reaction time tasks (SRT and CRT) involves enhancement of corticospinal excitability (CE). However, motor preparation also implies changes in inhibitory control that have thus far been much less studied. Short-interval intracortical inhibition (SICI) has been shown to decrease before CE increases. Therefore we reasoned that, if SICI contributes to inhibitory control of voluntary movement during the preparatory phase, it would be larger in CRT than in SRT because of the need to keep the movement unreleased until the uncertainty resolves on which task is required. We measured changes in SICI and in CE at different time points preceding motor reaction in normal subjects. Single-pulse transcranial magnetic stimulation (spTMS) and paired-pulse transcranial magnetic stimulation (ppTMS) produced time-dependent changes in both SRT and CRT, with shortening when applied close to the presentation of the imperative signal ("early") and lengthening when applied near the expected reaction ("late"). In addition, at all stimulation time points, reaction time was shorter with ppTMS than that with spTMS, but there was no consistent association between the amount of SICI and reaction time changes. At early stimulation time points, CE was reduced in CRT but not in SRT. However, SICI in CRT was not different from SICI in SRT. At late stimulation time points, SICI decreased just before enhancement of CE. Our findings indicate that inhibitory circuits other than SICI are responsible for setting the level of CE at earlier parts of the reaction time period. Although the decrease in SICI may contribute to the increase in CE at the last part of the premotor period, the two phenomena are not dependent on each other.
Involuntary eyelid closure (IEC) may occur after deep brain stimulation of the subthalamic nucleus (STN-DBS) in Parkinsons disease (PD) and is often categorised as apraxia of lid opening (ALO), albeit the appropriateness of this term is under debate. To gain insight into the hitherto undefined pathophysiology of IEC after STN-DBS, we performed a comprehensive clinical and electrophysiological characterisation of lid function in a total of six PD patients.
Axonal regeneration and organ reinnervation are the necessary steps for functional recovery after a nerve lesion. However, these processes are frequently accompanied by collateral events that may not be beneficial, such as: (1) Uncontrolled branching of growing axons at the lesion site. (2) Misdirection of axons and target organ reinnervation errors, (3) Enhancement of excitability of the parent neuron, and (4) Compensatory activity in non-damaged nerves. Each one of those possible problems or a combination of them can be the underlying pathophysiological mechanism for some clinical conditions seen as a consequence of a nerve lesion. Reinnervation-related motor disorders are more likely to occur with lesions affecting nerves which innervate muscles with antagonistic functions, such as the facial, the laryngeal and the ulnar nerves. Motor disorders are better demonstrated than sensory disturbances, which might follow similar patterns. In some instances, the available examination methods give only scarce evidence for the positive diagnosis of reinnervation-related disorders in humans and the diagnosis of such condition can only be based on clinical observation. Whatever the lesion, though, the restitution of complex functions such as fine motor control and sensory discrimination would require not only a successful regeneration process but also a central nervous system reorganization in order to integrate the newly formed peripheral nerve structure into the prepared motor programs and sensory patterns.
This study analyzed the relationship between the density of intraepidermal nerve fibers (IENF) and the characteristics of either nociceptive laser-evoked potentials (LEPs) or contact heat-evoked potentials (CHEPs) in patients with painful sensory polyneuropathy with the aim to determine which parameters of LEPs and CHEPs more reliably reflect IENF loss. A total of 96 patients and 35 healthy volunteers took part in the study. Based on clinical examination, nerve conduction tests, and quantitative sensory testing, we identified 52 patients with small-fiber neuropathy (SFN), 40 with mixed (small-fiber and large-fiber) neuropathy (MFN), and 4 who were excluded from the analysis because of no evidence of involvement of small fibers. The latency of the N2 was delayed for both LEPs and CHEPs in patients with MFN and for CHEPs only in patients with SFN. The amplitude of the vertex N2/P2 potential was similarly reduced in both types of neuropathy, but LEPs were more frequently absent than CHEPs in MFN patients (68% vs 40%). In general, latency and amplitude of LEPs and CHEPs were well correlated with IENF density. SFN patients were characterized by abnormal EPs and slightly decreased but morphologically abnormal IENF. MFN patients were characterized by frequently absent LEPs and CHEPs and a rather severe IENF loss. The correlation between nociceptive evoked potentials (laser-evoked potentials and contact heat-evoked potentials) and skin biopsy aids in the diagnosis of painful neuropathies.
Spasticity is common after spinal cord injury (SCI). Exaggerated tendon jerks, clonus, and spasms are key features of spasticity that result from hyperexcitability of the stretch reflex circuit. Here we studied the effects of vibration on the rectus femoris muscle (RF) on clinical and electrophysiological measures of spasticity in the leg.
Reorganization of the central nervous system following spinal cord injury (SCI) involves changes not only at the cortical level, but also at the level of the brainstem. To further understand changes in excitatory and inhibitory brainstem interneuronal circuits following SCI, we studied recovery curves of the blink reflex (BR) to paired suprathreshold stimuli at various intervals (160, 300, 500, and 1000 msec), and prepulse inhibition of the BR following right index finger stimulation 100 msec prior to supraorbital nerve stimulation. Both parameters were studied in patients with SCI without baclofen treatment (n = 19), in patients with continuous intrathecal baclofen (CITB) (n = 9), and in healthy controls (n = 13). R2 recovery, expressed as the ratio of R2 area following the second stimulus divided by the R2 area following the first stimulus, was significantly greater in SCI patients without baclofen compared to controls and patients with CITB at all intervals, while there was no difference between patients with CITB and controls. Prepulse inhibition of R2 was significantly less in patients without baclofen compared to patients with CITB and healthy controls. Our findings indicate enhanced excitability and reduced inhibition of brainstem interneuronal circuits in patients with SCI, that are restored in the presence of baclofen to levels comparable to controls. In conclusion, SCI patients show more extended alterations in brainstem circuitry than previously thought. Decreased GABAergic mechanisms seem to be related to both excitatory and inhibitory brainstem circuit alterations. Baclofen appears to effectively restore this decreased GABAeregic activity.
Spasticity with increased tone and spasms is frequent in patients after spinal cord injury (SCI). Damage to descending corticospinal pathways that normally exert spinal segmental control is thought to play an important causal role in spasticity. The authors examined whether the modulation of excitability of the primary motor cortex with high-frequency repetitive transcranial magnetic stimulation (rTMS) could modify lower limb spasticity in patients with incomplete SCI.
Among procyanidins (PC), monomers, such as catechin and epicatechin, have been widely studied, whereas dimer and trimer oligomers have received much less attention, despite their abundance in our diet. Recent studies have showed that as dimers and trimers could be important in determining the biological effects of procyanidin-rich food, understanding their bioavailability and metabolism is fundamental. The purpose of the present work is to study the stability of PC under digestion conditions, the metabolism and the bioavailability by using a combination of in vitro and in vivo models. Simultaneously, the matrix effect of a carbohydrate-rich food on the digestibility and bioavailability of PC is investigated. The results show a high level of stability of PC under gastric and duodenal digestion conditions. However, the pharmacokinetic study revealed limited absorption. Free forms of dimers and trimers have been detected in rat plasma, reaching the maximum concentration 1 h after oral intake of a grape seed extract.
Human gait involves a repetitive leg motor pattern that emerges after gait initiation. While the automatic maintenance of the gait-pattern may be under the control of subcortical motor centres, gait initiation requires the voluntary launching of a different motor program. In this study, we sought to examine how the two motor programmes respond to an experimental manipulation of the timing of gait initiation. Subjects were instructed to start walking as soon as possible at the perception of an imperative signal (IS) that, in some interspersed trials was accompanied by a startling auditory stimulus (SAS). This method is known to shorten the latency for execution of the motor task under preparation. We reasoned that, if the two motor programmes were launched together, the gait-pattern sequence would respond to SAS in the same way as gait initiation. We recorded the gait phases and the electromyographic (EMG) activity of four muscles from the leg that initiates gait. In trials with SAS, latency of all gait initiation-related events showed a significant shortening and the bursts of EMG activity had higher amplitude and shorter duration than in trials without SAS. The events related to gait-pattern were also advanced but otherwise unchanged. The fact that all the effects of SAS were limited to gait initiation suggests that startle selectively can affect the neural structures involved in gait initiation. Additionally, the proportional advancement of the gait-pattern sequence to the end of gait initiation supports the view that gait initiation may actually trigger the inputs necessary for generating the gait-pattern sequence.
Plastic changes in the human central nervous system can occur at multiple levels, including circuits rostral to the lesion level in spinal cord injury (SCI). GABA is the most important inhibitory neurotransmitter in the brain. The authors hypothesized that one of the consequences of plasticity in SCI patients could be enhancement of brainstem reflexes, and they investigated the effect of continuous intrathecal baclofen (CITB) on such enhancement.
Voluntary muscle contraction is accompanied by an increase in sympathetic nerve activity. The sympathetic skin response (SSR) is a simple and non-invasive method of autonomic assessment that reflects a synchronized activity of the sweat glands. The aim of our study was to examine the possible relationship between isometric muscle contraction (IC) and changes in the SSR.
In recent years, increasing knowledge of the positive health effects of food polyphenols has prompted the need to develop new separation techniques for their extraction, fractionation and analysis. This article provides an updated and exhaustive review of the application of counter-current chromatography, high performance liquid chromatography, capillary electrophoresis, and their hyphenation with mass spectrometry to the study of food polyphenols. Flavonoids constitute the largest class of polyphenols, widely spread in the plant kingdom and common in human diet which has been the most widely studied with respect to their antioxidant and biological activities. The main subgroups are anthocyanins, catechins, isoflavones, flavonols and flavones. They are reported to exhibit antioxidant, anti-carcinogenic, anti-inflammatory, anti-atherogenic, anti-thrombotic, and immune modulating functions, among others. Since red fruit anthocyanins, soy isoflavones and flavanols from grapes and teas are currently the most used phenolic compounds for producing new nutraceuticals and functional foods, this review is focused on these three flavonoid groups.
Unexpected sensory inputs can generate a patterned startle reaction, aimed at protection and defense. Experimentally, it is usually triggered by auditory stimuli while the startle reaction to somatosensory inputs (SSS) has not received much attention so far. This may be in part due to the fact that somatosensory inputs inevitably cause local reactions, such as short and long latency reflexes and withdrawal reactions, which could interfere with recognition of the startle-related activity. Therefore, we have undertaken a study aimed at separating the SSS from other responses by exploring the responses that are common to somatosensory stimuli applied to different sites and examining the inhibitory effects of prepulse stimuli. In 13 healthy naive subjects, we applied electrical stimuli to the median nerve at the wrist (MW) or the posterior tibial nerve at the ankle (PT) and recorded from orbicularis oculi (OOC), masseter (MAS), sternocleidomastoid (SCM) and representative muscles of the limbs being stimulated (flexor carpi radialis for MW and tibialis anterior for PT). In random trials, we also applied prepulse stimuli, either a low-intensity auditory stimulus or low-intensity electrical stimuli, 100 ms before the SSS-eliciting stimulus. The pattern of SSS was different for upper and lower limb stimuli. While stimuli applied to MW induced a prominent reaction of the OOC, at a mean latency of 61.1 ms (SD = 16.3 ms), followed by the SCM at a mean latency of 83.3 ms (SD = 28.6 ms), those applied to the PT caused a small or absent response in the OOC and a consistent response of the SCM at a mean latency of 89.7 ms (SD = 30.1 ms). Prepulse stimuli effectively inhibited the responses of facial and neck muscles but only partially those of the wrist flexors to MW or the tibialis anterior to PT. Our results indicate that, although there are common neck and facial muscle reactions to somatosensory stimuli applied to upper and lower limbs, the pattern of the SSS differs according to the source of the input. Prepulse inhibition is more effective on the responses of neck and facial muscles than on the responses of limb muscles to somatosensory stimuli. These results could help in distinguishing between withdrawal and SSS reactions.
Cold allodynia is a common sign of neuropathic pain patients but its underlying mechanisms are still largely unknown, partly because the populations of neurons responding to cold stimuli and their transduction mechanisms have not been fully determined. We report a patient with a small-fiber neuropathy of unknown origin, whose main complaint is cold allodynia. Microneurographic recordings showed ongoing spontaneous activity and abnormal responses to cold and menthol in identified subtypes of C-nociceptors. These findings provide the first direct evidence in human of abnormal peripheral nociceptor behavior potentially responsible for cold allodynia. The responsiveness of C-nociceptors to menthol suggests an abnormal expression or function of TRPM8 channels in this patient with a small-fiber polyneuropathy.
By using a combination of physiological and electrical peripheral nerve stimuli, the authors aimed to characterize the expected dysfunction of the circuits responsible for sympathetic skin response (SSR) in persons with spinal cord injury (SCI).
Behavioral consequences of a brain insult represent an interaction between the injury and the capacity of the rest of the brain to adapt to it. We provide experimental support for the notion that genetic factors play a critical role in such adaptation. We induced a controlled brain disruption using repetitive transcranial magnetic stimulation (rTMS) and show that APOE status determines its impact on distributed brain networks as assessed by functional MRI (fMRI).Twenty non-demented elders exhibiting mild memory dysfunction underwent two fMRI studies during face-name encoding tasks (before and after rTMS). Baseline task performance was associated with activation of a network of brain regions in prefrontal, parietal, medial temporal and visual associative areas. APOE ?4 bearers exhibited this pattern in two separate independent components, whereas ?4-non carriers presented a single partially overlapping network. Following rTMS all subjects showed slight ameliorations in memory performance, regardless of APOE status. However, after rTMS APOE ?4-carriers showed significant changes in brain network activation, expressing strikingly similar spatial configuration as the one observed in the non-carrier group prior to stimulation. Similarly, activity in areas of the default-mode network (DMN) was found in a single component among the ?4-non bearers, whereas among carriers it appeared disaggregated in three distinct spatiotemporal components that changed to an integrated single component after rTMS.Our findings demonstrate that genetic background play a fundamental role in the brain responses to focal insults, conditioning expression of distinct brain networks to sustain similar cognitive performance.
Nociceptive inputs reach the CNS by means of small myelinated and unmyelinated fibers. Owing to this, conventional nerve conduction studies and electromyography are less likely to demonstrate abnormalities in neuropathies affecting nociceptive fibers than in those involving large myelinated fibers. Therefore, to characterize painful neuropathies, clinicians evaluate the features of the lesion that cause pain rather than the feeling of pain itself. Clinical neurophysiological assessment of painful neuropathies still relies on conventional nerve conduction studies but slightly more sophisticated techniques bring more specific information. These are the nociceptive-evoked potentials, microneurography or autonomic nervous system functional tests. Neurophysiological techniques can also add information to quantitative sensory testing by recording autonomic responses such as the sudomotor skin response or the voluntary reaction. Functional magnetic resonance should also be considered as a neurophysiological technique, which allows for mapping the areas of the brain involved in nociceptive sensation and pain control.
The study of body representation and ownership has been a very active research area in recent years. Synchronous multisensory stimulation has been used for the induction of the illusion of ownership over virtual body parts and even full bodies, and it has provided experimental paradigms for the understanding of the brain processing of body representation. However, the illusion of ownership of a virtual body has rarely been used for patient evaluation and diagnosis. Here we propose a method that exploits ownership of a virtual body in combination with a simple brain computer interface (BCI) and basic physiological measures to complement neurological assessment. A male patient presenting a fixed posture dystonia featuring a permanently closed left fist participated in this case study. The patient saw a virtual body that substituted his own after donning a head-mounted display and thereby entering the virtual reality. The left virtual hand had the same posture as his corresponding real hand. After inducing virtual hand ownership by correlated visuo-tactile stimulation and dynamic reflections in a virtual mirror, the virtual hand would open either automatically or through a cognitive task assessed through a BCI that required him to focus attention on the virtual hand. The results reveal that body ownership induced changes on electromyography and BCI performance in the patient that were different from those in five healthy controls. Overall, the case study shows that the induction of virtual body ownership combined with simple electrophysiological measures could be useful for the diagnosis of patients with neurological conditions.
Patients with cervical dystonia (CD) present with an impaired performance of voluntary neck movements, which are usually slow and limited. We hypothesized that such abnormality could involve defective preparation for task execution. Therefore, we examined motor preparation in CD patients using the StartReact method. In this test, a startling auditory stimulus (SAS) is delivered unexpectedly at the time of the imperative signal (IS) in a reaction time task to cause a faster execution of the prepared motor programme. We expected that CD patients would show an abnormal StartReact phenomenon.
This paper aims to analyse the etiology, characterisation and outcomes of the different types of peripheral neuropathy in patients with primary Sjögrens syndrome (SS) and their association with clinical and immunological disease expression.
Epidemiological data suggest that plant-derived phenolics beneficial effects include an inhibition of LDL oxidation. After applying a screening method based on 2,4-dinitrophenyl hydrazine-protein carbonyl reaction to 21 different plant-derived phenolic acids, we selected the most antioxidant ones. Their effect was assessed in 5 different oxidation systems, as well as in other model proteins. Mass-spectrometry was then used, evidencing a heterogeneous effect on the accumulation of the structurally characterized protein carbonyl glutamic and aminoadipic semialdehydes as well as for malondialdehyde-lysine in LDL apoprotein. After TOF based lipidomics, we identified the most abundant differential lipids in Cu(++)-incubated LDL as 1-palmitoyllysophosphatidylcholine and 1-stearoyl-sn-glycero-3-phosphocholine. Most of selected phenolic compounds prevented the accumulation of those phospholipids and the cellular impairment induced by oxidized LDL. Finally, to validate these effects in vivo, we evaluated the effect of the intake of a phenolic-enriched extract in plasma protein and lipid modifications in a well-established model of atherosclerosis (diet-induced hypercholesterolemia in hamsters). This showed that a dietary supplement with a phenolic-enriched extract diminished plasma protein oxidative and lipid damage. Globally, these data show structural basis of antioxidant properties of plant-derived phenolic acids in protein oxidation that may be relevant for the health-promoting effects of its dietary intake.
A startling auditory stimulus (SAS) causes a faster execution of voluntary actions when applied together with the imperative signal in reaction time tasks (the StartReact effect). However, speeding up reaction time may not be the best strategy in all tasks. After a self-initiated fall, the program for landing has to be time-locked to foot contact to avoid damage, and therefore advanced execution of the program would not be convenient. We examined the effects of SAS on the landing motor program in 8 healthy subjects that were requested to let themselves fall from platforms either 50 or 80 cm high at the perception of a visual imperative signal and land on specific targets. In trials at random, SAS was applied either together with the imperative signal (SAS(IS)) or at an appropriate prelanding time (SAS(PL)). As expected, the latency of takeoff was significantly shortened in SAS(IS) trials. On the contrary, the timing of foot contact was not significantly different for SAS(PL) compared with control trials. No changes were observed in the size of the electromyograph bursts in the two experimental conditions with respect to the control condition. Our results indicate that the landing program after a self-initiated fall may in part be organized at the time of takeoff and involve precise information on timing of muscle activation. Once launched, the program is protected against interferences by external inputs.
Evaluation of nerve fibers in the skin provides a useful tool for the diagnosis of small fiber neuropathies (SFNs). Our aim was to determine whether mitochondria are involved in SFN, indicating early axonal damage. We quantified mitochondrial respiratory chain complex IV (OXPHOS) and axonal (PGP 9.5) fluorescence on skin sections from 32 SFN patients and 14 healthy controls. Also, a group of six patients were recruited before and after 30-day treatment with the mitotoxic antibiotic linezolid. We measured the co-localization of OXPHOS within the intraepidermal and subpapillary dermal axons (PGP-immunoreactive [PGP-ir]). SFN patients with relatively preserved intraepidermal nerve fibers (SFN borderline) showed statistically significant reduction of OXPHOS (50.5 ± 33.9 µm(2) vs. 107.6 ± 81 µm(2) in controls, p < 0.02). A positive correlation was found between both PGP-ir and OXPHOS in controls (Pearsons coefficient r = 0.59, p < 0.001), whereas such correlation was absent in SFN. With respect to baseline measurements, linezolid therapy increased both PGP-ir and OXPHOS, which could be considered an initial compensatory toxic-induced response. This study set out to identify a possible marker of axonal pre-degenerative state in SFN borderline patients.
A single-pulse transcranial magnetic stimulus (TMS) may induce contraction in many muscles of the body at the same time. This is specially the case when using the double-cone coil to obtain the motor evoked potentials in leg muscles. Even if intensity is kept below threshold for the soleus muscle, TMS induces facilitation of the soleus H reflex that is separated into two phases: the first, peaking at 10-20 ms and the second, peaking at 70-90 ms. We investigated the possibility that TMS-induced facilitation of the H reflex was related, at least in part, to the reafferentation volley reaching the alpha motoneuron after synchronized contraction of other muscles in the body. To test this hypothesis, we examined the effects of vibration on the TMS-induced facilitation of the soleus H reflex. As expected, vibration applied over the triceps tendon caused a significant reduction in H reflex amplitude: 42.4 ± 6.4 % of control values. When conditioned by TMS at intervals corresponding to the first phase, the H reflex was facilitated to the same extent in both conditions: with and without vibration. However, at intervals corresponding to the second facilitation phase, there was a significantly reduced facilitation with vibration. These differential effects of vibration on the two phases of the TMS-induced facilitation of the H reflex indicate a different mechanism for each facilitation phase. The first phase could result from direct corticospinal excitatory input, while the second phase might depend on inputs via Ia afferents from heteronymous muscles.
Verbal fluency relies on the coordinated activity between left frontal and temporal areas. Patients with Parkinsons disease (PD) present phonemic and semantic fluency deficits. Recent studies suggest that transcranial direct current stimulation (tDCS) enhances adaptative patterns of brain activity between functionally connected areas.
We quantified the immune histiocytic Langerhans cells (LCs) in skin biopsy samples of patients with distal small fiber neuropathy (SFN). Patients were divided according to the presence or absence of neuropathic pain (burning pain) assessed by a visual analogue scale (VAS). We studied 13 diabetic patients (pain-DSFN), 7 nondiabetic patients (pain-SFN) who reported relevant neuropathic pain (VAS ? 3), and 6 nondiabetic patients without neuropathic pain (no-pain-SFN). Using double immunofluorohistochemistry with the PGP 9.5 and the langerin/CD207, we quantified the intraepidermal nerve fibers density (IENFD) and LCs per square millimeter in the epidermis. A group of 10 skin samples from healthy subjects served as controls. Confocal analysis was performed to evaluate LC PGP 9.5-immunoreactivity. We found a mean value of 334.3LC/mm(2) in controls, 310.2LC/mm(2) in no-pain-SFN, 329.6LC/mm(2) in pain-SFN and 484.3LC/mm(2) in pain-DSFN (analysis of variance; P=.01). In patients, analysis of covariance adjusted by different covariables showed that the presence of diabetes (F=5.2, P=.03) was associated with an increased number of LC/mm(2). There was a negative correlation between the IENFD and the number of LCs (r(2)=-0.13, P=.03). No statistically significant differences were found among groups of subjects either for the co-localization or for the number of LCs that were PGP 9.5-immunoreactive (analysis of variance; P>.05). These results indicate that patients with neuropathic pain in the context of SFN, specially those who had diabetes (DSFN), had an increased number of LCs in the epidermis that may play a role in the generation or maintenance of neuropathic pain.
Evoked potentials (EPs) to radiant or contact heat pain stimuli reflect the synchronization of brain activity to noxious inputs. However, we do not know how they relate to conscious awareness (AW) of a sensation. In healthy volunteers, we determined the time of AW for thermal noxious and non-noxious sensory inputs and examined its correlation to parametric measures of vertex EPs. Subjects had to report the position of the hand of a Libets clock at the moment they perceived either a laser or a thermode stimulus. AW was determined after subtracting the position of the clock hand at the moment of stimulus delivery from the one reported by the subject, in ms. Subjects estimated AW in all single trials, including those in which no EPs could be identified. Mean AW was estimated earlier than the corresponding EP latency for both types and intensities of stimuli. There was a weak but significant negative correlation of AW to EPs amplitude, which was higher than the correlation of AW to EPs latency. Our results indicate that the timing of AW is influenced by the subjective relevance of sensory inputs. This feature could be used for the analysis of cognitive aspects of pain processing.
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