Platelets, inflammation, and atherothrombotic neurovascular disease: the role of endothelial dysfunction

The vascular endothelium is an indispensable organ in the regulation of tonicity and vascular homeostasis. Endothelial dysfunction is a marker of atherosclerosis and contributes to the atherogenic process and the development of atherothrombotic complications. Endothelial dysfunction is the common meeting point among factors for vascular risk and launches complex cellular and biochemical interactions that are characterized by oxidative stress and an intense inflammatory response. The strategic importance of the concept of endothelial dysfunction arises from the following facts: its diagnosis is simple, it allows the identification of asymptomatic arteriosclerotic subjects with a high risk of developing atherothrombotic complications, it is reversible, and it responds to various therapeutic strategies.     

The propagation of single motor unit action potentials detected by a surface electrode array

Propagation of single motor unit action potentials (MUAPs) was detected by surface electromyography. Sixteen EMG signals were simultaneously recorded by a linear bipolar electrode array placed along the longitudinal axis of the biceps brachii. EMGs were obtained from 8 healthy adults at 10-40% of the maximum contraction. Single MUAPs were extracted by superimposing and averaging the EMG signals at the timing of potential peaks. Most MUAPs were triphasic and propagated symmetrically in opposite directions from the middle length of the muscle to the tendons. Some MUAPs showed more than 5 phases and asymmetrical wave forms on the proximal and distal recording sites. The asymmetrical wave forms were assumed to be caused by the scatter of myoneural junctions and by the time delay of the excitation at the junctions. The position of the myoneural junctions on muscle fibers was estimated from the source of propagation. The innervation zone of individual motor unit was found to spread up to 14 mm in the muscle fiber directions.     

Unrecognized errors due to analog filtering of the brain-stem auditory evoked response

Analog filtering of the brain-stem auditory evoked response (BAER) and synthetic wave forms using steeply sloped filters are shown to produce significant distortion even when filter cut-off frequencies are well removed from the wave form spectrum. The degree of distortion is such that it may result in erroneous identification of peaks in the BAER. Reversal of the order of peaks may occur with high pass settings at only 1/4 the lowest constituent frequency. Filter effects were identified as a major source of cross-laboratory differences in BAERs recorded from laboratory rats. Filter transfer functions of a typical analog filter set were derived for both gain and phase as a function of frequency. Filtering of synthetic wave forms was used to elucidate and highlight distortion effects. A typical Long-Evans rat BAER wave form was spectrum analyzed and conclusions were drawn with respect to appropriate bandpass frequencies.     

Arterial stiffness and impaired renal function in patients with Alzheimer’s disease

Impaired renal function is regarded as a risk factor for vascular disease, and is associated with an increasing pulse wave velocity. Both renal dysfunction and arterial stiffness are associated with cognitive impairment and dementia. However, there have been few studies that have evaluated the relationship between albuminuria and arterial stiffness and Alzheimer’s disease (AD). We investigated renal dysfunction and arterial stiffness in AD, as compared to normal controls, patients with subjective memory impairment (SMI), and patients with mild cognitive impairment (MCI). Case–control comparisons were made between 29 patients with AD, 27 with MCI, 14 with SMI, and 25 healthy controls. All patients underwent clinical and neuropsychological assessments. The urine albumin/creatinine ratio and estimated glomerular filtration rate (eGFR) were determined. Pulse wave velocity and the ankle-brachial index were used to evaluate arterial stiffness. The urine albumin/creatinine ratio and eGFR were significantly different in patients with AD, compared with the results from cognitive normal controls. The pulse wave velocity was increased and the ankle-brachial index was decreased in AD. The eGFR was well correlated with other indices and decreasing eGFR was independently associated with cognitive decline. In conclusion, albuminuria, a decreased glomerular filtration rate, an increased pulse wave velocity, and a decreased ankle-brachial index were associated with AD. These finding suggests that impaired renal functions and arterial stiffness are related to AD, in which a vascular mechanism plays a prominent role in the cognitive dysfunction associated with the disease.     

Differential effects of changes in mechanical limb properties on physiological and pathological tremor.

The effect of changes in mechanical limb properties on the peak frequency of different tremor forms was analysed. Wrist tremor was recorded by an accelerometer fixed to the dorsum of the hand and demodulated surface EMG was recorded from the wrist extensors, while the extended hand was loaded with successively heavier weights. Physiological tremor was characterised by flat EMG spectra and a gradual decrease in tremor peak frequency with increasing load, as would be expected from the properties of a passive spring-mass-system. Also the peak frequency of activated physiological tremor characterised by increased synchronisation between motor units decreased in frequency with increasing loads. EMG spectra showed clear peaks of activity at the various mechanically determined tremor frequencies. In contrast, in two pathological tremor forms, the postural tremor in Parkinsonian patients and essential tremor, peak frequency tended to remain stable irrespective of changes in load. The method therefore allows a simple distinction between physiological and these two pathological tremors.     

Temporal relationships of EMG changes preceding voluntary movement to premovement cortical potential shifts

The silent period and a rhythmic slower wave in EMG appear preceding a rapid voluntary movement (Tanii 1984). The present study was performed to investigate temporal relationships of the EMG changes preceding movement to premovement cortical potential shifts, in order to clarify whether the EMG changes are related to preparation and initiation of voluntary movement. A strong push of a hard band with the right wrist was conducted rapidly following a slightly sustained contraction. The surface EMG was detected from the right triceps brachii muscle. The EEG was recorded from C3, Cz and C4. Slowing of the EMG occurred before the movement in addition to the slower wave. The EMG slower waves were accompanied by a negative deflection of raw EEG potentials. The averaged cortical potentials preceding movement fell into 3 negative potentials. The first potential started about 1.0 sec before the EMG burst. Many of the EMG slower waves occurred in the phase of the second potential occurring 330-510 msec before the EMG burst. Premovement silent period appeared in the phase of the third potential occurring 30-60 msec before the EMG burst. Amplitude of these potentials was larger in the contralateral hemisphere than in the ipsilateral one. This asymmetry became statistically significant in the phase of the second potential. The results suggest that the EMG slower waves and the premovement silent period are associated with preparation and initiation of voluntary movement.     

Brain-stem auditory evoked potentials in squirrel monkey (Saimiri sciureus)

To more fully characterize brain-stem auditory evoked potentials (BAEPs) in non-human primates, BAEPs were recorded from chronically implanted epidural electrodes in 10 squirrel monkeys (Saimiri sciureus). The effects of stimulus intensity, repetition rate, and anesthesia (ketamine 20 mg/kg i.m.) on peak latencies and inter-peak intervals were evaluated. Monkey wave forms consisted of approximately 7 peaks (I-VII), each exhibiting similar latencies across sessions, with later peaks exhibiting greater variability. In some subjects, additional peaks (IIa, IIIa) and slow potentials were recorded. The slow potentials provided a substratum for peaks IV through VII. As with human, monkey peaks exhibited systematic changes in latency with changes in stimulus intensity or repetition rate. These shifts included significant decreases in latency with increasing intensity for peaks I-IV and increases in latency with increases in repetition rate for peaks III, V, and VI. Inter-peak intervals were similar to those observed in human. Furthermore, ketamine anesthesia significantly delayed the latencies of most peaks (except I, V, and VII). Some differences between monkey and human BAEPs were evident in the relative amplitude of specific peaks. For example, peak V is typically most prominent in human, while this was true for peak III in monkey. The similarities between unanesthetized monkey and human inter-peak intervals suggest that the times required for impulses to reach particular brain-stem areas are conserved across primate species that vary in brain size. This supports the hypothesis that comparably numbered BAEP peaks in monkey and human index homologous processes. The data also suggest that the differences between animal and human BAEPs commonly reported may result from the use of anesthetics. In summary, unanesthetized monkey BAEPs resemble human BAEPs in morphology, number of peaks, polarity, latency variability, inter-peak intervals, slow potentials superimposed on the high-frequency peaks, and variations in morphology, amplitude, and resolution of peaks as a function of recording site. Thus, unanesthetized monkey BAEPs may be an excellent model for investigating the neural substrates of human BAEP or for determining species differences in acoustic processing among primates.     

Directional tuning of speed-related activation for reaching in the vertical plane in cerebellar ataxia

The role of the cerebellum in the spatial tuning of goal-directed multi-joint movements in human is unknown. We analyzed the directional tuning of phasic EMG activities associated with upper limb reaching movements (12 targets) in the vertical plane in healthy subjects and in patients exhibiting cerebellar ataxia. Tuning of phasic EMG activities was investigated in seven muscles (brachioradialis, biceps, medial and long head of triceps, anterior and posterior deltoid, latissimus dorsi). We digitally compressed the EMG activities corresponding to slow reaches to the same targets into the time frame of the fast EMG traces. Estimates of gravity-related components were subtracted. Peaks of EMG activities in the resulting phasic traces were identified for each muscle and each target. Aberrant privileged directions of M Peak EMG (directions associated with the maximal peak of EMG amongst the 12 peaks of EMG activity in the sagittal plane) were found in all ataxic patients. Directional dominance, defined as the ratio of the M Peak EMG divided by the peak EMG in the opposite direction, was significantly higher in controls than in ataxic patients for one distal muscle (brachioradialis) and one proximal muscle (anterior deltoid). The spreading of EMG activities assessed by the global areas of the polar plots of phasic traces was broader in patients for the biceps and medial head of triceps. The distribution of densities of EMG activities (DDEMG) amongst the four quarters of the vertical plane, an index of the contrast in the intensities between quarters in polar plots, revealed increased values in control subjects for the brachioradialis, the biceps and the anterior deltoid as compared to ataxic patients. Representation of Net Vectors obtained from polar plots of peaks of EMG activities demonstrated an abnormal directional tuning in ataxic patients. In the majority of the cases, the Net Vector was outside the normal range for the following muscles: brachioradialis, biceps, anterior deltoid, posterior deltoid. This study reveals that cerebellar ataxia is associated with defective spatial properties of EMG activity during multiple joint movements. Privileged directions associated with M Peak EMG and Net Vectors are erroneous. We demonstrate that the cerebellum plays a determinant and unsuspected role in the spatial modulation of activation during speed-related action for reaching.     

Motor control after spinal cord injury: Assessment using surface EMG

The brain motor control assessment (BMCA) protocol is a comprehensive multichannel surface EMG recording used to characterize motor control features in persons with upper motor neuron dysfunction. Key information is contained in the overall temporal pattern of motor unit activity, observed in the EMG (RMS) envelope. In paralysis, a rudimentary form of suprasegmental control of tonic and phasic reflexes can be demonstrated. EMG patterns evoked by voluntary and passive maneuvers and by volitional modulation of reflex responses reveal features of motor control not apparent in the clinical examination. Such subclinical findings may explain paradoxically different responses in apparently similar SCI subjects, and may be used to monitor spontaneous or induced changes. The recording protocol, examples of EMG patterns, and their prevalence in 40 spinal cord injured (SCI) subjects are presented, and compared with 5 healthy subjects. © 1996 John Wiley & Sons, Inc.     

How to diagnose MSA early: the role of sphincter EMG

Summary. Multiple system atrophy (MSA) is a degenerative disease manifesting a combination of parkinsonism, cerebellar, pyramidal, and autonomic (including urinary, sexual and anorectal) dysfunction. It is pathomorphologically defined, but lacks a definitive clinical diagnostic test. In patients with probable MSA, abnormal sphincter EMG, as compared to control subjects, has been found in the majority of patients in all the different forms of the disease in most studies, including patients who, as yet, have no urological or anorectal problems. Patients with Parkinson’s disease (PD) as a rule do not show marked sphincter EMG abnormalities in the first five years of the disease. Thus, abnormal spontaneous activity or marked motor unit potential changes in sphincter muscles are helpful in distinguishing MSA from PD in the first five years after the onset of symptoms and signs, and from pure autonomic failure, as well as from cerebellar ataxias, if other causes for sphincter denervation have been ruled out. EMG does not distinguish MSA from progressive supranuclear palsy. How early in the course of MSA these abnormalities become significant enough to support diagnosis remains to be established by prospective studies.     

Olfactory dysfunction in Parkinson's disease

The olfactory system is one of the nonmotor systems severely affected in Parkinson's disease (PD). Olfactory dysfunction occurs early in the disease process, is independent of disease stage, duration, and treatment. However, olfactory dysfunction appears to be dependent on disease subtype. Olfaction is mildly impaired or preserved in most of the parkinsonism-plus syndromes (PPS). This provides a means of differential diagnosis between typical PD and PPS. Olfactory function is impaired also in familial forms of parkinsonism in which the genetic defect is known. In familial parkinsonism, olfactory function is impaired in both typical PD and PPS phenotypes. Olfactory dysfunction does not appear to be a manifestation of dopamine deficiency. Olfactory dysfunction is also associated with other neurodegenerative diseases such as Alzheimer's disease (AD), Huntington's disease (HD), as well as with normal aging. The neuropathological changes observed in the olfactory system in PD and other neurodegenerative diseases appear to be disease-specific, raising the possibility that olfactory dysfunction may be the result of a central rather than a peripheral process. The cellular and molecular mechanisms underlying olfactory dysfunction in PD and other neurodegenerative diseases remain unknown.     

Onset and offset of electromyographic (EMG) silence in asterixis.

The onset and offset of electromyographic (EMG) silence were studied physiologically by silent period locked averaging method (SPLA) combined with a computer-assisted method for detecting EMG changes in 11 patients with asterixis of various aetiologies. The onset followed the EMG discharge which was closely associated with a sharp wave probably generated by the motor cortex in three patients. No EEG activity could be shown to be related to the offset of EMG silence in every patient. Jerky movement of asterixis was temporally related to the offset of EMG silence rather than the onset.     

A review of transcranial magnetic stimulation in the in vivo functional evaluation of central cholinergic circuits in dementia

Central cholinergic circuits of human brain can be tested non-invasively by coupling electrical peripheral stimulation with transcranial magnetic stimulation (TMS) of the motor cortex. The short-latency afferent inhibition (SAI) is reduced in cholinergic forms of dementia, such as Alzheimer disease (AD) and dementia with Lewy bodies, while it is normal in non-cholinergic forms of dementia, such as frontotemporal dementia. This finding suggests that this method can be used as a non-invasive additional tool for discriminating between cholinergic and non-cholinergic forms of dementia. Interestingly, SAI was also found to be significantly smaller in early AD patients. Identification of SAI abnormalities that occur early in the course of AD will allow earlier diagnosis and treatment with cholinergic drugs. In patients with vascular dementia, SAI responses varied widely; the number of patients with abnormal SAI conceivably reflects the percentage of subjects with a significant cholinergic dysfunction. It has recently been demonstrated that brain microbleeds have an impact on SAI that is independent of the extent of associated white matter changes and ischemic stroke. Since SAI can be increased by acetylcholinesterase inhibitors, TMS may help in identifying the patients who would be suitable for long-term treatment with cholinergic agents.     

Changes of electroencephalographic findings in a case of migraine with various neurological symptoms

We report here an 1-year-old boy who was diagnosed as sporadic hemiplegic migraine demonstrated transient changes in electroencephalographic (EEG) background activity accompanied with migraine attacks. The attacks were associated with various neurological complications such as impairment of consciousness and hemiplegia and so on, which coincided with the changes of EEG findings. When his first headache developed with fever and impairment of consciousness, diffuse slow waves (1-2 Hz, 250-300 microV) appeared transiently. The slow wave gradually improved thereafter, and disappeared on the 24th day. On the 25th day, when he had the second attack with left hemiplegia and impairment of consciousness and sensation, slow waves, (2-3 Hz, 250-300 microV) appeared on right side of the brain. Constriction of the right middle cerebral artery was found on MR angiography at that time. The EEG change had improved to normal background activity 3 days after the episode. This unique case demonstrated that transient EEG changes seem to be correlated with the existence of unconsciousness and the laterality of the ischemic insult. We may assume that the changes of electroencephalographic findings may represent the cortical dysfunction caused by vascular constriction.     

Peripheral neuropathy in the hypereosinophilic syndrome: a case report

We observed a patient with the hypereosinophilic syndrome that showed as a prominent clinical feature peripheral nerve dysfunction. The neuropathy evolved over 4 months and affected sensory and motor functions. Nerve conduction studies and EMG were compatible with axonal neuropathy. Nerve and muscle biopsies revealed severe axonal degeneration with neurogenic atrophy of muscle. Morphometry of peroneal nerve showed marked axonal loss, more prominent in large myelinated fibers. There was no evidence of vasculitis process. Neuropathy is produced by eosinophil-released substances exerting a neurotoxic effect through direct altered vascular endothelial permeability and local mast cell histamine release.     

Abnormal corticomuscular coherence is associated with the small amplitude cortical myoclonus in Parkinson's disease.

Coherence is the degree of time-locked correlation between two signals as a function of frequency. The purpose of this study was to test the following hypotheses: (1) corticomuscular coherence is abnormally increased in those Parkinson's disease (PD) patients with small amplitude cortical myoclonus, and (2) corticomuscular coherence peaks around the time of the myoclonus electromyographic (EMG) discharge. We studied Parkinson's disease patients with and without myoclonus and controls. The data were digitally collected and processed off-line with EMG rectification, creation of 511-msec epochs, Fast-Fourier transform, and coherence analysis. In the 12 to 30 Hz frequency band, but not at 30 to 60 Hz or above, coherence peaks were observed in the PD subjects with myoclonus that were significantly greater than in the control subjects (P < 0.001) and in PD subjects without myoclonus (P < 0.001). The abnormal coherence values are evidence for abnormal rhythmic activity in cortical motor areas in those Parkinson's disease patients with myoclonus. In combination with previous findings on back-averaging, our results show that this myoclonus occurs when neuronal populations are driven to an extreme amount of synchronous activity with higher corticomuscular coherence values. These results have mechanistic implications for cortical dysfunction in Parkinson's disease and for cortical myoclonus in general.     

Changes in activity of motor units preceding a rapid voluntary movement

Motor unit activity was studied during slightly sustained contraction of the erector spinal muscle before a rapid trunk extension from a moderately bent position, with special reference to a change of the surface EMG to a rhythmic slower wave with a periodicity of 20-30 msec preceding the movement. Synchronous discharge of a few motor units appeared at regular intervals of 20-30 msec during the slower wave. EMG peaks in the slower wave corresponded to synchronous discharges at the regular intervals.     

Arterial elasticity,endothelial function and intracranial vascular health: A multimodal MRI study

Vascular dysfunctions, including arterial stiffness and endothelial dysfunction, are prevalent in hypertensive subjects. We aimed to study their relations to subclinical intracranial vascular health in this study. A total of 200 older hypertensive males without overt cardiovascular or cerebrovascular diseases were recruited. Arterial elasticity was measured as carotid-femoral pulse wave velocity (cfPWV) and endothelial function was measured as digital reactive hyperemia index (RHI). Cerebrovascular health was evaluated using MRI in four aspects: intracranial atherosclerosis, brain perfusion as cerebral blood flow (CBF), vascular rarefaction analyzed as visible arterial branches on angiography using a custom-developed analysis technique and small vessel disease measured as white matter hyperintensity (WMH). There was a significant negative association between cfPWV and CBF, suggesting a link between arterial stiffness and CBF decline. Higher cfPWV was also associated with presence of intracranial stenotic plaque and greater WMH volume. RHI was positively related to CBF, indicating that endothelial dysfunction was associated with reduced CBF. All the associations remained significant after adjustment for confounding variables. Arterial stiffness and endothelial dysfunction are associated with reduced brain perfusion in older hypertensive males. Arterial stiffness is also associated with global cerebral vascular injury, affecting both small and medium-to-large arteries.     

Quantitative analysis of reflex responses in the averaged surface electromyogram.

The relationship between the averaged surface electromyogram (EMG) and the activity of motoneurones in reflex studies is analysed mathematically. This analysis reveals that, subject to certain conditions being met, the integral of the average of the unrectified EMG is linearly related to the activity of motor units in the muscle. This was tested with experimental data. The activity of 2 motor units, and the surface EMG, were recorded directly in a reflex paradigm. A close match was found between the integral of the average of the unrectified EMG and the summed peristimulus time histograms (PSTHs) of the units' activity. This analysis gives more quantitative measurements of the timing of motoneuronal activity in reflexes than the conventional analysis of the EMG. It also offers the potential for making quantitative measurements of changes in motor unit activity evoked by different stimuli. This analysis avoids the pitfall of the artefactual peaks that can occur in the average of the rectified EMG as a consequence of the full-wave rectification. It is concluded that the integral of the unrectified average offers a valuable adjunct to the conventional analysis in many reflex studies. The analysis can also be applied to quantitative studies of neurograms.     

Axotomy-like changes in cat motoneuron electrical properties elicited by botulinum toxin depend on the complete elimination of neuromuscular transmission.

The electrical properties of cat medial gastrocnemius (MG) spinal motoneurons were studied 14-21 d following injection of type A botulinum toxin (BTX) into the MG muscle. Treated MG muscles were atrophic, displayed pronounced fibrillation activity, and were markedly but not completely paralyzed. MG motoneuron electrical properties from animals with the highest MG muscle-twitch forces (greater than 20 gm) appeared normal, while motoneuron properties from animals with the lowest MG muscle-twitch forces (less than 10 gm) exhibited axotomy-like changes, though these changes were less pronounced than after axotomy itself. No changes in the axonal conduction velocity were observed, however. Motoneuron connectivity with MG muscle fibers was determined following intracellular stimulation of MG motoneurons by averaging EMG signals from 3 or 4 pairs of recording electrodes inserted into the BTX-treated MG muscles. Normal electrical properties were observed among motoneurons in which detectable EMG activity linked to the intracellular stimulation pulse was observed. The level of this connectivity, however, indicated that a relatively small number of muscle fibers were activated by individual motoneuron action potentials. Axotomy-like changes of electrical properties were observed in MG motoneurons that could not be associated with detectable EMG activity in the BTX-treated MG muscle following repeated trials of intracellular stimulation. These results indicate that the existence of effective neuromuscular transmission at a small number of motor terminals is sufficient to prevent the appearance of axotomy-like changes in motoneuron electrical properties, and that the absence of such transmission at all motor terminals is associated with the appearance of axotomy-like changes. The results suggest that the effects of axotomy itself on motoneuron properties may be based upon the loss or elimination of a potent interaction between muscle and motoneurons normally mediated by neuromuscular transmission.