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The Effect of APOE ε4 Allele on Dynamic Local Spontaneous Brain Activity and Functional Integration in Alzheimer's Disease.

The apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for sporadic Alzheimer's disease (AD), yet its mechanisms in AD pathology and cognitive decline remain unclear. Using a sliding-time window approach to directly quantify the instantaneous fluctuations of various local metrics based on continuous time series and calculate voxel-wise concordance of these metrics, we explored the impact of APOE ε4 on dynamic local brain activity and functional integration in AD, and its interrelations with plasma biomarkers and cognition. Results showed that APOE ε4 widely affected dALFF, dReHo, dGSCorr, and voxel-wise concordance. For AD patients, APOE ε4 carriers uniquely exhibited correlations between dALFF in the right angular gyrus/supramarginal gyrus and MoCA scores and orientation function, and between voxel-wise concordance in the right caudate nucleus (CAU) and general cognition, attention, language function, orientation function, plasma Aβ42. Critically, APOE ε4-related altered voxel-wise concordance in the right CAU mediated the relationship between plasma Aβ and language cognition in AD. Moreover, the combined model incorporating dynamic metrics, plasma AD biomarkers, and demographic data effectively distinguished AD from NC (AUC = 0.94, sensitivity = 87.69%, specificity = 86.84%). In conclusion, the APOE ε4 allele might play a pivotal role in modulating brain dynamic functional activities in AD, which may contribute to the association between Aβ pathology and cognitive decline. Our findings may provide imaging markers and targets for the diagnosis and treatment of AD.

Humans

Painful neuropathy: altered central processing maintained dynamically by peripheral input.

We performed sensory assessments before and during diagnostic tourniquet-cuff and local anesthetic blocks in 4 patients diagnosed with reflex sympathetic dystrophy (RSD). All patients complained of mechano-allodynia; lightly touching the skin evoked an intense pain sensation. At detection levels, electrical stimuli were perceived as painful, suggesting that the mechano-allodynia was mediated by A beta low-threshold mechanoreceptor afferents. A beta-mediated allodynia was further supported by reaction time latencies to painful electrical stimuli at threshold for A-fiber activation and, in 1 patient, by differential cuff blocks which abolished A beta function and allodynia while thermal sensation (warm and cold) were preserved. Local anesthetic block of painful foci associated with previous trauma abolished mechano-allodynia, cold allodynia, and spontaneous pain in all patients and relieved the motor symptoms in 1 patient with tonic contractures of the toes. Tactile and thermal perception in the previously allodynic area was preserved. When the local anesthetic block waned, spontaneous pain, allodynia, and motor symptoms returned. We propose a model of neuropathic pain in which ongoing nociceptive afferent input from a peripheral focus dynamically maintains altered central processing that accounts for allodynia, spontaneous pain, and other sensory and motor abnormalities. Blocking the peripheral input causes the central processing to revert to normal, abolishing the symptoms for the duration of the block. The model accounts for sympathetically maintained (SMP) and sympathetically independent (SIP) pain. The peripheral input can be independent of sympathetic activity or driven completely or in part by activity in sympathetic efferents or by circulating catecholamines. The shared final common pathway may explain the common features of SMP and SIP.

Adult

Afferent sympathetic unmyelinated fibres with left ventricular endings in cats.

1. We recorded the electrical impulse activity of thirty-three single afferent fibres with left ventricular endings from the third and fourth left thoracic sympathetic rami communicantes of anaesthetized cats. Their conduction velocity ranged from 0.23 to 0.98 m/sec (group C). 2. The endings of each fibre were localized to the left ventricle by mechanical probing performed at the end of the experiment on the non-beating heart. No fibre had multiple sensory fields. 3. The impulse activity (0.95 +/- 0.2 impulses/sec) was spontaneous but most often a fixed temporal correlation between impulses and ventricular dynamics was not detectable. It was increased during occlusion of the thoracic aorta, I.V. administration of isoprenaline or infusion of saline. It was unaffected by asphyxia, haemorrhage and I.V. administration of acetylcholine. It was decreased during occlusion of inferior vena cava. Therefore these ventricular receptors appeared to be mainly sensitive to mechanical events. 4. The fibres were excited during the occlusion of the left main coronary artery, after a latency of 14.5 +/- 1.3 sec. They were also excited during ventricular fibrillation, exhibiting the highest values of impulse activity (2.51 +/- 0.4 impulses/sec). The increase in impulse activity during ventricular fibrillation was sometimes immediate and extreme, with peak frequencies of about 50 impulses/sec. 5. These spontaneously active ventricular receptors with unmyelinated nerve fibres participate in the transmission of the continuous impulse activity which from the cardiovascular system reaches the spinal cord through the sympathetic nerves and which is likely to contribute to the neural control of circulation. Thus the unmyelinated cardiac sympathetic afferents should not be considered as purely nociceptive in function.

Action Potentials

Role of the myogenic mechanism in the genesis of microvascular oscillations (vasomotion): analysis with a mathematical model.

The possibility that spontaneous oscillations in microvessel caliber, called vasomotion, arise from the activity of the local myogenic mechanism is analyzed in this work using an original mathematical model. According to experimental results, the model assumes that the myogenic response in microcirculation (transverse arterioles and terminal precapillary-postcapillary microvessels) is characterized by both a static and a dynamic (i.e., rate-dependent) component. Computer simulations demonstrate that the myogenic mechanism of action, thanks to its strong rate-dependent component in terminal arterioles, can produce vascular instability and oscillations of vessel caliber without the need to assume the existence of a local pacemaker in smooth muscle cells. Moreover, these oscillations turn out similar, both in frequency and in shape, to those experimentally observed in microvascular networks. Finally, according to experimental data, several kinds of vasodilatory stimuli (such as arterial hypotension, increase in the tissue metabolic rate, and postischemic reactive hyperemia) cause stoppage of vasomotion and stabilization of vessel caliber.

Animals

Nature of motions between sarcomeres in asynchronously contracting cardiac muscle cells.

We observed the asynchronized motions that occur between the sarcomeres during spontaneous contractions to study the mechanical nature of the intact cardiac muscle cell (guinea pig, rat). The cell's striated image is detected by a photodiode array, and sarcomere length is measured very precisely 526/s in two separate, selected fixed regions of the image from the localized frequency of the array's video signal (Krueger and Denton, 1992, Biophys. J., 61:129-144, second of two companion manuscripts). An extension of this approach is described here in which the spatial variation of sarcomere length is visualized by scanned sampling, i.e., displacing the first window along the length of the cell, and nonuniform strain is deduced from the histograms of sarcomere length. The nature of asynchronous motion that was obtained from both fixed sampling of the sarcomere's dynamics and by scanned sampling of sarcomere length was consistent. In spontaneously active cells, sarcomeres lengthen approximately 0.1 micron beyond their rest length before the arrival of the propagated wave of contraction. Such prelengthening extends in a nonuniform fashion for approximately 10 to 15 microns in the unattached cell. Shortening and lengthening motions, being in proportion for both large and small displacements, are well coupled. Lifting the cell from the substrate showed that the force that sustains prelengthening arises within the cell. Differences in the sarcomere's dynamics in synchronous and asynchronous contractions corroborate that asynchrony imposes an additional internal restoring force. The extra force estimated to account for prelengthening (0.5-0.7 mN/mm2) has little effect on the velocity of shortening, and so the true intracellular restoring force must be correspondingly larger. The intracellular restoring force may contribute significantly to the rapid 'diastolic' recoil of the heart muscle at short sarcomere lengths.

Animals

A mathematical analysis of vasomotion in the peripheral vascular bed.

Arterioles and microvascular venules often show rhythmic spontaneous changes in diameter, called vasomotion. In this study, we analyze the possibility that vasomotion originates from the activity of the local myogenic mechanism. This analysis uses an original mathematical model of the peripheral circulation. The peripheral vascular bed has been represented as a series of three consecutive segments, each characterized by its value of vascular resistance per unit weight of tissue. The internal radius of the vessels in the last two segments, and hence their hydraulic resistance, has been assumed to be affected by the local myogenic response of the vascular smooth muscle. This dependence has been reproduced using the Laplace law. Both the static and dynamic (i.e. rate-dependent) components of the myogenic response have been included in the model, in accordance with recent experimental results. Simulations demonstrate that rhythmic, self-sustained oscillations can develop when the dynamic component of the myogenic response of terminal arterioles is much greater than that of more proximal microvessels. A moderate increase in arterial pressure favors the occurrence of oscillations, whereas vasodilatory stimuli tend to suppress vasomotion and contribute to the stabilization of vascular diameters.

Animals

[Responses of the units of the nerve of the frog semicircular canal to caloric stimuli of changing amplitude].

In curarized frogs, responses of isolated neural units of the lateral semicircular canal (LSC) to short local caloric stimuli of different amplitudes (0.5--12.0 degrees C over the canal temperature) inducing excitatory current of endolymph in the LSC, were studied. Estimation of maximal (peak) frequences (PF) in the responses showed the PFs in responses of 52% units (group A) to be either linearly or semilogarithmically related to peak temperature (PT). In 22% units (group B), PFs revealed saturation at PT8--12 degrees C. In 25% units (group C) PFs were related to PT first in direct and then--along with increase of PT--in reverse proportion. Duration of the group A responses is linearly for semilogarithmically related to PT. This was not observed in groups B and C. Two cases of correlation between spontaneous activity and dynamic characteristics of units from groups A and C were found. The results are in agreement with the literature references concerning data obtained in frogs using angular acceleration and stop-stimuli. The controlled caloric stimulus was concluded to be convenient for studying the dynamic characteristics of the semicircular canals afferents.

Acceleration

[Immune reactions in assessing the disease prognosis in soft tissue sarcomas].

Under examination were 60 patients with local forms of soft tissue sarcomas of various histological structure. By means of skin delayed hypersensitivity test for dinitrochlorobenzene (DNCB) and tuberculin as well as cell immunity reaction in vitro the immune response was shown to be of value in estimating the prognosis of the disease. The dynamics of immune reactions 2-3 months following the operation proved to be of greatest prognostic value. Among the employed immunological tests the skin test for DNCB and the reaction of spontaneous rosette-forming provided the most comprehensive information as to the control over the clinical course of malignant lesion.

Adolescent

Spontaneous alternation of the working arm in one-arm cranking.

One-arm cranking was done by ten healthy male adults at an oxygen intake level of about 1.0 liter/min. Each subject performed two kinds of cranking at a speed of 60 rpm: forced cranking using only one arm continuously for 15 min and free cranking for 30 min with the instructions to alternate from one arm to the other whenever fatigue set in. The results, excluding those of a subject who changed arms very frequently, were analyzed. In forced cranking, oxygen intake and heart rate steadily increased, the average time of appearance of local fatigue being 161 sec for the stronger arm and 122 sec for the weaker one. In free cranking, the working arm was changed 6 to 23 times during the 30-minute period, while oxygen intake and heart rate increased with fluctuations. The mean duration interval was 175 sec with the stronger arm and 123 sec with the weaker one. The mean interval of arm alternation was positively correlated with the individual time of onset of the sensation of local rigidness during forced cranking, but not with the individual time of initiation of respiratory distress. It is suggested that alternation of active muscles in moderately dynamic work may be linked with an early stage of local fatigue which is different from that of static work.

Adult

Intracellular crystal-bearing vesicles in the epidermis of scleractinian corals, Astrangia danae (Agassiz) and Porites porites (Pallas).

Orthorhombic aragonitic crystals, embedded with a granular lipo-protein matrix and surrounded by a trilaminar membrane, are localized in the apical cytoplasm of epidermal cells of Scleractinian corals. Adult specimens of Astrangia danae (Agassiz) and settled planulae of Porites porites (Pallas) contain crystals averaging 0.7 mu by 0.1 mu by 0.3 mu within Golgi-derived vesicles. Short-term labelling with 45Ca reveals distribution of radioactivity amont a basic tissue fraction (92%) an acid tissue fraction (5%) and a skeletal fraction (3%). Identification of the primordial crystal population within membrane-bound visicles provides overwhelming evidence for the intracellular mode of calcification in Scleractinia. Moreover, it permits development of a novel concept of cellular regulation over these dynamic events. The membrane-bound vesicel is a miniature crystal fabrication station and a vehicle responsible for transportation of seed crystals and an organic matrix material to sites of discharge from the cell. The vesicle membrane becomes a probable locus of active transport and enzymatic activity as well as a physical barrier to be penetrated for release of vesicle contents into the extracellular milieu. Contact between the vesicle membrane and the plasmalemma would result in exocytosis and the onset of skeletogenesis. Principles governing crystal growth would prevail from then on. The released crystal becomes a nucleation catalyst and the organic matrix, a supply of ionic calcium for self-limiting crystallization. Crystals are produced by the organism spontaneously and continuously from shortly after larval attachment throughout the life of the polyp. Therefore, these membrane-bound vesicles signal the dynamic process by which initiation, differentiation, growth and limitation of the coral skeleton is regulated.

Animals

Sustained and transient discharges of retinal ganglion cells during spontaneous eye movements of cat.

Discharges of 223 retinal ganglion cells during spontaneous eye movements (saccades) across a stationary grating pattern were studied in chronically prepared cats. Of these 83 showed sustained responses to local differences in luminance of the grating stripes (S-units); 84 showed transient responses to saccades and did not register local differences in luminance (T-units); and 56 showed mixed responses, i.e., transient responses to saccades and sustained firings in response to local luminance (M-units). When tested with diffuse light, 93.9% of the S-units showed either ON-sustained or OFF-sustained responses; 95.2% of the T-units showed either ON-transient, OFF-transient, or ON-OFF-transient responses; and 50% of the M-units showed ON-OFF responses. In the overall responses properties, most S-units corresponded to the X-cells, most T-units to the Y-cells of retinal ganglion cells previously known from acute experiments. Under normal conditions of active eye movements, the major function of the S-units would be to register the differences in luminance in their receptive fields, and subserve the mechansim of form recognition. The major function of the T-units would be to register information related to quick image motion, induced either by eye or object movements, and subserve the mechanism of detecting the dynamic aspects of visual stimuli. The other important functions of the T-units are their possible participation in the afferent routes for two recently proposed mechanisms; one for goal-directed saccades and the other for saccadic suppression. The M-units would possess the functions of both S- and T-units.

Animals

[The comparison of human reflex and instinct behaviour (author's transl)].

On the basis of characteristics of the exteroceptive reflexes and of the instincts it was shown that instinct behaviour developed from reflex characteristics (local characteristic of the stimuli, pos. and neg. taxis, habituation, conditioning). Most similarities are found between reflex and avoidance instinct behaviour (instincts for excretion, thermoregulation, body care, pain avoidance and safety). Except the safety instinct, all others react on stimuli, characterised by the localisation of the receptors. In the safety instinct the structure of the stimulus becomes important, together with the growing importance of the third dimension. This instinct shows also for the first time a variability of the threshold with spontaneous remaining low for some time after stimulation of the system. Inverse the gain instincts (nutrition, sex and social instinct). Here the threshold falls spontaneously, when stimuli are lacking and raises, when stimuli are found. The spontaneous motor expression of the lowering of the threshold is the appetite behaviour. It means seeking stimuli, which will be gained by elements of the initial and terminal success behaviour. The successfull nutritional and sexual behaviour is stopped by success inhibition, whereas the social instinct remains in the terminal success behaviour with group dynamic hierarchy, with imitating and helping behaviour. Overchanging of the gain instincts provokes avoidance behaviour with constant threshold. The neural systems of most reflexes lie distributed in the spinal cord and brainstem, the ones of the instincts in the limbic part of the brain, the nutrition and sex instinct with a hypothalamic pacemaker. Simultaneous activation of two or many instinct motivation systems result, not comparable with the direct reflex interaction, in interactions on the level of the global interaction, in interactions on the level of the global integration (summation, mixture, synthesis, rest, oscillation, intention) which projects the activity patterns via the motor cortex to the peripheral neurons. There it is completed by the reflexes. The hormonal and vegetative projection instead go directly to the end organs. The motivation is responsible for the subjective experience, the dominating integration with its motor projection for the instinct behaviour.

Behavior

Parallel processing of tactile information in the cerebral cortex of the cat: effect of reversible inactivation of SI on responsiveness of SII neurons.

1. Localized cortical cooling was employed in anesthetized cats for the rapid reversible inactivation of the distal forelimb region within the primary somatosensory cortex (SI). The aim was to examine the responsiveness of individual neurons in the second somatosensory area (SII) in association with SI inactivation to evaluate the relative importance for tactile processing of the direct thalamocortical projection to SII and the indirect projection from the thalamus to SII via an intracortical path through SI. 2. Response features were examined quantitatively before, during, and after SI inactivation for 29 SII neurons, the tactile receptive fields of which were on the glabrous or hairy skin of the distal forelimb. Controlled mechanical stimuli that consisted of l-s trains of either sinusoidal vibration or rectangular pulses were delivered to the skin by means of small circular probes (4- to 8-mm diam). 3. Twenty-three of the 29 SII neurons (80%) showed no change in response level (in impulses per second) as a result of SI inactivation. These included seven neurons activated exclusively or predominantly by Pacinian corpuscle (PC) receptors, six that received hair follicle input, four activated by convergent input from hairy and glabrous skin, and six driven by dynamically sensitive but non-PC inputs from the glabrous skin. 4. Six SII neurons (20%), also made up of different functional classes, displayed a reduction in response to cutaneous stimuli when SI was inactivated. 5. Stimulus-response relations, constructed by plotting response level in impulses per second against the amplitude of the mechanical stimulus, showed that the effect of SI inactivation on individual neurons was consistent over the whole response range. 6. The reduced response level seen in 20% of SII neurons in association with SI inactivation cannot be attributed to direct spread of cooling from SI to the forelimb area of SII, as there was no evidence for a cooling-induced prolongation in SII spike waveforms, an effect that is known to precede any cooling-induced reduction in responsiveness. 7. As SI inactivation produced a fall in spontaneous activity in the affected SII neurons, we suggest that the inactivation removes a source of background facilitatory influence that arises in SI and affects a small proportion of SII neurons. 8. Phase-locking and therefore the precision of impulse patterning were unchanged in the responses of SII neurons to vibration during SI inactivation. This was the case whether response levels of neurons were reduced or unchanged by SI inactivation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals