Progressive Reduction In Amplitude Research Articles

Skin innervation across amyotrophic lateral sclerosis clinical stages: new prognostic biomarkers.

Over recent decades, peripheral sensory abnormalities, including the evidence of cutaneous denervation, have been reported among the non-motor manifestations in amyotrophic lateral sclerosis (ALS). However, a correlation between cutaneous innervation and clinical features has not been found. The aims of this study were to assess sensory involvement by applying a morpho-functional approach to a large population of ALS patients stratified according to King's stages and correlate these findings with the severity and prognosis of the disease. We recruited 149 ALS patients and 41 healthy controls. Patients undertook clinical questionnaires for small fibre neuropathy symptoms (Small Fiber Neuropathy Symptoms Inventory Questionnaire) and underwent nerve conductions studies (NCS) and 3-mm punch skin biopsies from leg, thigh and fingertip. We assessed intraepidermal nerve fibre (IENF) and Meissner corpuscle (MC) density by applying an indirect immunofluorescence technique. Moreover, a subset of 65 ALS patients underwent a longitudinal study with repeat biopsies from the thigh at 6- and 12-month follow-ups. Serum NfL levels were measured in 40 patients. Sensory symptoms and sensory NCS abnormalities were present in 32.2% and 24% of patients, respectively, and increased across clinical stages. Analogously, we observed a progressive reduction in amplitude of the sensory and motor ulnar nerve potential from stage 1 to stage 4. Skin biopsy showed a significant loss of IENFs and MCs in ALS compared with healthy controls (all P < 0.001). Across the clinical stages, we found a progressive reduction in MCs (P = 0.004) and an increase in IENFs (all P < 0.027). The increase in IENFs was confirmed by the longitudinal study. Interestingly, the MC density inversely correlated with NfL level (r = -0.424, P = 0.012), and survival analysis revealed that low MC density, higher NfL levels and increasing IENF density over time were associated with a poorer prognosis (all P < 0.024). To summarize, in patients with ALS, peripheral sensory involvement worsens in parallel with motor disability. Furthermore, the correlation between skin innervation and disease activity may suggest the use of skin innervation as a putative prognostic biomarker.

Hand Dexterity and Pyramidal Dysfunction in Friedreich Ataxia, A Finger Tapping Study.

Loss of hand dexterity has a profound impact on disability in patients with cerebellar, pyramidal, or extrapyramidal diseases. Analysis of multiple finger tapping (FT) parameters can contribute to identify the underlying physiopathology, while providing a quantitative clinical assessment tool, particularly in patients not reliably evaluated using clinical rating scales. Here, we used an automated method of FT analysis in Friedreich ataxia (FRDA) to disentangle cerebellar (prominent FT rate variability), extrapyramidal (FT progressive amplitude reduction without slowing of tapping rate), and pyramidal (progressive decrease of FT rate and amplitude) contribution to upper limb loss of dexterity. FT parameters were then related to FRDA clinical parameters and upper limbs motor evoked potential (MEPs). Twenty-four FRDA patients and matched healthy subjects performed FT with the dominant hand for 90 seconds. FT rate, FT rate variability, FT amplitude, and linear regressions of FT movement parameters were automatically computed. Eleven patients underwent MEPs, measured at the first dorsal interosseous of the dominant hand to determine central motor conduction time (CMCT). FRDA patients had slower and more regular FT rate than controls. Eleven FRDA patients showed FT rate slowing. Those patients had longer disease duration and higher Scale for the Assessment and Rating of Ataxia (SARA) scores. Seven patients with FT rate slowing had MEP and all displayed prolonged CMCT, whereas the 4 other patients with constant FT rate had normal CMCT. This study provides evidence for a prominent involvement of pyramidal dysfunction in upper limb dexterity loss as well as a potential outcome measure for clinical studies in FRDA.

Effects of Transcranial Alternating Current Stimulation on Repetitive Finger Movements in Healthy Humans.

Transcranial alternating current stimulation (tACS) is a noninvasive neurophysiological technique that can entrain brain oscillations. Only few studies have investigated the effects of tACS on voluntary movements. We aimed to verify whether tACS, delivered over M1 at beta and gamma frequencies, has any effect on repetitive finger tapping as assessed by means of kinematic analysis. Eighteen healthy subjects were enrolled. Objective measurements of repetitive finger tapping were obtained by using a motion analysis system. M1 excitability was assessed by using single-pulse TMS and measuring the amplitude of motor-evoked potentials (MEPs). Movement kinematic measures and MEPs were collected during beta, gamma, and sham tACS and when the stimulation was off. Beta tACS led to an amplitude decrement (i.e., progressive reduction in amplitude) across the first ten movements of the motor sequence while gamma tACS had the opposite effect. The results did not reveal any significant effect of tACS on other movement parameters, nor any changes in MEPs. These findings demonstrate that tACS modulates finger tapping in a frequency-dependent manner with no concurrent changes in corticospinal excitability. The results suggest that cortical beta and gamma oscillations are involved in the motor control of repetitive finger movements.

The bicentenary of James Parkinson's “An Essay on the Shaking Palsy”

James Parkinson was already age 62 and in the autumn of his career as a surgeon–apothecary when “An Essay on the Shaking Palsy” appeared in 1817. His assertion that what he had described was a distinct “medical species” (now referred to as a “syndrome”) was accepted and, thanks to Charcot, Parkinson's name has become famous throughout the medical world, even though few practising physicians know anything about his life. Parkinson himself realized the limitations of his findings and couched them in modesty, which has long since disappeared from medical writings. The “shaking palsy” had escaped the attention of medical nosologists up to that time, and he hoped that his monograph would stimulate anatomists to locate the site of damage in the nervous system by post-mortem examination. After its publication, Parkinson's monograph was accepted by the medical establishment without criticism and also received favorable reviews in the press. It was almost as if he had described something that was already recognized, but which no one had made an effort to describe clearly in writing. Charcot recommended the paper to his students, telling them it would provide them with the satisfaction and knowledge that one always gleans from a direct clinical description made by an honest and careful observer. Nevertheless, he considered the account incomplete while emphasizing the fact that, in some patients, tremor may be miniscule and that rigidity played a significant part in the motor handicap. Most of Charcot's original observations can be found in the records of his Lecons du mardi a la Salpetriere made between 1868–1888. The most important embellishment to Parkinson's description, however, came from Armand Trousseau in his “Lectures on Clinical Medicine” delivered at Hotel-Dieu Hospital in 1868. His description of the particular nature of the movement disorder anticipated our modern understanding of bradykinesia, and postulated a lack of cerebral vigor as an important factor in the progressive reduction of amplitude and speed in the performance of sequential motor tasks. It took another hundred years before Konstantin Tretiakoff produced evidence to indicate that loss of nerve cells in the substantia nigra was the most consistent pathological signature. In contrast to Parkinson's clinical findings, which had been rapidly and widely accepted by the medical profession, it took another 50 years before it was generally agreed that the pars compacta was the area that was responsible for the slowness and stiffness in Parkinson's disease. Careful reading of “An Essay of the Shaking Palsy” clearly indicates that Parkinson considered a particular form of weakness to be an integral part of the disease. He also described, but with less emphasis, symptoms such as drooling of saliva and constipation, and considered that rheumatic pain could precede and even cause the malady. Nosography reflects the history of medicine, and what has emerged over the last two centuries is a parkinsonian hybrid informed by clinical methods and patients’ accounts combined with basic and applied science. Technological advances have also played an important part in both Tretiakoff's findings and the “dopamine miracle”; two advances that if Parkinson were alive today would be what he would be most excited about. As our notions of neurological disease continue to extend beyond the traditional clinicopathological paradigm to embrace a more dynamic consideration of pathological events and chemical processes, neurologists may be forced more and more to fall back on the classic clinical methods in which scrupulous observations and descriptions are combined with modern techniques of longitudinal neuroimaging and laboratory biomarkers. Starting from scratch with an open mind may also open up new vistas of understanding and finally lead to the cure that Parkinson hoped his essay would pave the way towards.

A long-term self-managed handwriting intervention for people with Parkinson’s disease: results from the control group of a phase II randomized controlled trial

Objective: To report on the control group of a trial primarily designed to investigate exercise for improving mobility in people with Parkinson’s disease (pwP). The control group undertook a handwriting intervention to control for attention and time spent practising a specific activity. Design: Secondary analysis of a two-arm parallel phase II randomized controlled trial with blind assessment. Setting: Community. Participants: PwP able to walk ⩾100 m and with no contraindication to exercise were recruited from the Thames Valley, UK, and randomized (1:1) to exercise or handwriting, via a concealed computer-generated list. Intervention: Handwriting was undertaken at home and exercise in community facilities; both were delivered through workbooks with monthly support visits and involved practice for 1 hour, twice weekly, over a period of six months. Main measures: Handwriting was assessed, at baseline, 3, 6 and 12 months, using a pangram giving writing speed, amplitude (area) and progressive reduction in amplitude (ratio). The Movement Disorder Society (MDS)–Unified Parkinson’s Disease Rating Scale (UPDRS) item 2.7 measured self-reported handwriting deficits. Results: In all, 105 pwP were recruited (analysed: n = 51 handwriting, n = 54 exercise). A total of 40 pwP adhered to the handwriting programme, most completing ⩾1 session/week. Moderate effects were found for amplitude (total area: d = 0.32; 95% confidence interval (CI): −0.11 to 0.7; P = 0.13) in favour of handwriting over a period of12 months; effects for writing speed and ratio parameters were small ≤0.11. Self-reported handwriting difficulties also favoured handwriting (UPDRS 2.7: odds ratio (OR) = 0.55; 95% CI: 0.34 to 0.91; P = 0.02). No adverse effects were reported. Conclusion: PwP generally adhere to self-directed home handwriting which may provide benefit with minimal risk. Encouraging effects were found in writing amplitude and, moreover, perceived ability.

18. Simultaneous recording of motor related cortical potentials to different basal components of voluntary movements during a sustained fatigue task

Our aim was to study the effects of a sustained fatigue task on Motor Related Cortical Potentials (MRCPs) to basic components of voluntary movements. In 10 normal volunteers MRCPs to Ballistic, Extension movements and Relaxation of the right index finger, according to the method described in the companion paper (Troni et al.,1966) were recorded during a sustained (80 min) fatigue task. The task consisted in continuous finger extension to maintain a fixed position at half of maximal range of motion (basal position) while supporting a load (30–50 g) hanging on distal phalanx. The sequence of the 3 motor tasks was superimposed to the fatigue task. Fatigue was monitored using a 10 points Visual Analogic Scale (VAS). A significant increase in amplitude of all post-movement components was observed in Bt- and Ex-MRCPs, associated with a substantial stability of pre-movement components (early- and late-BP) throughout the experimental session. A similar trend was initially observed for Re-MRCP, later followed by a progressive reduction in amplitude of both late-BP and post-movement components. The post-movement changes of Bt- and Ex-MRCP can hardly be attributed to fatigue because of early occurrence and temporal stability. The late and progressive deterioration of Re-MRCP strongly indicates a fatigue effect.

The Effect of L-Dopa/Carbidopa Intestinal Gel in Parkinson Disease Assessed Using Neurophysiologic Techniques.

By providing a stable and smooth L-dopa plasmatic level, L-dopa/carbidopa intestinal gel reproduces the physiological continuous dopaminergic receptor stimulation in patients with Parkinson disease (PD), and it therefore represents a suitable tool to investigate the role of the altered dopaminergic neurotransmission in the pathophysiology of motor and sensory abnormalities in this condition. We studied 11 patients with advanced PD being treated with L-Dopa/carbidopa intestinal gel (LCIG) and 11 age-matched healthy subjects. Bradykinesia was measured by kinematic recording of repetitive finger movements (finger tapping), whereas sensory abnormalities were evaluated using the somatosensory tactile discrimination threshold. All the patients were studied off and on medication, in 2 different experimental sessions. Parkinson disease patients were very slow and hypokinetic during finger tapping, with no progressive reduction in amplitude or speed being observed during movement repetition. Somatosensory temporal discrimination threshold values were higher in PD patients than in healthy subjects. The neurophysiologic assessment of the effects of LCIG in advanced PD patients demonstrates an improvement, although not normalization, of motor and sensory abnormalities. The study provides an objective evaluation of the effects of LCIG on motor and sensory abnormalities in PD. The results suggest that besides dopaminergic mechanisms motor and sensory abnormalities in PD reflect a varying combination of pathophysiologic mechanisms.

Finger tapping analysis in patients with Parkinson’s disease and atypical parkinsonism

The goal of this study was to investigate repetitive finger tapping patterns in patients with Parkinson’s disease (PD), progressive supranuclear palsy–Richardson syndrome (PSP-R), or multiple system atrophy of parkinsonian type (MSA-P). The finger tapping performance was objectively assessed in PD (n=13), PSP-R (n=15), and MSA-P (n=14) patients and matched healthy controls (HC; n=14), using miniature inertial sensors positioned on the thumb and index finger, providing spatio-temporal kinematic parameters. The main finding was the lack or only minimal progressive reduction in amplitude during the finger tapping in PSP-R patients, similar to HC, but significantly different from the sequence effect (progressive decrement) in both PD and MSA-P patients. The mean negative amplitude slope of −0.12°/cycle revealed less progression of amplitude decrement even in comparison to HC (−0.21°/cycle, p=0.032), and particularly from PD (−0.56°/cycle, p=0.001), and MSA-P patients (−1.48°/cycle, p=0.003). No significant differences were found in the average finger separation amplitudes between PD, PSP-R and MSA-P patients (pmsa-pd=0.726, pmsa-psp=0.363, ppsp-pd=0.726). The lack of clinically significant sequence effect during finger tapping differentiated PSP-R from both PD and MSA-P patients, and might be specific for PSP-R. The finger tapping kinematic parameter of amplitude slope may be a neurophysiological marker able to differentiate particular forms of parkinsonism.

Progression of motor axon dysfunction and ectopic Nav1.8 expression in a mouse model of Charcot-Marie-Tooth disease 1B

Mice heterozygously deficient for the myelin protein P0 gene (P0+/−) develop a slowly progressing neuropathy modeling demyelinating Charcot-Marie-Tooth disease (CMT1B). The aim of the study was to investigate the long-term progression of motor dysfunction in P0+/− mice at 3, 7, 12 and 20months. By comparison with WT littermates, P0+/− showed a decreasing motor performance with age. This was associated with a progressive reduction in amplitude and increase in latency of the plantar compound muscle action potential (CMAP) evoked by stimulation of the tibial nerve at ankle. This progressive functional impairment was in contrast to the mild demyelinating neuropathy of the tibial nerve revealed by histology. “Threshold-tracking” studies showed impaired motor axon excitability in P0+/− from 3months. With time, there was a progressive reduction in threshold deviations during both depolarizing and hyperpolarizing threshold electrotonus associated with increasing resting I/V slope and increasing strength-duration time constant. These depolarizing features in excitability in P0+/− as well as the reduced CMAP amplitude were absent in P0+/− NaV1.8 knockouts, and could be acutely reversed by selective pharmacologic block of NaV1.8 in P0+/−. Mathematical modeling indicated an association of altered passive cable properties with a depolarizing shift in resting membrane potential and increase in the persistent Na+ current in P0+/−. Our data suggest that ectopic NaV1.8 expression precipitates depolarizing conduction failure in CMT1B, and that motor axon dysfunction in demyelinating neuropathy is pharmacologically reversible.

Progressive reduction of visual P300 amplitude in patients with first-episode schizophrenia: an ERP study.

To understand the underlying dynamic neurophysiological changes over the course of schizophrenia, it is important to study subjects longitudinally from the early stage of the illness. We previously reported that visual P300 was already impaired in patients with first-episode schizophrenia (FESZ). This study demonstrates how the visual P300, as well as earlier components P1, N1, and N200, changed at the 1-year follow-up after their initial measurement. Visual ERPs were recorded with the same experimental paradigm and acquisition protocol at both time points in FESZ (n = 18) and healthy comparison subjects (n = 24). Participants silently counted infrequent target stimuli ("x") amid standard stimuli ("y") presented on the screen while the 64-channel electroencephalogram was recorded. FESZ showed smaller visual P300, N200, P1 (trend level) amplitude and delayed P300 and N1 latency at both time points; however, only P300 showed progressive amplitude reduction over the course of the illness at 1-year follow-up. P300 latency did not change over time in either group. FESZ showed significantly reduced Spatial Span total score at both time points, and there was a significant negative correlation between P300 peak amplitude and the Brief Psychiatric Rating Scale positive symptom score at baseline. These data show progressive P300 amplitude reduction in response to visual stimuli in the early stage of schizophrenia. These visual P300 findings support the concept of progression of schizophrenia, suggesting the usefulness of the visual P300 as a biological marker of progression.

Kinematic Analysis in Patients with Parkinson's Disease and SWEDD

The differential diagnosis between mild Parkinson's disease (PD) and Scan Without Evidence of Dopaminergic Deficit(SWEDD) is challenging. Progressive reduction in amplitude and speed of finger tapping (sequence effect) has been considered as the most useful sign for discriminating PD from SWEDD. However, a video analysis reported that sequence effect is a major confounding factor for the misdiagnosis of PD. Our objective was to perform a kinematic analysis of finger tapping to explore parameters for distinguishing between patients with PD and SWEDD. We enrolled 14 patients with PD, 17 patients with SWEDD and 18 age- and sex-matched healthy controls. Amplitude, speed and frequency of finger tapping were measured using gyroscopes, and the means, decrement and variability in kinematic parameters for specific tapping duration were calculated. Compared to SWEDD group, PD group showed more decrement in amplitude and speed of the first 20 taps, more decrement in frequency after 20 taps and more variability in speed of 15 seconds of taps. However, none of parameters was a practically useful indicator distinguishing individual patients with PD from those with SWEDD. Analysis of finger tapping, even using an apparatus, is not useful for distinguishing mild PD and SWEDD.

Hypokinesia without decrement distinguishes progressive supranuclear palsy from Parkinson's disease

Repetitive finger tapping is commonly used to assess bradykinesia in Parkinson's disease. The Queen Square Brain Bank diagnostic criterion of Parkinson's disease defines bradykinesia as 'slowness of initiation with progressive reduction in speed and amplitude of repetitive action'. Although progressive supranuclear palsy is considered an atypical parkinsonian syndrome, it is not known whether patients with progressive supranuclear palsy have criteria-defined bradykinesia. This study objectively assessed repetitive finger tap performance and handwriting in patients with Parkinson's disease (n = 15), progressive supranuclear palsy (n = 9) and healthy age- and gender-matched controls (n = 16). The motion of the hand and digits was recorded in 3D during 15-s repetitive index finger-to-thumb tapping trials. The main finding was hypokinesia without decrement in patients with progressive supranuclear palsy, which differed from the finger tap pattern in Parkinson's disease. Average finger separation amplitude in progressive supranuclear palsy was less than half of that in controls and Parkinson's disease (P < 0.001 in both cases). Change in tap amplitude over consecutive taps was computed by linear regression. The average amplitude slope in progressive supranuclear palsy was nearly zero (0.01°/cycle) indicating a lack of decrement, which differed from the negative slope in patients with Parkinson's disease OFF levodopa (-0.20°/cycle, P = 0.002). 'Hypokinesia', defined as <50% of control group's mean amplitude, combined with 'absence of decrement', defined as mean positive amplitude slope, were identified in 87% of finger tap trials in the progressive supranuclear palsy group and only 12% in the Parkinson's disease OFF levodopa group. In progressive supranuclear palsy, the mean amplitude was not correlated with disease duration or other clinimetric scores. In Parkinson's disease, finger tap pattern was compatible with criteria-defined bradykinesia, characterized by slowness with progressive reduction in amplitude and speed and increased variability in speed throughout the tap trial. In Parkinson's disease, smaller amplitude, slower speed and greater speed variability were all associated with a more severe Unified Parkinson's Disease Rating Scale motor score. Analyses of handwriting showed that micrographia, defined as smaller than 50% of the control group's mean script size, was present in 75% of patients with progressive supranuclear palsy and 15% of patients with Parkinson's disease (P = 0.022). Most scripts performed by patients with progressive supranuclear palsy did not exhibit decrements in script size. In conclusion, patients with progressive supranuclear palsy have a specific finger tap pattern of 'hypokinesia without decrement' and they do not have criteria-defined limb bradykinesia. Similarly, 'micrographia' and 'lack of decrement in script size' are also more common in progressive supranuclear palsy than in Parkinson's disease.

Paraneoplastic retinopathy associated with retroperitoneal liposarcoma

We report a case of paraneoplastic retinopathy associated with a retroperitoneal liposarcoma. A 42-year-old man was referred to our hospital with complaints of night blindness and blurred vision in the peripheral field. Electroretinograms showed a progressive amplitude reduction in his both eyes. Abdominal magnetic resonance imaging showed a large retroperitoneal mass, and pathologic examination revealed a dedifferentiated liposarcoma. Western blot analysis showed an antiretinal antibody in the serum of our patient, and his serum reacted with the photoreceptors of a bovine retina. To the best of our knowledge, this is the first case of paraneoplastic retinopathy associated with a liposarcoma.

Static input-output non-linearity as the source of non-linear effects in maximum length sequence click-evoked OAEs.

The application of the maximum length sequence (MLS) technique to the recording of click-evoked otoacoustic emissions (CEOAEs) allows for a reduction in test time by one to two orders of magnitude. This is because the technique permits the use of extremely high click rates, as inter-click intervals are not constrained to be greater than the duration of the response. However, increasing the click rate also causes a progressive reduction in amplitude, or 'suppression', of the CEOAE. The origin of this suppression is unclear, with diverse suggestions in the literature as to its nature and mechanism. This paper presents a simple model of the well-known compressive non-linearity of the CEOAE level function, based on a static amplitude non-linearity within each of a number of narrowband frequency channels. The response of the model to MLS stimulation demonstrates suppression broadly of the form and magnitude previously reported in experimental studies. Furthermore, the model exhibits the generation of additional non-linear components that have been speculated on in connection with CEOAE recordings using the MLS technique. It is concluded that the MLS suppression phenomenon is derived largely, if not entirely, from the static non-linearity of the CEOAE level function. The approach to modelling the phenomenon as described here also bears promise for understanding various aspects of non-linearity in MLS-based CEOAE recordings.

Effect of acute haemorrhage on QRS amplitude of the lead II canine electrocardiogram.

To examine the effect of acute haemorrhage on the QRS amplitude of the canine lead II surface electrocardiograph (ECG). Ten adult racing Greyhounds were tranquilised, anaesthetised, positioned in right lateral recumbency and connected to recording electrodes of an ECG unit. Baseline six-lead ECG traces were recorded, and further traces were obtained after one unit (460 mL) of blood, and then a second unit, were collected from the femoral artery. There was a consistent and progressive reduction in amplitude of the QRS complex in all leads during acute haemorrhage. QRS amplitude in lead II after removal of two units of blood averaged 74% of the baseline voltage, with individual values of 61 to 91% (P < 0.0001). There were even greater reductions in QRS amplitudes in lead aVL during haemorrhage. In three additional dogs, reductions in QRS voltages were shown to be accompanied by reductions in end-diastolic left ventricular internal dimensions measured echocardiographically. Furthermore, the effects of haemorrhage on the QRS amplitude and echocardiographic measurements were reversed when circulating blood volume was restored by re-infusion of blood removed previously. Acute haemorrhage corresponding to an approximately one-third reduction in blood volume caused a substantial reduction in QRS voltage of the surface ECG. It is postulated that this resulted from diminished ventricular distension as a consequence of reduced venous return. A similar mechanism may account for the small-amplitude ECG complexes associated with pericardial effusion, severe dehydration and hypovolaemia.

Synaptic interactions in a newly identified excitatory synapse of Helix aspersa: concurrent enkephalinergic and GABAergic modulation

Mollusc neurons, including those from Helix aspersa, have been extensely used for studies on synaptic plasticity and for pharmacological experiments. Synaptic interactions in H. aspera are less well documented. In this work, I describe the identification and electrophysiological characteristics of a chemical synapse which is modulated by Met-Enkephalin (ME) and GABA. Low frequency repetitive presynaptic stimulation leads to a progressive amplitude reduction of the EPSPs (homosynaptic depression) of 45% after 20 stimuli and up to 80% after long-lasting repetitive stimulation (150–200 stimuli). The values of the smallest detectable EPSP after profound depression under normal neurotransmitter release levels corresponded to those obtained under high Mg 2+-low Ca 2+ conditions (0.33±0.045mV) and to the spontaneous EPSPs (0.4mV, σ 2=0.02). Recovery after homosynaptic depression could occur by withdrawing the stimulation during 25 s after 15–20 stimuli or 2 min after 150–200 stimuli. Both, ME and GABA reduced the amplitude of the evoked EPSPs and augmented homosynaptic depression although this inhibition was independent of the homosynaptic depression trend. The amplitude of the spontaneous EPSPs was not affected. Naloxone alone did not produce any effect, making it unlikely that the enkephalinergic system could be recruited during homosynaptic depression. ME also shortened the duration of the presynaptic action potential and enhanced its afterhyperpolarization. These results suggest that ME and GABA exert a presynaptic modulation.

Changes in bit-mapped contingent negative variation (CNV) activity due to initial normal involutional processes of the human brain

Bit-color mapped multicomponent CNV complexes and RTs to S2 evoked with a simple warned CNV/RT paradigm were recorded and measured in 20 selected right-handed very healthy volunteers (10 young adults and 10 presenile subjects, mean age 28.3 and 59.6, respectively). EEG and CNV components (post S1, N1, P2, P3; early CNV; N1200; late CNV; CNV resolution) were recorded from Fz, C3, Cz, C4, P3, Pz, and P4 referenced to linked mastoid electrodes. EOG, RT and stimuli were also recorded. The presenile group differed significantly from the younger group in the auditory post-S1 N1 and early (O-wave) and late (P-wave) CNV complex components. A progressive amplitude reduction limited to frontal leads between O-wave and P-wave, the lowest point being reached in the P-wave, was characteristic in the presenile group. Moreover, presenile subjects showed relatively flat CNV waveshapes of low amplitude and, on the whole, performed a little less well than young ones. This finding suggests that the statistically significant changes in auditory post-S1 N1 and CNV activity recorded in our presenile subjects, without any appreciable deficits in behavioral or mental performance, could be alerting signs of early brain involutional processes related to minimal and subclinical decline in orienting, attentiveness and response preparation capabilities. If such is the case, and it could be confirmed in a larger sample of very healthy subjects, these age-related changes in the presenium might prove to be of considerable practical importance for clinical research.

Age differences in contingent negative variation activity of healthy young adults and presenile subjects

20 selected right-handed very healthy subjects (10 young adults and 10 presenile subjects mean age 28.3 and 59.6) were tested for CNV activity with a simple warned reaction time (RT) paradigm. EEG and CNV components (post-S1, N1, P2, P3; early CNV; N1200; late CNV; CNV resolution) were recorded from Fz, C3, Cz, C4, P3, Pz, and P4 referenced to linked mastoid electrodes. EOG, RT and stimuli were also recorded. The presenile group differed significantly from the younger group in the auditory post-S1 N1 and P3, and in the early (O-wave) and late (P-wave) CNV complex components. A progressive amplitude reduction only in frontal leads between O-wave and P-wave with the lowest point being reached in the P-wave was characteristic in the presenile group. Further, presenile subjects showed relatively flat CNV waveshapes of low amplitude and, as a whole, performed a little less well than young persons. This finding suggests that the statistically significant changes in post-S1 EPRs and CNV activity recorded in our presenile subjects, without appreciable deficits in behavioral and mental performance, could be alerting signs of early brain involutional processes related to minimal and subclinical decrement of orienting, attentiveness and response preparation capabilities. If such is the case and it could be confirmed in a larger sample of very healthy subjects, these age-related changes in the presenium could be of considerable practical importance for clinical and research applications.

Central nervous sensitization and dishabituation of reflex action in an insect by the neuromodulator octopamine.

Habituation of excitatory synaptic inputs onto identified motor neurons of the locust metathoracic ganglion, driven electrically and by natural stimuli, was examined using intracellular recording. Rapid progressive reduction in amplitude of EPSPs from a variety of inputs onto fast-type motor neurons occurred. The habituated EPSPs were quickly dishabituated by iontophoretic release of octopamine from a microelectrode into the neuropilar region of presumed synaptic action. The zone within which release was effective for a given neuron was narrowly-defined. With larger amounts of octopamine applied at a sensitive site the EPSP became larger than normal, and in many instances action potentials were initiated by the sensitized response. Very small EPSPs onto a motor neuron, which were associated with proprioceptive feedback, and which were originally too small to be detected above the noise, were potentiated to a level of several mV by the iontophoresed octopamine. A DUM neuron (presumed to be octopaminergic) was found, whose direct stimulation was followed by a strong dishabituating and sensitizing action leading to spikes, of inputs to an identified flexor tibiae motor neuron. The action and its time course were closely similar to those evoked by octopamine iontophoresed into the neuropil in the region of synaptic inputs to the motor neuron. It is concluded that DUM (octopaminergic) neurons exert large potentiating actions on central neuronal excitatory synaptic transmission in locusts.

Regulation of efficacy at central synapses

The quantal nature of synaptic depression produced by high frequency stimulations has been analyzed at a central synapse for the first time. Simultaneous intracellular recordings were obtained from the Mauthner cell and adjacent identifiable inhibitory interneurons. The presynaptic cells were stimulated at frequencies from 2 to 33 Hz, and the corresponding release parameters were determined using a computational procedure described elsewhere (Korn, H., A. Triller, A. Mallet, and D. S. Faber (1981) Science 213: 898-901). As in our previous studies, these entities were correlated with histological features of the neurons following systematic horseradish peroxidase injections and reconstructions. Evidence was obtained that, in the range of physiological conditions used, the binomial parameter n (number of available quanta for release) remains constant; thus every synaptic bouton continues to function as an independent all-or-none releasing unit. The progressive reduction in amplitude of postsynaptic potentials can be attributed solely to a lower probability of release, as shown by the fall of the binomial parameter p. This evidence supports the concept that p is a critical variable for short-term modifications of synaptic efficacy and may provide insight for instances of synaptic plasticity underlying those behavioral changes which can be attributed to presynaptic loci. The present study also represents a necessary step toward linking mathematical variables of models for transmitter exocytosis with subcellular events.