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Biomedical subjects

B Feige

Publications and source records attributed to B Feige.

At least 19 recordsLinked to original sources

Impact of experimentally induced serotonin deficiency by tryptophan depletion on saliva cortisol concentrations.

BACKGROUND: Tryptophan depletion (TD) has been shown to induce a transient mood-lowering effect in psychiatric patients and susceptible healthy subjects. We investigated the effects of TD on cortisol secretion in psychiatric patients and healthy subjects based on the hypothesis that the potential mood-lowering effects may be associated with increased activity of the hypothalamic-pituitary-adrenal axis, thus leading to a rise of cortisol secretion. METHODS: After TD at 18.00 h, salivary cortisol was sampled in the evening and on the following morning. The first study was a randomized, placebo-controlled, crossover study in healthy subjects. Two further open trials in patients with obsessive-compulsive disorder (OCD) and primary insomnia compared the effects of TD on cortisol with baseline conditions. RESULTS: In healthy subjects, TD significantly diminished cortisol the next morning compared with placebo. In OCD patients and primary insomniacs, cortisol the morning after TD was lowered compared with baseline. Evening cortisol was not affected by TD in any of the groups. CONCLUSIONS: Contrary to expectation, TD led to a comparable decrease of morning cortisol in all groups investigated. However, these findings are consistent with former studies analyzing the impact of antiserotonergic drugs on cortisol secretion. The results underline that the antiserotonergic effects caused by TD may influence cortisol secretion.

Adult↗

Event-related potential correlates selectively reflect cognitive dysfunction in schizophrenics.

UNLABELLED: Schizophrenics show event-related potential (ERP) and particularly P3 abnormalities. To study the more detailed relationships between these ERP alterations and cognitive dysfunction we recorded and analyzed ERPs using a particular experimental approach. In 34 schizophrenics and 25 controls ERPs were obtained by a visual Go/Nogo task requiring response inhibition and were decomposed into temporally independent topographical components using Independent Component Analysis (ICA). ICA disentangled different subcomponents of P3. Subcomponent P3b with a parietal maximum amplitude was significantly reduced in the schizophrenics, probably reflecting their attentional deficits. Subcomponent P3ng with a frontal maximum amplitude and enhanced during Nogo condition appeared as an electrophysiological index of response inhibition. A significantly reduced P3ng enhancement, found in schizophrenics, probably reflects their impaired response control. CONCLUSIONS: ICA can successfully identify ERP subcomponents with distinct scalp topographies representing significant differential indices of normal and abnormal cognitive processing. Involvement of frontal brain areas in disturbed executive control in schizophrenics is supported by our ICA findings.

Adult↗

[The importance of sleep for healthy alcohol consumers and alcohol dependent patients].

This article deals with the effects of alcohol on sleep and sleep EEG of healthy individuals and alcohol-dependent patients during different phases of alcohol dependency. Healthy individuals initially experience an improvement in sleep, although a greater quantity of alcohol can lead to problems of sleep maintenance during the second half of the night. Pre-existing sleep deprivation or sleep restriction potentiates the effects of alcohol. Alcohol-dependent patients are found to be more prone to sleep problems than healthy individuals, which can facilitate the development of alcoholism. These patients experience difficulty falling asleep and suffer from a reduced total sleep time during all phases of the disorder, often accompanied by other sleep disorders such as sleep apnea syndrome or periodic leg movements during sleep. Certain predictors for the risk of relapse in abstinent alcoholics have been identified. Neurobiological findings in sleep and alcohol dependency are discussed. The cholinergic-aminergic reciprocal interaction model of REM and non-REM sleep regulation is significant in this context. Therapeutic implications are discussed.

Alcohol-Induced Disorders↗

Polysomnography during withdrawal with clomethiazole or placebo in alcohol dependent patients--a double-blind and randomized study.

INTRODUCTION: The present study was designed to assess if the routine application of clomethiazole to ameliorate withdrawal symptoms in chronic alcohol dependent patients perpetuates sleep disturbances. METHODS: Twenty inpatients with alcohol dependence according to DSM-IV criteria received clomethiazole or placebo in a double-blind, randomized design upon admission. 11 patients were randomized to the clomethiazole group and 9 patients to the placebo group. During the first 5 days of treatment the patients received either clomethiazole (1st day: 3 x 384 mg, 2nd day: 4 x 384 mg, 3rd day: 3 x 384 mg, 4th day: 2 x 384 mg and 5th day: 1 x 384 mg) or placebo capsules at constant intervals. The patients spent two consecutive nights in the sleep laboratory at each of three assessment times: the first time at the beginning of abstinence (night 1 and 2, T0), the second time 6 days later (i. e. after 5 days of treatment and one day of discontinuation of clomethiazole or placebo: nights 6 and 7, T1) and the third time after 13 days (nights 13 and 14, T2). The first night at each of the three assessment times was an adaptation night. RESULTS: During the first two weeks of abstinence, the analysis of variance demonstrated a significant variation of Rapid Eye Movement (REM) sleep variables in the clomethiazole group. The placebo group showed no such variation. Clomethiazole evidently had a pronounced REM sleep suppressing effect, whereas the discontinuation of clomethiazole led to a REM sleep rebound. Furthermore, analysis of sleep continuity and sleep architecture variables showed that the clomethiazole group had significantly disturbed sleep at T1 in comparison to the placebo group. Simultaneous statistical testing with alcohol intake as covariate reduced the test power so that contrasts between the groups became nonsignificant. CONCLUSIONS: The REM sleep results are in line with earlier findings that REM sleep disinhibition in primary alcohol dependency is partly due to a REM sleep rebound after withdrawal from medication. Differences in the polysomnographic variables of sleep continuitiy and sleep architecture at T0 and T1 found between the clomethiazole and the placebo patients correspond to rebound insomnia following discontinuation of clomethiazole. Our findings indicate that drugs enforcing GABAergic neurotransmission may perpetuate the neuroadaptative effects caused by chronic alcohol consumption.

Adult↗

Sleep and the cholinergic rapid eye movement sleep induction test in patients with primary alcohol dependence.

BACKGROUND: The present study investigated polysomnographically assessed sleep parameters in alcohol-dependent patients after withdrawal and in healthy control subjects during baseline and after a cholinergic stimulation paradigm. The aim of the study was to test whether sleep parameters, especially rapid eye movement (REM) sleep variables, may serve as predictors for relapse in alcohol-dependent patients. METHODS: Forty patients diagnosed with alcohol dependence were admitted to a specialized ward for alcohol withdrawal and were investigated by polysomnography at three time points: 2-3 weeks after withdrawal (T0) and at follow-up investigations 6 (T1) and 12 (T2) months after discharge from the hospital. A subgroup of patients (n = 17) was studied at T0 after challenge with galanthamine, a reversible cholinesterase inhibitor (cholinergic REM induction test, CRIT). Patients were compared with two control groups: a) 30 healthy control subjects (matched for age- and gender-distribution) for comparison at baseline conditions; and b) 17 age- and gender-matched control subjects for comparison with the CRIT. RESULTS: At baseline the patients showed significant disturbances of sleep continuity and sleep architecture (decreased slow-wave sleep, SWS) and exhibited an increase of "REM sleep pressure" (a combined index of REM latency, REM density, and REM sleep percent). Galanthamine provoked significant alterations of sleep continuity, sleep architecture (reduced SWS), and increased most of the components of REM pressure, taking patients and control subjects together. Apart from SWS %SPT (sleep period time) no significant drug-group interactions occurred. Patients who remained abstinent (n = 11) for at least 6 months at follow-up exhibited significantly less abnormalities of REM sleep at T0 compared to the group of patients that relapsed at 6 months follow-up. CONCLUSIONS: It is concluded that increased REM sleep pressure after alcohol withdrawal is a robust predictor of vulnerability to relapse. Thus, a subgroup of alcoholic patients appears to exhibit distinct neurobiological abnormalities assessable by polysomnography that are related to an increased vulnerability for alcoholism and early relapse.

Adult↗

A double-blind, randomized and placebo-controlled study on the polysomnographic withdrawal effects of zopiclone, zolpidem and triazolam in healthy subjects.

Rebound effects after withdrawal from hypnotics are believed to trigger their chronic use and to enhance the risk of tolerance and dependence. It was the purpose of this study to investigate the acute polysomnographic withdrawal effects after a 4 week treatment with standard doses of the non-benzodiazepine hypnotics zopiclone and zolpidem compared with triazolam and placebo. Healthy male subjects between 22 and 35 years of age participated in a parallel study design. They received either zopiclone 7.5 mg (n=11), zolpidem 10 mg (n=11), triazolam 0.25 mg (n=10) or placebo (n=7) over 4 weeks in randomized and double-blind order. Sleep EEG was registered during 2 nights before treatment under placebo, on days 1, 27 and 28 of treatment and on days 29,30,41 and 42 under placebo. Total sleep time and sleep efficiency were lower in the 1st night after discontinuation of triazolam (p < 0.05, t-test). After withdrawal from zopiclone or zolpidem slight but not significant rebound effects concerning sleep continuity were observed. Self-rating scales showed minimal rebound insomnia after discontinuation of all three hypnotics. In the placebo group no changes of sleep parameters were observed. Assuming that rebound insomnia is part of a withdrawal reaction, this study indicates that the risks of tolerance and dependency are low when administering zopiclone or zolpidem at the recommended doses.

Adult↗

Auditory and visual event-related potentials in alcoholics: abnormalities of components and brain electrical field.

Alterations of ERPs recorded over midline scalp sites have frequently been reported in alcoholics. To assess the P3 and other ERP components topographically, auditory and visual ERPs were recorded from 33 scalp electrodes in abstinent alcoholics and healthy controls using an oddball paradigm. At the Cz electrode the alcoholics showed decreased visual N1 and increased auditory N2 amplitudes. Topographically, the negative centroids of the visual N1 and P3 and the auditory N2 differed between groups, and the positive centroid of the visual P3 was displaced toward the right hemisphere. While no valid diagnostic classification could be obtained by using the traditional ERP component P3 recorded from Pz, the combination of visual N1 and auditory N2 amplitudes at Cz with centroid parameters amounted to 51% explained variance and 92% correct discrimination of alcoholics from controls. Abnormalities of N1 amplitude and P3 topography similar to the current findings in alcoholics have previously been described for schizophrenics.

Adult↗

Oscillatory cortical activity and movement-related potentials in proximal and distal movements.

OBJECTIVES: Event-related desynchronization (ERD) of alpha- and beta-rhythms, the post-movement beta-synchronization and the cortical movement-related potentials were analyzed in distal (finger) and proximal (shoulder) movements. METHODS: EEG was recorded in 7 healthy right-handed men using a 59-channel whole-head EEG system while subjects performed self-paced movements. RESULTS: The amplitude of the Bereitschaftspotential (BP) was greater over the central midline area and smaller over the contralateral sensorimotor hand area in shoulder than in finger movements. The maximal alpha- and beta-ERD was localized at parietal electrodes in shoulder movements and over the left and right sensorimotor hand area in finger movements. The post-movement beta-ERS was greater in shoulder than in finger movements, especially at the electrode located 3.5 cm left of the central midline electrode. A significant correlation between the slope of the terminal portion of the BP (negative slope) and amplitude of the post-movement beta-synchronization was observed in shoulder but not in finger movements. CONCLUSIONS: Enhancement of BP over the central midline electrode suggests increased activation of the supplementary motor area in proximal movements. The spatial distribution of the alpha- and beta-ERD and of the post-movement beta-ERS shows topographic differences which may refer to the somatotopic organization of the primary sensorimotor cortex with shoulder representation medial to hand and fingers. The correlation between the negative slope and the post-movement beta-ERS in proximal movements supports the view that the brief post-movement inhibition over the motor cortical area is related to the pre-movement activation of that area.

Adult↗

Effects of repetitive transcranial magnetic stimulation on movement-related cortical activity in humans.

Several lines of evidence suggest that low-rate repetitive transcranial magnetic stimulation (rTMS) of the motor cortex at 1 Hz reduces the excitability of the motor cortex and produces metabolic changes under and at a distance from the stimulated side. Therefore, it has been suggested that rTMS may have beneficial effects on motor performance in patients with movement disorders. However, it is still unknown in what way these effects can be produced. The aim of the present study is to investigate whether rTMS of the motor cortex (15 min at 1 Hz) is able to modify the voluntary movement related cortical activity, as reflected in the Beretischaftspotential (BP), and if these changes are functionally relevant for the final motor performance. The cortical movement-related activity in a typical BP paradigm of five healthy volunteers has been recorded using 61 scalp electrodes, while subjects performed self-paced right thumb oppositions every 8-20 s. After a basal recording, the BP was recorded in three different conditions, counterbalanced across subjects: after rTMS stimulation of the left primary motor area (M1) (15 min, 1 Hz, 10% above motor threshold), after 15 min of sham rTMS stimulation and following 15 min of voluntary movements performed with spatio-temporal characteristics similar to those induced by TMS. The tapping test was used to assess motor performance before and after each condition. Only movement-related trials with similar electromyographic (onset from muscular 'silence') and accelerometric patterns (same initial direction and similar amplitudes) were selected for computing BP waveforms. TMS- evoked and self-paced thumb movements had the same directional accelerometric pattern but different amplitudes. In all subjects, the real rTMS, but neither sham stimulation nor prolonged voluntary movements, produced a significant amplitude decrement of the negative slope of the BP; there was also a shortening of the BP onset time in four subjects. The effect was topographically restricted to cortical areas which were active in the basal condition, irrespective of the basal degree of activation at every single electrode. No changes in the tapping test occurred. These findings suggest that rTMS of the motor cortex at 1 Hz may interfere with the movement related brain activity, probably through influence on cortical inhibitory networks.

Adult↗

Dynamic synchronization between multiple cortical motor areas and muscle activity in phasic voluntary movements.

To study the functional role of synchronized neuronal activity in the human motor system, we simultaneously recorded cortical activity by high-resolution electroencephalography (EEG) and electromyographic (EMG) activity of the activated muscle during a phasic voluntary movement in seven healthy subjects. Here, we present evidence for dynamic beta-range (16-28 Hz) synchronization between cortical activity and muscle activity, starting after termination of the movement. In the same time range, increased tonic activity in the activated muscle was found. During the movement execution a low-frequency (2-14 Hz) synchronization was found. Using a novel analysis, phase-reference analysis, we were able to extract the EMG-coherent EEG maps for both, low- and high-frequency beta range synchronization. The electrical source reconstruction of the EMG-coherent EEG maps was performed with respect to the individual brain morphology from magnetic resonance imaging (MRI) using a distributed source model (cortical current density analysis) and a realistic head model. The generators of the beta-range synchronization were not only located in the primary motor area, but also in premotor areas. The generators of the low-frequency synchronization were also located in the primary motor and in premotor areas, but with additional participation of the medial premotor area. These findings suggest that the dynamic beta-range synchronization between multiple cortical areas and activated muscles reflects the transition of the collective motor network into a new equilibrium state, possibly related to higher demands on attention, while the low-frequency synchronization is related to the movement execution.

Adult↗

The role of higher-order motor areas in voluntary movement as revealed by high-resolution EEG and fMRI.

In the human motor cortex structural and functional differences separate motor areas related to motor output from areas essentially involved in higher-order motor control. Little is known about the function of these higher-order motor areas during simple voluntary movement. We examined a simple finger flexion movement in six healthy subjects using a novel brain-imaging approach, integrating high-resolution EEG with the individual structural and functional MRI. Electrical source reconstruction was performed in respect to the individual brain morphology from MRI. Highly converging results from EEG and fMRI were obtained for both executive and higher-order motor areas. All subjects showed activation of the primary motor area (MI) and of the frontal medial wall motor areas. Two different types of medial wall activation were observed with both methods: Four of the subjects showed an anterior type of activation, and two of the subjects a posterior type of activation. In the former, activity started in the anterior cingulate motor area (CMA) and subsequently shifted its focus to the intermediate supplementary motor area (SMA). Approximately 120 ms before the movement started, the intermediate SMA showed a drop of source strength, and simultaneously MI showed an increase of source strength. In the posterior type, activation was restricted to the posterior SMA. Further, three of the subjects investigated showed activation in the inferior parietal lobe (IPL) starting during early movement preparation. In all subjects showing activation of higher-order motor areas (anterior CMA, intermediate SMA, IPL) these areas became active before the executive motor areas (MI and posterior SMA). We suggest that the early activation of the anterior CMA and the IPL may be related to attentional functions of these areas. Further, we argue that the intermediate part of the SMA triggers the actual motor act via the release of inhibition of the primary motor area. Our results demonstrate that a noninvasive, multimodal brain imaging technique can reveal individual cortical brain activity with high temporal and spatial resolution, independent of a priori physiological assumptions.

Adult↗

Independent sleep EEG slow-wave and spindle band dynamics associated with 4 weeks of continuous application of short-half-life hypnotics in healthy subjects.

OBJECTIVES: Habituation and adverse withdrawal reactions after prolonged medication with benzodiazepine (BZ) hypnotics are believed to play a role in dose escalation and the development of dependence. METHODS: In the current sleep EEG study in 43 healthy male subjects, the known property of BZ- and similar hypnotics to change the NREM sleep EEG spectrum is utilized for a detailed quantitative analysis across 4 weeks of continuous medication and a subsequent two-week withdrawal period. The BZ hypnotic triazolam and the non-BZ hypnotics zopiclone and zolpidem, differing in pharmacological properties and reported adverse effects, were examined in parallel to a placebo group. RESULTS: Reliably occurring spectral effects in the sleep stage 2 EEG were found in the 3 frequency bands 0.8-5 Hz, 5-10 Hz and 10-15 Hz. All 3 hypnotics showed the typical 'benzodiazepine signature', a 10-15 Hz increase and lower-frequency (<10 Hz) suppression relative to the preceding drug-free night. However, these effects developed differently across the first medication night, across the 4 medication weeks and after withdrawal: While the 5-10 Hz effect covaried with the blood presence of the drugs as estimated from the known plasma half-lifes, showed habituation and a rebound after withdrawal, the 10-15 Hz power increased across medication days and showed no rebound. Effects in the 0.8-5 Hz band in the first medication night correlated with the decrease of sleep efficiency at later withdrawal for triazolam and zolpidem.

Adult↗

Reproducibility and validity of electric source localisation with high-resolution electroencephalography.

The present study investigates the reproducibility and validity of the EEG source localisation of somatosensory evoked potentials (SEPs) using high-resolution EEG (61 scalp electrodes) and a source reconstruction on the basis of the individual brain morphology as obtained from magnetic resonance images (MRIs). The somatosensory evoked potentials (SEPs) to electrical stimulation of the right median nerve were repeatedly collected from the scalp of one healthy subject in 9 replications run on 9 different days. The source reconstruction for the 19 ms SEP component was performed by using a single moving dipole model as a source model. Two different head models were used: a spherical 3 shell model and a more realistically shaped 3 compartment model computed using the boundary element method (BEM). The source locations of the 19 ms SEP component were found to be highly reproducible using both head models: the mean standard deviation of the dipole locations was found to be 2.6 mm for the 3 shell model and 4 mm for the more realistically shaped head model. By projection into the individual MRI, the dipoles resulting from either head models were found to be located within the postcentral gyrus. The electric source locations were consistent with the maximum of the task-specific changes seen in a functional magnetic resonance imaging (fMRI) experiment when using the same somatosensory stimulation protocol.

Brain Mapping↗

The bereitschaftspotential paradigm in investigating voluntary movement organization in humans using magnetoencephalography (MEG).

In 1965, Kornhuber and Deecke first described the bereitschaftspotential (BP), a paradigm for investigating the organization of voluntary movement in humans, using electroencephalography (EEG). This paradigm has since been used in many studies for investigating motor control in healthy humans and patients. Over the last years, the advantages of magnetoencephalography (MEG) have been applied to the BP paradigm by a number of researchers. The main advantage of magnetoencephalography over electroencephalography is that MEG has a higher localization accuracy. This is due to the fact that the different structures of the head (brain, liquor cerebrospinalis, skull and scalp) influence the magnetic fields less than the volume current flow that causes the EEG. Additionally, the MEG is reference free, so that the localization of sources with a given precision is easier for MEG than it is for EEG. The present protocol shows in detail how the bereitschaftspotential paradigm can be applied using MEG. Some additional paradigms for investigating motor plasticity, somatosensory gating, Parkinson disease, and the efference copy theory are suggested as well.

Adult↗

Neuromagnetic study of movement-related changes in rhythmic brain activity.

Neuromagnetic fields from the left cerebral hemisphere of five healthy, right-handed subjects were investigated in a typical Bereitschaftspotential paradigm consisting of self-paced voluntary movement of the right index finger. To assess movement-related spectral changes of the spontaneous magnetoencephalogram. latency-dependent short-time spectra were obtained by Fourier analysis for each single trial. The number of trials in which the spectral estimate for a certain frequency and latency deviated from reference values was then transformed into a probabilistic relative power measure. A spectral power depression around 20 Hz was observed starting about 2.5 s before movement onset, followed by elevated power in the 20-35 Hz range starting about 500 ms after movement onset. Generally, the power increase differed from the prior depression in both spectrum and topography, suggesting different generating processes rather than just a 'rebound' effect of the idling rhythm generator. The time course and topography of spectral power changes are discussed in relation to the corresponding properties of the movement-related neuromagnetic fields (readiness field, motor field, and movement-evoked field I).

Adult↗

Changes in movement-related brain activity during transient deafferentation: a neuromagnetic study.

Neuromagnetic fields from the left cerebral hemisphere of three healthy, right-handed subjects were investigated preceding and during voluntary index finger movements performed every 8-15 s under two different experimental conditions: before (stage A) and during (stage B) anesthetic block of median and radial nerves at the wrist. The anesthesia caused blocking of cutaneous receptors and some of the proprioreceptors from a wide hand area, including the entire index finger. However, the index finger movements were not impaired because the muscles participating in the task were not anesthetized. The magnetic signals of the brain sources corresponding to the main components of the movement-related neuromagnetic fields (motor field, MF and movement-evoked field I, MEFI) were mapped and localized using a moving dipole model. In the three investigated subjects the MF and MEFI dipole sources were stronger (30% on average) during stage B than during stage A. No significant changes in spatial coordinates of the estimated dipole locations between stages A and B were observed. This was true for both MF and MEFI. The results show that the MEFI reflects not only proprioceptive input from the periphery but cutaneous inputs as well. In this way the results support the view that cutaneous inputs play a specific role in the cortical control of movement.

Action Potentials↗

Slow potentials, event-related potentials, "gamma-band" activity, and motor responses during aversive conditioning in humans.

We examined slow potentials, transient event-related potentials, and oscillatory-like responses in the electroencephalogram during aversive conditioning in humans, in order to determine what is happening in the neocortex when behavioral adaptations are learned. Pictures of an angry and a happy human face served as reinforced (CS+) and unreinforced (CS-) conditioned stimuli, respectively, in one group, and either the reversed condition or two discriminably different neutral faces in two other groups (total n = 48 subjects). The unconditioned stimulus (US) was intracutaneous shock delivered to the left hand 5 s after CS+ onset. The electroencephalographic (EEG) activity was recorded from Fz, Cz, Pz, C3, and C4, electromyographic (EMG) activity from bilateral forearm and corrugator muscles, and skin conductance from the right hand. During acquisition a negative slow potential developed after CS+ (not CS-), which was more pronounced when a neutral face served as CS+. Early (iCNV, initial contingent negative variation) and late (tCNV, terminal contingent negative variation) components of the slow-potential response were positively related to the magnitude of conditioned EMG responses. Differentiation of tCNV was larger when neutral faces signaled the US; iCNV persisted during extinction when a happy face served as CS+. Late-occurring event-related potentials (ERPs) elicited by the US diminished over conditioning, whereas short-latency US components and ERPs elicited by CS events did not. Fourier analysis revealed oscillatory ("gamma-band") activity between 30 and 40 Hz, which persisted up to 3 s after US delivery and diminished as conditioning progressed. Our findings indicate that learning is expressed in neocortical structures at the earliest stages of conditioning. The functional roles of the three types of EEG response in learning are discussed.

Adult↗

High-frequency cortical responses reflect lexical processing: an MEG study.

Meaningful words and matched pseudowords, such as moon vs. noom, are of equal perceptual complexity, but invoke different cognitive processes. To investigate high-frequency cortical responses to these stimuli, biomagnetic signals were recorded simultaneously over both hemispheres of right-handed individuals listening to words and pseudowords. Consistent with earlier EEG studies, evoked spectral responses recorded from the left hemisphere revealed depression of spectral power in the low gamma band (around 30 Hz) after pseudowords but not after words. Similar differences between stimulus categories were present in the beta range. These results indicate that distinct patterns of high-frequency cortical responses correspond to the different cognitive processes invoked by words and pseudowords. It is hypothesized that differential high-frequency cortical responses signal the activation or activation failure of distributed Hebbian cell assemblies representing words and other elements of cognitive processing.

Adult↗