Behavioral measures and event-related potentials reveal different aspects of sentence processing and comprehension in patients with major depression.

BACKGROUND: We used the method of event-related potentials (ERPs) during standard semantic judgment task to explore the functional relationship between the deficit in semantic comprehension in women with depression and the potential dysfunction of brain processes mediating language comprehension. METHOD: Eleven patients with major depression and 13 healthy participants were required to read congruous and incongruous sentences and to judge if they made sense. Accuracy and reaction times for semantic judgment were analyzed conjointly with the latency and the peak amplitudes of N100, P200, N400 and LPC components which were recorded at the final word of correctly judged sentences. RESULTS: Patients were less accurate in semantic judgment in comparison to healthy participants. They exhibited slower reaction times and prolonged latency of the N400 and the LPC. A congruity effect was observed in both groups in P200, N400 and LPC interval. The peak amplitude of the ERP components did not differ between patients and healthy participants. In patients lower accuracy was correlated with more prolonged N400 latency and more negative N400 amplitude for congruous sentence endings. Age correlated with prolonged latency and amplitude reduction of the LPC component. LIMITATIONS: Small number of participants, exclusively female patients. CONCLUSIONS: Combined analyses of behavior and ERP measures of semantic processes in depression showed that semantic impairments, motor slowness and a delay in the timing of neural processes which mediate language comprehension might be functionally related and may be influenced by the age of the patients.

Bioactive N-terminal undecapeptides derived from parathyroid hormone: the role of alpha-helicity.

The N-terminal 1-34 segment of parathyroid hormone (PTH) is fully active in vitro and in vivo and it can reproduce all biological responses in bone characteristic of the native intact PTH. Recent studies have demonstrated that N-terminal fragments presenting the principal activating domain such as PTH(1-11) and PTH(1-14) with helicity-enhancing substitutions yield potent analogues with PTH(1-34)-like activity. To further investigate the role of alpha-helicity on biological potency, we designed and synthesized by solid-phase methodology the following hPTH(1-11) analogues substituted at positions 1 and/or 3 by the sterically hindered and helix-promoting C(alpha)-tetrasubstituted alpha-amino acids alpha-amino isobutyric acid (Aib), 1-aminocyclopentane-1-carboxylic acid (Ac(5)c) and 1-aminocyclohexane-1-carboxylic acid (Ac(6)c): Ac(5)c-V-Aib-E-I-Q-L-M-H-Q-R-NH(2) (I); Aib-V-Ac(5)c-E-I-Q-L-M-H-Q-R-NH(2) (II); Ac(6)c-V-Aib-E-I-Q-L-M-H-Q-R-NH(2) (III); Aib-V-Ac(6)c-E-I-Q-L-M-H-Q-R-NH(2) (IV); Aib-V-Aib-E-I-Q-L-M-H-Q-R-NH(2) (V); S-V-Aib-E-I-Q-L-M-H-Q-R-NH(2) (VI), S-V-Ac(5)c-E-I-Q-L-M-H-Q-R-NH(2) (VII); Ac(5)c-V-S-E-I-Q-L-M-H-Q-R-NH(2) (VIII); Ac(6)c-V-S-E-I-Q-L-M-H-Q-R-NH(2) (IX); Ac(5)c-V-Ac(5)c-E-I-Q-L-M-H-Q-R-NH(2) (X); Ac(6)c-V-Ac(6)c-E-I-Q-L-M-H-Q-R-NH(2) (XI). All analogues were biologically evaluated and conformationally characterized in 2,2,2-trifluoroethanol (TFE) solution by circular dichroism (CD). Analogues I-V, which cover the full range of biological activity observed in the present study, were further conformationally characterized in detail by nuclear magnetic resonance (NMR) and computer simulations studies. The results of ligand-stimulated cAMP accumulation experiments indicated that analogues I and II are active, analogues III, VI and VII are very weakly active and analogues IV, V, VIII-XI are inactive. The most potent analogue, I exhibits biological activity 3500-fold higher than that of the native PTH(1-11) and only 15-fold weaker than that of the native sequence hPTH(1-34). Remarkably, the two most potent analogues, I and II, and the very weakly active analogues, VI and VII, exhibit similar helix contents. These results indicate that the presence of a stable N-terminal helical sequence is an important but not sufficient condition for biological activity.

Conformational and biological characterization of human parathyroid hormone hPTH(1-34) analogues containing beta-amino acid residues in positions 17-19.

The N-terminal 1-34 fragment of parathyroid hormone (PTH) elicits the full spectrum of bone-related biological activities of the intact native sequences. It has been suggested that the structural elements essential for bioactivity are two helical segments located at the N-terminal and C-terminal sequences, connected by hinges or flexible points around positions 12 and 19. In order to assess the relevance of the local conformation around Gly(18) upon biological function, we synthesized and characterized the following human (h) PTH(1-34) analogues containing beta-amino acid residues: [analogues: see text]. Biological activity and binding affinity of analogue I are one order of magnitude lower than those of the parent compound. In analogue II, both binding affinity and biological activity are partially recovered. Analogues III and V have no binding affinity and very low biological activity. Both bioactivity and binding affinity are partially recovered in analogue IV. The conformational properties of the analogues in aqueous solution containing dodecylphosphocholine micelles were studied by CD, 2D-nuclear magnetic resonance and molecular dynamics calculations. The results confirmed the presence in all analogues of two helical segments located at the N-terminal and C-terminal sequences. The insertion of beta-amino acid residues around position 18 does not cause appreciable conformational differences in the five analogues. The differences in biological activity and binding affinity among the five analogues cannot be related to structural differences in the membrane mimetic environment reported in this study. Our results stress the importance of the side-chain functionalities in the sequence 17-19 for biological function.

An ERP study of famous face incongruity detection in middle age.

Age-related changes in famous face incongruity detection were examined in middle-aged (mean = 50.6) and young (mean = 24.8) subjects. Behavioral and ERP responses were recorded while subjects, after a presentation of a "prime face" (a famous person with the eyes masked), had to decide whether the following "test face" was completed with its authentic eyes (congruent) or with other eyes (incongruent). The principal effects of advancing age were (1) behavioral difficulties in discriminating between incongruent and congruent faces; (2) a reduced N400 effect due to N400 enhancement for both congruent and incongruent faces; (3) a latency increase of both N400 and P600 components. ERPs to primes (face encoding) were not affected by aging. These results are interpreted in terms of early signs of aging.

Event-related potentials to structural familiar face incongruity processing.

Thirty scalp sites were used to investigate the specific topography of the event-related potentials (ERPs) related to face associative priming when masked eyes of familiar faces were completed with either the proper features or incongruent ones. The enhanced negativity of N210 and N350, due to structural incongruity of faces, have a "category specific" inferotemporal localization on the scalp. Additional analyses support the existence of multiple ERP features within the temporal interval typically associated with N400 (N350 and N380), involving occipitotemporal and centroparietal areas. Seven reliable dipole locations have been evidenced using the brain electrical source analysis algorithm. Some of these localizations (fusiform, parahippocampal) are already known to be involved in face recognition, the other ones being related to general cognitive processes related to the task's demand. Because of their specific topography, the observed effects suggest that the face structural congruency process might involve early specialized neocortical areas in parallel with cortical memory circuits in the integration of perceptual and cognitive face processing.

Differential processing of part-to-whole and part-to-part face priming: an ERP study.

We provide electrophysiological evidence supporting the hypothesis that part and whole face processing involve distinct functional mechanisms. We used a congruency judgment task and studied part-to-whole and part-to-part priming effects. Neither part-to-whole nor part-to-part conditions elicited early congruency effects on face-specific ERP components, suggesting that activation of the internal representations should occur later on. However, these components showed differential responsiveness to whole faces and isolated eyes. In addition, although late ERP components were affected when the eye targets were not associated with the prime in both conditions, their temporal and topographical features depended on the latter. These differential effects suggest the existence of distributed neural networks in the inferior temporal cortex where part and whole facial representations may be stored.

Face and shape repetition effects in humans: a spatio-temporal ERP study.

The neural bases of repetition effects for faces and non-significant shapes was studied using Mooneys' faces presented upright (face) or upside down (shape) with a repetition interval of 8 min 30 s-1. Scalp potentials and current density maps on 30 electrodes were compatible with an involvement of the infero-temporal and fusiform gyri (from 50 to at least 250 ms), mainly on the right, for both faces and shapes; the hippocampus and adjacent areas (around 300 ms), specifically for faces; the medial temporal lobes (450-650 ms) again independent of stimulus meaning. These results suggest that the facilitation of perception due to repetition involves both neocortical specialized areas and the medial temporal lobe, with different timings of activation. They further suggest that memory updating takes place more rapidly for faces than for meaningless shapes and that face recognition may be, at least partly, functionally encapsulated.

Brain events related to normal and moderately scrambled faces.

The neural basis of normal and scrambled face processing was investigated by recording evoked potentials from 21 electrodes at standard EEG sites, with respect to a nose reference. Temporal negativities were found that result from two overlapping phenomena: they arise from the polarity reversal on temporal electrodes of the vertex P2, a positive wave peaking about 170-200 ms after the onset of a face stimulus, and also from an overlapping 'processing negativity' of long duration associated with the processing difficulty of the scrambled face stimulus. The comparisons of scalp potential and current density mappings support the proposal that some neuronal networks are active both for faces and scrambled faces and are compatible with the involvement of the superior temporal sulcus, the inferotemporal cortex and the parahippocampal and fusiform gyri, whereas the processing negativity would only involve the deepest generators of this network. Furthermore, the encoding of both faces and scrambled faces seems to take place predominantly in the right hemisphere.

Mental processing during reactions toward and away from a stimulus: an ERP analysis of auditory congruence and S-R compatibility.

In its first usage, stimulus-response (S-R) compatibility defined strict S-R relationships. The later use of more complex two-dimensional stimuli led to the formulation of the Simon effect as a tendency to respond toward the side of stimulation. Ragot and Guiard (1992, European Journal of Cognitive Psychology, 4, 219-232) observed an inversion of the Simon effect in the auditory modality. The present study was undertaken to present a more thorough observation of this seemingly paradoxical inversion through the use of brain event-related potentials (ERPs). Two experimental variables were manipulated: (a) stimulus congruence, expressing the degree of correspondence between two randomly varying conflictual or nonconflictual attributes of the stimulus (spoken word droite or gauche presented to the right or left ear), and (b) S-R compatibility as such, expressing the relationship between the relevant stimulus attribute (word) and the responding hand. Results show that the nature of the spoken word acts on N100 latency and is therefore the first stimulus attribute to be processed. Data on P300 indicate that S-R compatibility is the last variable to be taken into account. The observed results are integrated into a cascade/parallel model.

Effect of target position on the sequential organization of processing stages.

In order to study the organization of processing stages taking place in a choice reaction time (RT) situation, the three following experimental variables were manipulated: (1) S-R compatibility; (2) movement direction; and (3) time uncertainty, these variables being known to influence distinct information processing stages. Both behavioural (RT and movement time, MT) and electrophysiological (N200 and P300 latencies) indices of processing time were analysed. All three experimental variables showed significant, additive effects on RT. Only the preparatory period had a significant effect on N200 and on P300 latencies. These results support the construction of a serial model. Furthermore, the analysis of the time intervals between electrophysiological and behavioural indices allows one to infer the relative order of the different stages in this model, as follows: motor pre-initiation, motor pre-programming, response selection and programming, and motor initiation.

Latencies of event related potentials as a tool for studying motor processing organization.

The aim of this experiment was to better define the relative organization of motor processing using both behavioral measures and ERPs. Using the additive factors method, three motor variables; (1) stimulus-response (S-R) compatibility, (2) movement extent, and (3) time uncertainty, were all manipulated in a visuo-bimanual, four-choice, pointing task. As expected, all three variables significantly lengthened RT without interaction. All three motor variables also affected ERP latencies. Both P300 and N200 latencies were lengthened by greater movement extent. Moreover, N200 and P300 latencies were differentially affected by S-R compatibility and time uncertainty. Finally, both RT-minus-N200 and RT-minus-P300 were significantly lengthened by S-R incompatibility and greater time uncertainty whereas movement extent had no effect. In sum, ERP results did not support the assumptions of the classical serial model but rather of a contingent-parallel model. Furthermore, the ERP data can be used to infer the relative order of the different stages in this model.

The pulmonary and systemic response to recurrent endotoxemia in the adult sheep.

The pulmonary and systemic hemodynamic effects of recurrent endotoxemia were studied in the adult sheep with lung lymph fistulas. Six sheep were given 1 mu/kg Escherichia coli endotoxin every 12 hours for 5 days, after which animals were monitored for another 3 days. The pulmonary response to the first three injections was characterized by an initial severe pulmonary hypertension, hypoxia, and a two- to threefold increase in lymph flow, QL. Lymph and plasma thromboxane A2 (TxB2) and prostacyclin (6-keto-PGF1 alpha) levels increased from baseline values of nearly 200 pg/ml to values exceeding 2000 pg/ml. The systemic response to initial doses was characterized by an increase in systemic vascular resistance, a decrease in cardiac index, and a transient 20% increase in oxygen consumption. With later endotoxin doses, the pulmonary response was markedly attenuated, with only modest changes in pulmonary artery pressure, lymph flow, and arterial oxygen tension noted. TxB2 increases were less than 800 pg/ml, and 6-keto-PGF1 alpha levels remained unchanged. However, we noted the progressive onset of a hyperdynamic state characterized by a sustained increase in cardiac index and body temperature, and a 50% increase in oxygen consumption, whereas systemic vascular resistance decreased by 45%. Three days after endotoxin injections were discontinued, the hyperdynamic state (including leukocytosis) was still present, whereas pulmonary variables returned to baseline levels. We conclude that a hyperdynamic state can be produced by repeated doses of endotoxin that will present even after the endotoxin insult is discontinued, which is a characteristic of the multisystem organ failure syndrome.