Influence of language structure on brain-behavior development.

Lack of exposure to specific sensory patterns during critical periods of development can result in a lack of responsiveness to those stimuli in adulthood. The present study extends these observations to native speakers of Japanese, a language which does not contain the contrastive /r/ and /l/ sounds present in English. Both electrophysiological (P3 event-related evoked potential) and behavioral results indicate deficient or absent discrimination of /r/ versus /l/ sounds in Japanese adults compared to native speakers of English. Thus, language structure appears to provide a subtle yet measurable effect on specific aspects of brain development and function.

Long-latency auditory-evoked potentials: role of polysensory association cortex in the cat.

The objective of this study has been to define the role of polysensory association cortex in the generation of "wave NA" and of "wave C," long-latency auditory-evoked potentials recorded from the vertex of conscious cats as, respectively, a marked negative potential of latency 30-48 msec followed by a broad positive wave of latency 50-75 msec. Wave C may represent the feline analogue of the longer latency human auditory-evoked potential wave P2, insofar as both waveforms are very large amplitude, long duration positivities characterized by long recovery cycles. Based on previous studies of wave C and the generators of other middle-latency evoked potentials, we hypothesized that both wave NA and wave C might reflect, at least in part, the cortical culmination of a nonlemniscal line auditory association system arising in reticulothalamic projections to intralaminar and associated ventral thalamic regions. Relays from these thalamic areas are known to project to polysensory association cortex, including pericruciate gyrus, anterolateral gyrus, and medial suprasylvian gyrus. Therefore we implemented a series of lesion experiments to characterize the role of each of these cortical areas in the production of wave NA and wave C. Our results indicate that all three polysensory association areas contribute significantly to both waves NA and C, although the largest effects followed ablation of the pericruciate area alone. Thus, the generator substrates of waves NA and C appear to involve a long-recovery cycle system which functionally incorporates activation of association cortex.

Midlatency auditory evoked responses: P1 abnormalities in adult autistic subjects.

MLR recordings from a group of 11 high-functioning adult autistic subjects were compared with those from a control group of 11 normal subjects. Components selected for analysis were "Pa", the maximum positivity in the 25-40 msec latency range following stimulus onset, "P1", the maximum positivity within the 50-65 msec latency range, and "Nb," the maximum negative deflection in the 40-50 msec latency range. Statistical analyses of amplitude and latency data were conducted using repeated measures analysis of variance and t test group comparisons. The Pa component showed no significant difference between autistic and control groups. However, 2 types of abnormality were noted in the P1 component: (1) the P1 component was significantly smaller in the autistic subjects at slow rates of stimulation, and (2) the autistic P1 did not change as rates of click stimulation increased from 0.5 to 10/sec, in contrast to the normally produced P1 decrement. Data from the P1 model in the cat, and complementary data from the human, closely link the generator substrate of the P1 potential to cholinergic components of the ascending reticular activating system (RAS) and their thalamic target cells. This is the first report of abnormal P1 responses in autism and strongly suggests that the RAS and/or its post-synaptic thalamic targets may be dysfunctional in this syndrome.

Cat 'P300' and cholinergic septohippocampal neurons: depth recordings, lesions, and choline acetyltransferase immunohistochemistry.

The role of septohippocampal circuits in the generation of the P300 response in cats (n = 12) was explored in a series of depth recording, tract-tracing and lesion experiments. Systematic mapping of the hippocampus in 1-mm increments from rostral to caudal extent revealed large positive potentials, greater in amplitude to rare than to frequent stimuli, within the 200-500 ms range. Each map revealed maximal amplitude responses at diverse, widely distributed hippocampus loci. Furthermore, these electrical responses displayed polarity inversion within the hippocampus that was generally localized to the pyramidal cell layer; polarity inversion was also observed in the adjacent entorhinal cortex and amygdala. Injections of propidium iodide, a tract-tracing agent, into these inversion sites resulted in retrograde labeling of small clusters of choline acetyltransferase (ChAT)-positive neurons in the medial septal nucleus and vertical limb of the diagonal band. Aspiration lesions that bilaterally destroyed large amounts of caudal hippocampus from stereotaxic levels A4 to A1 resulted in a decreased number of cells expressing ChAT in the rostral basal nuclear complex. In only 2 cats was the preoperative presence of a significant vertex P300 absent postoperatively. In the majority of cases (5 of 8 animals), hippocampal aspiration produced an enhancement of the preoperative P300 potential. We conclude that cholinergic mechanisms are importantly, albeit not exclusively, involved in the mediation of P300 potentials in cats. Neurons mediating P300 responses appear to be organized in diverse clusters of septal and diagonal band cells. These septal cells may facilitate, and in turn be facilitated or inhibited as a function of hippocampal, or other, allocortical feedback loops.

P3 responses to prosodic stimuli in adult autistic subjects.

Autistic persons are known to have serious abnormalities in speech prosody. The present study attempted to ascertain whether autistic persons could discriminate and/or recognize prosodic contrasts in auditory stimuli. A group of 11 adult autistic subjects with normal IQ and an age-matched group of normal subjects were studied electrophysiologically and behaviorally during presentations of prosodic and phonemic stimuli. The cognitive P3 potential was recorded in response to rare (20%)/frequent (80%) presentations of phonemic stimuli, 'ba/pa,' linguistic-prosodic stimuli, 'Bob.' (statement)/'Bob?' (question), and emotional-prosodic stimuli, 'Bob' (happy)/'Bob' (angry). Behaviorally, auditory discrimination was tested by requiring a button-press response to each presentation of the rare target stimulus and cognitive association was tested by requiring a match between the verbalized stimulus and an appropriate picture/word. Contrary to our hypothesis, the autistic subjects generally showed normal P3 responses to all stimuli and performed at a normal level in all behavioral tests. However, a significant autistic P3 response to the phoneme 'pa' was not demonstrated. This surprising result was reexamined and shown to reflect an unusually large autistic response to 'pa' as the frequent stimulus in the first recording block, this initial hyper-reactivity prevented a 'frequent/rare' differential when 'pa' was presented as the rare stimulus in a later recording block. In the P3 latency window, both the autistic and control groups showed the largest amplitude responses to emotional-prosodic stimuli; neither the N1 nor P2 showed these stimulus effects. Thus, 'emotional sounds' appear to be particularly effective in activating the neural substrate of the P3 generator system. Overall, these data indicate remarkably normal P3 and behavioral processing of prosodic stimuli by the high-functioning autistic subjects of this study.

Midlatency auditory evoked responses: differential effects of a cholinergic agonist and antagonist.

The effects of a cholinergic antagonist (scopolamine) and agonist (physostigmine) on the auditory middle latency evoked responses (MLRs) were studied in 7 normal male volunteers. Scalp recordings were made from a central (Cz) electrode referenced to linked ear lobes on one channel and to a non-cephalic, sternovertebral reference on a second channel. Three components were statistically analyzed for changes in latency and amplitude: Pa, with peak positivity in the 25-40 msec latency range, Nb, with peak negativity 40-50 msec, and P1, with peak positivity 50-65 msec. Control recordings included responses to click rates of 1, 5, 8 and 10/sec; as has been previously reported, P1 showed a marked decrease and disappeared at the faster rates of stimulation whereas Pa showed no change in amplitude. Intravenous injections of scopolamine resulted in a rapid and complete disappearance of P1 and a slight increase in Pa; concurrently, the subjects reported feeling drowsy but were awake with eyes open through the recordings. Subsequent injections of physostigmine resulted in a rapid reversal of the scopolamine effects so that the subjects became alert, Pa decreased, and P1 reappeared and increased to control amplitudes. Rapid click rates caused P1 to diminish, as in the control period, indicating a common P1 recovery cycle in both the control and physostigmine conditions. These data are discussed in terms of the hypothesis that the P1 generator system is comprised of a cholinergic brain-stem-thalamic component of the ascending reticular activating system.

Midlatency auditory-evoked responses: effect of scopolamine in the cat and implications for brain stem cholinergic mechanisms.

The objective of this study has been to define the role of cholinergic mechanisms in the generation of "wave A," a middle latency auditory-evoked potential recorded as a positivity with a 20-25 ms peak latency from the vertex of conscious cats. Wave A and its generator system have particular significance as an experimental model of the human middle latency component "P1." Both the feline wave A and the human P1 are characterized by a long recovery cycle, disappearance during slow wave sleep, and reappearance during rapid eye movement (REM) sleep and during wakefulness. The orchestration of several phenomena of REM sleep are known to involve muscarinic cholinergic mechanisms in the brain stem. Therefore, middle latency auditory-evoked potentials were studied in awake cats before and after injection of a cholinergic antagonist, scopolamine. Wave A and the successive negative potential were abolished by scopolamine in a dose-dependent fashion. This effect occurred within 5-15 min and was spontaneously reversible within a few hours. Although individual subjects were differentially susceptible to lower doses of the drug, all six subjects in this study demonstrated a well-defined statistically significant response at higher doses of the drug. In addition, careful parametric baseline studies were performed in each cat to strengthen the evidentiary linkage between wave A as recorded from the vertex in these experiments and previous studies describing the origin and trajectory of wave A in the brainstem reticular formation and several regions of thalamus, including the intralaminar nuclei. Thus, we conclude that the production of wave A depends substantially on the postsynaptic activation of muscarinic cholinergic receptors whose cells of origin lie within the brainstem reticular formation.

Significance testing of difference potentials.

This note provides a statistical-graphical method for the evaluation of the statistical significance of difference potentials from a group of subjects, and for the comparison of difference potentials between two groups. A table of the lengths of statistically significant intervals for various sampling interval lengths, numbers of subjects, and autocorrelation parameters is presented.

The effects of articulation on the acoustical structure of feline vocalizations.

Feline isolation calls were analyzed, and a model was developed to relate the acoustical features of these calls to the physical processes used in their production. Fifty isolation calls were recorded from each of five cats for a total sample of 250 vocalizations. By combinations of Fourier transform, autocorrelation, and linear prediction methods, the fundamental frequency (glottal-pulse period) F0, the energy of F0, the frequency having maximum energy Fmax (not always F0), and the energy at this frequency were computed. Mean F0 ranged from 400-600 Hz for individual cats. For some cats F0 was consistent within calls, but for other cats sudden shifts in F0 occurred within calls. Here, Fmax was almost a harmonic of F0 and generally ranged from 1-2 kHz. For individual cats, the energy ratio E = (energy of Fmax/energy of F0) varied from 1 to 60 and the grand average E over the time course of the call varied from about 12 to 38. The mean rms call intensity was an inverted-U function of time. Measured jaw opening was strongly correlated with acoustical features of call. A Bessel-horn model with time-varying flare gave a good account of acoustical parameters such as Fmax. The presence of formantlike resonances in cat vocalizations and the important role of jaw movements (vocal gestures) in the production of these calls suggest that cats may provide a useful model for some aspects of human vocal behavior.

Cholinergic neurons of the feline pontomesencephalon. I. Essential role in 'Wave A' generation.

Wave A in the cat appears to be analogous to P1 in the human. Both are positive middle-latency auditory-evoked potentials, present at slow click rates during wakefulness and REM sleep but absent during slow-wave sleep. Wave A has been recorded in the parabrachial and medial tegmental areas of the midbrain and in thalamic target projections of the reticular activating system. Two nuclei in this system, the pedunculopontine tegmental (PPT) and laterodorsal tegmental (LDT) nuclei, contain cholinergic cells; the cholinergic antagonist scopolamine eliminates Wave A. To test whether PPT and LDT were important in Wave A generation, we attempted to lesion these nuclei bilaterally in 11 cats. Wave A was markedly diminished or absent in all but 2 cats, in which the lesions did not include PPT. Loss of choline acetyltransferase-positive cells in PPT, but not LDT, was correlated with effects on Wave A, i.e. greatest cell loss occurred in cats in which Wave A disappeared, and least cell loss in cats with no change in Wave A. We conclude that the PPT nucleus, and particularly its cholinergic cell component, is essential for Wave A generation and suggests that a similar substrate may be significant for generation of the human P1.

Cholinergic neurons of the feline pontomesencephalon. II. Ascending anatomical projections.

Immunoreactivity for choline acetyltransferase (ChAT) was analyzed in unoperated cats and in cats in which stereotaxic lesions were made in the pedunculopontine and laterodorsal tegmental nuclei. The fine reaction product revealed moderate to dense ChAT-immunoreactive fiber plexuses throughout the telencephalon, diencephalon, and midbrain. A pontomesencephalic origin of cholinergic innervation to virtually every nucleus of the diencephalon, as well as to various midbrain and basal telencephalic sites was indicated in the cats with lesions, in which the optical density of ChAT-immunoreactivity was significantly decreased as compared to controls. Pontomesencephalic lesions produced no changes, however, in the density of ChAT staining in the cerebral cortex, basolateral amygdala, or caudate nucleus. In addition to ChAT-positive terminal fiber arborizations which were widely distributed, cholinergic fibers-of-passage were traced in the unoperated and operated feline brains. The general course of ChAT fibers cut in cross-section was followed in successive transverse levels, and although pathways originating from the pedunculopontine nucleus demonstrated orientations in every direction, many demonstrated a rostral course. A particularly dense aggregate of ascending ChAT-positive fibers was localized in the dorsolateral sector of the pedunculopontine area which could be followed at more rostral levels into the central tegmental fields and the compact part of the substantia nigra. From the central tegmental fields, numerous ChAT-immunopositive fibers cut in cross-section continued to course rostrally in the intralaminar, reticular and lateroposterior nuclei of the thalamus, and a distinct bundle of ChAT fibers coursing dorsolaterally was observed medial to the optic tract ascending to the lateral geniculate. ChAT fibers with dorsolateral orientations were additionally observed in the zona incerta, ventral anterior thalamus, and ansa lenticularis on route to the reticular thalamus, the globus pallidus, and the substantia innominata. Pathways consisting of fibers traced from ChAT-containing cells in the laterodorsal tegmental nucleus could be traced to medial structures such as the periaqueductal gray, ventral tegmental area and dorsal raphe. Medially placed ChAT fibers were additionally followed through the ventral tegmental area, the midline thalamus, and the hypothalamus, up to the medial and lateral septal nuclei. The trajectories of the ascending cholinergic pathways from the pontomesencephalon are discussed in relation to locally generated electrophysiological responses in the cat.

Cat-P300 present after association cortex ablation.

The cat-P300 is a positive endogenous potential, larger to a stimulus when rare than when frequent, with a latency of 200-500 msec. The role of polysensory association cortex, postulated to be important in human P300 generation, was assessed in the cat. EEG was recorded in 13 awake cats from a skull screw at the vertex. Stimuli included frequent (P = 0.80) 1 kHz and rare (P = 0.10) 2 kHz tone pulses with probabilities counterbalanced across 260-trial blocks. After 12 preoperative sessions, bilateral ablations were made of pericruciate cortex (4 cats), anterior lateral and medial suprasylvian gyri (4 cats) and all 3 areas (5 cats). Postoperatively, all 13 cats showed a P300 across 12 recording sessions. Thus polysensory association cortex is not essential for generation of the cat-P300.

Comparison of plasticity in sensory and cognitive processing systems.

The term "brain plasticity" can be applied to a number of processes, each with its own set of complex mechanisms. The plasticity of the human brain during postnatal development has been contrasted for a sensory, i.e., auditory, and cognitive system by comparing the development of two different evoked potential components. The short-latency auditory brainstem responses (ABRs), which are generated by auditory neurons within the brainstem auditory pathway, are mature by 1 to 2 years after birth. The rate of ABR development, as shown by longitudinal recordings from preterm infants, appears to be equally rapid in intrauterine and extrauterine environments. In contrast, the long-latency P300 cognitive potential, which reflects such processes as sequential information processing and short-term memory, does not show a mature waveform and latency until 14 to 17 years of age. This protracted rate of development cannot yet be related to a brain substrate, as the generator origins of the P300 are unknown. Clinical and animal data suggest, however, that limbic structures are critically involved. The long developmental history of the P300, in contrast to the ABRs, provides a functional measure of developmental plasticity in a cognitive versus a sensory brain system.

Midlatency auditory evoked responses: differential abnormality of P1 in Alzheimer's disease.

The human 'P1' middle latency evoked potential is postulated to be generated in the thalamus by a cholinergic component of the ascending reticular activating system. To test the hypothesis that P1 and its generator substrate are abnormal in Alzheimer's disease (AD), a disorder of marked cholinergic deficiency, recordings of middle latency responses to click stimuli were carried out. Comparisons between the AD and age-matched control groups indicated normal auditory brain-stem and Pa responses but a significant decrease in P1 amplitude. This P1 abnormality suggests that the midbrain cholinergic cells in AD may be dysfunctional.

Voiced calls evoked by hypothalamic stimulation in the cat.

Voiced vocalizations evoked by hypothalamic stimulation were studied in a series of six awake adult cats. Electrical stimulation was found to evoke vocalizations at numerous sites within the hypothalamus, ranging from A + 8 to A + 16. Regions showing the largest number of responsive sites were the preoptic region, the ventromedial area, the perifornical region, the lateral and the dorso-medial hypothalamus. The form of the evoked calls was generally similar to the spontaneous calls of the same animal. Call latency, duration, and intensity were not significantly affected by changes in stimulus intensity or duration but all three of these call parameters were significantly affected by changes in stimulus frequency. In general, call latency was longest at sites in the rostral hypothalamus and shortest at sites in the caudal hypothalamus. This study is the first to investigate systematically voiced call producing areas in the hypothalamus of awake cats and to document similarities between these calls and spontaneously produced voiced calls.

The role of auditory feedback in the vocalizations of cats.

The vocalizations of deaf cats were compared with those of littermate hearing controls at 30 days, 50 days, 1 year and 3 years of age. At all ages, deaf cats called more loudly than hearing animals. At 30 days, 50 days, and 3 years, deaf cats called about twice as loudly as hearing animals while at 1 year the calls of the deaf animals were approximately 6 times louder than those of the hearing littermates. Analysis of variance revealed significant differences in call loudness between deaf and hearing animals at 30 days, 1, and 3 years. Deaf and hearing animals did not differ in rate of calling or in the duration of individual vocalizations at 30 days, 50 days, and 1 year. At 3 years, the calls of the deaf animal were shorter than those of the hearing control. The calls of deaf animals were less variable than those of hearing animals at 30 days, 50 days, and 3 years. There was a tendency for the fundamental frequency of the calls of deaf animals to be higher than that of hearing animals at 30 days, 50 days, and 1 year. These results document the importance of auditory feedback in the regulation of feline vocalization.

'Cat P300' disappears after septal lesions.

Endogenous responses were recorded from 9 awake cats with loud and soft clicks randomly presented as rare (P = 0.15) or frequent (P = 0.80) stimuli; a reinforced tone CS (P = 0.05) resulted in a conditioned eye blink response and focused the cat's attention on the auditory stimuli. Subsequent to 12 preoperative recording sessions the medial septal area was lesioned in 7 cats and similar but more rostral lesions were placed in 2 cats. Thereafter, 12 postoperative recording sessions were carried out, the animals were terminated, and the brains processed for AChE histochemistry and histology of the lesioned areas. Destruction of the medial septum and vertical limb of the diagonal band of Broca resulted in a transient postoperative 'cat P300' followed by reduction and disappearance of the response. The hippocampus of these animals was characterized by marked AChE depletion. In contrast, the animals with lesions rostral to the medial septal area showed no postoperative change in the P300 response and no depletion of hippocampal AChE. These data indicate an important role for the medial septal area as a modulator of 'cat P300' generation possibly through the cholinergic component of the septohippocampal projection system.

Midlatency auditory evoked responses in the human and the cat model.

Findings from the experiments summarized above indicate that the MRL components, Pa and P1, are differentially affected by several functional and parametric variables, suggesting that each of these components reflects a separate and distinct generator system. Moreover, the similarities between the human Pa and the cat wave 7 suggest an auditory cortex origin of this component. The similarities between the human P1 and the cat wave A suggest that in the human, as in the cat, this potential may be generated by a component of the ascending reticular activating system.

Midlatency auditory evoked responses: differential recovery cycle characteristics.

Middle latency responses (MLRs), in the 10-100 msec latency range evoked by click stimuli, were examined in two sets of 7 adult subjects utilizing 5 randomly ordered rates of stimulus presentation: 0.5/sec, 1/sec, 5/sec, 8/sec and 10/sec. Evoked potentials were collected in 250 trial averages for each rate, and a replication across rates yielded 500 trial averages. Peak-to-peak measurements for Pa-Nb and P1-Nb components revealed that the P1 component was reduced in amplitude or absent at the faster rates, while the amplitude of the Pa component remained unchanged across rates. In addition, the latency of Pa was significantly longer for the faster rates of stimulation. These findings were similar across both mastoid and sternovertebral references. Taken together with previous work, these data suggest that the human Pa and P1 potentials reflect different generator systems. Moreover, the physiological similarities between the human P1 potential and the cat wave A suggest that in the human, as in the cat, this potential may be generated within the ascending reticular activating system, whereas the physiological similarities between the human Pa and the cat wave 7, as well as previous clinical data, suggest an auditory cortex origin of this component.