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The effect of normal aging on the coupling of neural activity to the bold hemodynamic response.

The use of functional neuroimaging to test hypotheses regarding age-related changes in the neural substrates of cognitive processes relies on assumptions regarding the coupling of neural activity to neuroimaging signal. Differences in neuroimaging signal response between young and elderly subjects can be mapped directly to differences in neural response only if such coupling does not change with age. Here we examined spatial and temporal characteristics of the BOLD fMRI hemodynamic response in primary sensorimotor cortex in young and elderly subjects during the performance of a simple reaction time task. We found that 75% of elderly subjects (n = 20) exhibited a detectable voxel-wise relationship with the behavioral paradigm in this region as compared to 100% young subjects (n = 32). The median number of suprathreshold voxels in the young subjects was greater than four times that of the elderly subjects. Young subjects had a slightly greater signal:noise per voxel than the elderly subjects that was attributed to a greater level of noise per voxel in the elderly subjects. The evidence did not support the idea that the greater head motion observed in the elderly was the cause of this greater voxel-wise noise. There were no significant differences between groups in either the shape of the hemodynamic response or in its the within-group variability, although the former evidenced a near significant trend. The overall finding that some aspects of the hemodynamic coupling between neural activity and BOLD fMRI signal change with age cautions against simple interpretations of the results of imaging studies that compare young and elderly subjects.

Adolescent↗

Dopamine-rich grafts ameliorate whole body motor asymmetry and sensory neglect but not independent limb use in rats with 6-hydroxydopamine lesions.

The capacity of dopamine (DA)-rich embryonic grafts to influence performance in a skilled motor task has been assessed. In two separate experiments, unilateral 6-hydroxydopamine lesions of forebrain DA systems induced a neglect of the contralateral limb and an almost total preference for use of the ipsilateral limb when reaching through the bars of a cage for food pellets. If the food paw was restrained, either by a bracelet or by injection of a local anaesthetic, the lesioned rats would continue to make many reaching attempts with the contralateral paw, but on the great majority of these attempts they were unsuccessful in grasping or retrieving food. DA-rich grafts, reinnervating the denervated caudate-putamen, provided no detectable benefit to the lesioned rats, neither in reducing the ipsilateral bias in their side preference, nor in increasing their success when constrained to reaching with the contralateral limb. This failure to benefit from the grafts is not due to the grafts themselves not being viable, since the same rats showed substantial compensation of whole body motor asymmetries in spontaneous and drug-induced rotation, and a reduction of asymmetry in a battery of neurological tests of sensorimotor function. The results are discussed in terms of the degree of anatomical integration of the grafts into the host neural circuitry, and the neural organization necessary for the performance of different classes of behavior.

Animals↗

Middle age increases tissue vulnerability and impairs sensorimotor and cognitive recovery following traumatic brain injury in the rat.

With increasing age comes an increased risk for sustaining traumatic brain injuries (TBI). However, the effect of age is rarely studied in animal models of TBI. The present study evaluated the effect of increased age on recovery of function following bilateral medial frontal cortex injury. Groups of young (3 months) and middle-aged (14 months) rats received bilateral frontal cortex contusions or sham injuries. The rats were tested on a variety of tests to measure sensorimotor performance (bilateral tactile adhesive removal test), skilled forelimb use (staircase test), and the acquisition of reference and working memory in the Morris water maze. Results indicated that injury produced significant impairments on all behavioral tests compared to sham controls. Middle-aged rats that received cortical contusions were significantly impaired on the bilateral tactile adhesive removal test, acquisition of a reference memory task, and working memory compared to young-injured rats. Histological analysis showed that middle-aged rats developed significantly larger lesion cavities but did not show an increase in the number of glial fibrillary acidic protein (GFAP+) cells compared to young-injured rats. Age alone also significantly impaired function on the bilateral adhesive tactile removal test, skilled forelimb use, the acquisition of a reference memory task, and also increased the number of GFAP+ cells compared to young rats. These results indicate that middle-aged rats respond to brain injury differently than young rats and that age is an important factor to consider in pre-clinical efficacy studies.

Age Factors↗

Is postnatal neocortical maturation hierarchical?

To understand the postnatal development of the cerebral cortex we must know how changes in one cortical area depend on inputs from other cortical areas. Do cortical areas serving early stages of processing (primary sensory receiving areas) mature first, passing relatively stable outputs about sensorimotor relationships to cortical areas involved in higher stages of processing that are still developing? And, if some areas mature later than others, do they have functions that can account for aspects of adolescent behavior? Some observations support concurrent maturation in all cortical areas, others support a hierarchical sequence. Here, evidence on this important issue is evaluated, and means of obtaining reliable information are presented.

Animals↗

Increasing CNS norepinephrine levels by the precursor L-DOPS facilitates beam-walking recovery after sensorimotor cortex ablation in rats.

The present investigation was conducted to document a role of L-threo-3,4-dihydroxyphenylserine (L-DOPS), precursor of L-norepinephrine (NE), in the functional recovery from beam-walking performance deficits in rats after unilateral sensorimotor cortex ablation. L-DOPS was administered simultaneously with benserazide (BSZ; a peripheral aromatic amino acid decarboxylase inhibitor), and the regional contents of NE in the cerebral cortex, hippocampus, and cerebellum were assayed. Behavioral recovery was demonstrated by the rats treated with L-DOPS and BSZ, and the rate of recovery was significantly different from that of either BSZ-treated or vehicle-treated control rats. The NE tissue levels in the three discrete regions of the rat brain were significantly elevated in the experimental rats receiving both L-DOPS and BSZ. The present studies indicate that increasing NE levels by the precursor L-DOPS may be responsible for facilitating behavioral recovery from beam-walking performance deficits in rats, and further suggest that L-DOPS may become one of the candidate compounds for further clinical human trials promoting functional recovery after injuries to the cerebral cortex.

Animals↗

Multisensory interaction in saccadic reaction time: a time-window-of-integration model.

Saccadic reaction time to visual targets tends to be faster when stimuli from another modality (in particular, audition and touch) are presented in close temporal or spatial proximity even when subjects are instructed to ignore the accessory input (focused attention task). Multisensory interaction effects measured in neural structures involved in saccade generation (in particular, the superior colliculus) have demonstrated a similar spatio-temporal dependence. Neural network models of multisensory spatial integration have been shown to generate convergence of the visual, auditory, and tactile reference frames and the sensorimotor coordinate transformations necessary for coordinated head and eye movements. However, because these models do not capture the temporal coincidences critical for multisensory integration to occur, they cannot easily predict multisensory effects observed in behavioral data such as saccadic reaction times. This article proposes a quantitative stochastic framework, the time-window-of-integration model, to account for the temporal rules of multisensory integration. Saccadic responses collected from a visual-tactile focused attention task are shown to be consistent with the time-window-of-integration model predictions.

Adaptation, Physiological↗

Figure drawing as an expression of self-esteem.

Figure drawings were obtained from 97 preadolescent males who differed in self and behavioral assessments of self-esteem. These subjects had been selected from a much larger sample and represented five different types of self-esteem. The figure drawings were scored for 15 variables, dealing with formal characteristics, content, and global-interpretations of the total drawings. Five significant differences were obtained, with the content and global-interpretative categories proving more differentiating between self-esteem groups than did the formal characteristics. Behavioral expressions of self-esteem were more associated with figure drawing characteristics than were subjective evaluations. Discussion focuses on the nature of self-concept and self-esteem in children as a sensorimotor rather than symbolic expression.

Child↗

Psychosocial and academic characteristics of extremely low birth weight (< or =800 g) adolescents who are free of major impairment compared with term-born control subjects.

OBJECTIVE: To compare academic and cognitive ability, attention, attitudes, and behavior of extremely low birth weight (ELBW) adolescents who are free of major impairments at 17 years of age with term-born control subjects. METHODS: Between January 31, 1981, and February 9, 1986, 250 infants of < or =800 g were admitted for intensive care in British Columbia, 98 (39%) of whom survived to late adolescence. Teens with major sensorimotor handicaps and/or IQ <70 were excluded (n = 19). Of the 79 eligible ELBW teens, 53 (67%) were assessed at 17.3 (16.3-19.7) years (birth weight: 720 [520-800 g]; gestation: 26 [23-29] weeks). The test battery screened the following areas: cognitive (Wechsler Intelligence Scale for Adults Third Edition, 3 subtests), academic (Wide Range Achievement Test-3), attention (Connors' Continuous Performance Task), self-report (Harter Self-Perception Profile for Adolescents; Job Search Attitude Inventory), and parent report (Child Behavior Check List). A comparison group of term born control subjects (n = 31) were also assessed (birth weight: 3506 [3068-4196] g; gestation: 40 [39-42] weeks) at age 17.8 (16.5-19.0) years. Multivariate analysis of variance (group x gender) was conducted for each domain (cognitive, academic, self-report, and parent report). RESULTS: The ELBW group showed lower cognitive scores (vocabulary, block design, and digit symbol) and academic skills (reading and arithmetic) compared with control subjects, with no gender differences. There were no differences in attention between the 2 groups using a repetitive computer task. ELBW teens reported lower scholastic, athletic, job competence, and romantic confidence and viewed themselves as more likely to need help from others in finding a job. In the behavioral domain, parents reported their ELBW teens to display more internalizing, more externalizing, and more total problems than the control teens, with ELBW boys showing more problems. ELBW teens showed a higher percentage of clinically significant behavior problems than control subjects. CONCLUSIONS: In a provincial cohort of unimpaired survivors of birth weight < or =800 g, psychosocial and educational vulnerabilities persist into late adolescence and may complicate the transition to adult life compared with their peers.

Adolescent↗

Human hippocampal theta activity during virtual navigation.

This study examines whether 4-8-Hz theta oscillations can be seen in the human hippocampus, and whether these oscillations increase during virtual movement and searching, as they do in rodents. Recordings from both hippocampal and neocortical depth electrodes were analyzed while six epileptic patients played a virtual taxi-driver game. During the game, the patients alternated between searching for passengers, whose locations were random, and delivering them to stores, whose locations remained constant. In both hippocampus and neocortex, theta increased during virtual movement in all phases of the game. Hippocampal and neocortical theta activity were also significantly correlated with each other, but this correlation did not differ between neocortex and hippocampus and within disparate neocortical electrodes. Our findings demonstrate the existence of movement-related theta oscillations in human hippocampus, and suggest that both cortical and hippocampal oscillations play a role in attention and sensorimotor integration.

Adult↗

Formation of the conditioned reflexes to a complex signal in ontogenesis under alternate choice conditions.

The formation of a conditioned reflex to a complex signal, "light + sound," and its components under alternate choice conditions was studied in kittens aged 1.5-10 months. A preference for one of the food dispensers and a low percent of correct reactions (48-57%) was characteristic during the process of training for kittens aged from 1.5 to 5 months. Successful training using the alternate choice method was achieved in kittens whose training began at six months of age. A lesion of the sensorimotor region of the cortex in the same kittens following the achievement of a high level of correct reactions (75-80%) led to a disturbance in the previously developed reflex to the complex signal and its components. The latter was expressed in the manifestation of unidirectional motoric reactions and a sharp decrease in the percent of correct reactions. The question of the confinement of the development of different forms of interaction of the sensory and motor systems to specific age periods and the participation in this process of the sensorimotor region of the cortex is discussed.

Acoustic Stimulation↗

Balance control and posture differences in the anxious BALB/cByJ mice compared to the non anxious C57BL/6J mice.

A relation between anxiety disorders and balance control dysfunctions has been observed in many studies in humans. A mismatch in the integration of sensory inputs could trigger these disturbances. Very few experimental animal procedures have been designed to study the functional link between anxiety and balance control. A task was therefore developed, challenging the visual, vestibular and somesthesic sensory systems in mice. The test, called the 'rotating beam', gave an accurate assessment of balance control and the posture, using sensitive measures (number of falls and imbalances, position of tail and trunk). Striking differences were observed between the two inbred strains of mice known to have radically different anxiety-related behaviour. The highly anxious strain, BALB/cByJ, performed poorly compared to the non anxious strain, C57BL/6J. Balance control and postural abilities of anxious mice were improved by acute anxiolytic diazepam treatment. Lower behavioural performance level was registered in non anxious mice given anxiogenic beta-CCM treatment. The findings account for a strong relationship between anxiety and balance control in mice. Finally, the highly sensitive procedure proved to be well suited to the study of functional links between anxiety and sensorimotor processes.

Animals↗

Representation of time by neurons in the posterior parietal cortex of the macaque.

The neural basis of time perception is unknown. Here we show that neurons in the posterior parietal cortex (area LIP) represent elapsed time relative to a remembered duration. We trained rhesus monkeys to report whether the duration of a test light was longer or shorter than a remembered "standard" (316 or 800 ms) by making an eye movement to one of two choice targets. While timing the test light, the responses of LIP neurons signaled changes in the monkey's perception of elapsed time. The variability of the neural responses explained the monkey's uncertainty about its temporal judgments. Thus, in addition to their role in spatial processing and sensorimotor integration, posterior parietal neurons encode signals related to the perception of time.

Action Potentials↗

Effects of deafening on the development of nestling and juvenile vocalizations in budgerigars (Melopsittacus undulatus).

The effects of complete and partial cochlear extirpation at ages 9-11 days posthatch were assessed in 5 nestling budgerigars (Melopsittacus undulatus) to determine if auditory feedback is necessary for the production of nestling vocalizations. Although early deafening had no effect on the production of food-begging calls produced during the first 2 weeks posthatch, deafening did disrupt the expected transition from these early calls to the longer and more complex frequency-modulated, patterned food-begging calls normally appearing 3-4 weeks posthatch. All birds sustaining either complete or partial cochlear extirpation failed to develop stereotyped contact calls around the time of fledging at 5 weeks. These results are consistent with previous research showing that deafened nestlings do not develop normal contact calls (R. J. Dooling, B. F. Gephart, P. H. Price, C. McHale, & S. E. Brauth, 1987) and also indicate that a form of sensorimotor learning is involved in the production of mature, patterned food-begging calls in budgerigars.

Animals↗

Speed and accuracy of olfactory discrimination in the rat.

The sense of smell is typically thought of as a 'slow' sense, but the true temporal constraints on the accuracy of olfactory perception are not known. It has been proposed that animals make finer odor discriminations at the expense of additional processing time. To test this idea, we measured the relationship between the speed and accuracy of olfactory discrimination in rats. We found that speed of discrimination was independent of odor similarity, as measured by overlap of glomerular activity patterns. Even when pushed to psychophysical limits using mixtures of two odors, rats needed to take only one sniff (<200 ms at theta frequency) to make a decision of maximum accuracy. These results show that, for the purpose of odor quality discrimination, a fully refined olfactory sensory representation can emerge within a single sensorimotor or theta cycle, suggesting that each sniff can be considered a snapshot of the olfactory world.

Animals↗

Striatal preprotachykinin gene expression reflects parkinsonian signs.

Striatal preprotachykinin (PPT) gene expression was measured in MPTP-treated cats when symptomatic and during various stages of recovery from parkinsonism using in situ hybridization histochemistry. Animals expressing severe (1 week post-MPTP) or moderate (3 weeks post-MPTP) parkinsonian sensorimotor deficits had significantly reduced striatal PPT mRNA expression. In contrast, fully recovered animals (6 weeks post-MPTP) had striatal PPT mRNA levels that were not significantly different from normal. Thus, PPT gene expression in the striatum appears to reflect presence or absence of sensorimotor deficits in MPTP-treated cats.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

Timing and velocity randomization similarly affect anticipatory pursuit.

Smooth pursuit eye movements are guided largely by retinal-image motion. To compensate for neural conduction delays, the brain employs a predictive mechanism to generate anticipatory pursuit that precedes target motion (E. Kowler, 1990). A critical question for interpreting neural signals recorded during pursuit concerns how this mechanism is interfaced with sensorimotor processing. It has been shown that the predictor is not simply turned-off during randomization because anticipatory eye velocity remains when target velocity is randomized (E. Kowler & S. McKee, 1987; G. W. Kao & M. J. Morrow, 1994). This study was completed to compare pursuit behavior during randomized motion-onset timing with that occurring during direction or speed randomization. We found that anticipatory eye velocity persisted despite motion-onset randomization, and that anticipation onset time was between that observed in the different constant-timing conditions. This centering strategy was similar to the bias of eye velocity magnitude away from extremes observed when direction or speed was randomized. Such a strategy is comparable to least-squares error minimization, and could be used to facilitate acquisition of a target when it begins to move. Centering was in some observers accounted for by a shift of eye velocity toward that generated in the preceding trial. The results make unlikely a model in which the predictor is disengaged by randomizing stimulus timing, and suggest that predictive signals always interact with those used in sensorimotor processing during smooth pursuit.

Humans↗

Medial prefrontal cortex volume loss in rats with isolation rearing-induced deficits in prepulse inhibition of acoustic startle.

Rearing rats in isolation produces perturbations in behavior and brain neurochemistry suggested to resemble those of schizophrenia. In particular, isolation-reared rats display deficits in prepulse inhibition of acoustic startle that in humans are associated with disorders including schizophrenia and are interpreted as abnormalities in sensorimotor gating. The prefrontal cortex is considered important in the regulation of prepulse inhibition of acoustic startle and postmortem studies suggest that neuropil and total volume, but not total number of neurons, are decreased in this region of the brains of schizophrenic patients. In this study we used design-based stereological techniques to examine the brains of Lister Hooded rats, reared in isolation and which displayed prepulse inhibition of acoustic startle deficits, for changes in morphology compared with the brains of their socially-reared littermates. Pooled data from three batches of animals revealed a significant 7% volume loss of the medial prefrontal cortex of isolation-reared rats whereas neuron number in this region was unchanged. In contrast, volume and total neuron number were unaffected in the rostral caudate putamen. The robust reduction in prefrontal cortical volume observed in isolation-reared rats, in the absence of reductions in total neuron number, suggest that there is a loss of volume of the neuropil. These changes parallel those reported in schizophrenia patients and therefore support the construct validity of this model.

Acoustic Stimulation↗