Biomedical subjects
Publications and source records attributed to R Romo.
Neuroimaging techniques may aid in the identification of areas of the human brain that are involved in tactile shape perception. Bodegård et al. (2001) relate differences in the properties of tactile stimuli to differences in areas of cortical activation to infer tactile processing in the somatosensory network.
A complex sequence of neural events unfolds between sensory receptor activation and motor activity. To understand the underlying decision-making mechanisms linking somatic sensation and action, we ask what components of the neural activity evoked by a stimulus are directly related to psychophysical performance, and how are they related. We find that single-neuron responses in primary and secondary somatosensory cortices account for the observed performance of monkeys in vibrotactile discrimination tasks, and that neuronal and behavioral responses covary in single trials. This sensory activity, which provides input to memory and decision-making mechanisms, is modulated by attention and behavioral context, and microstimulation experiments indicate that it may trigger normal perceptual experiences. Responses recorded in motor areas seem to reflect the output of decision-making operations, which suggests that the ability to make decisions occurs at the sensory-motor interface.
The flutter sensation is felt when mechanical vibrations between 5 and 50 Hz are applied to the skin. Neurons with rapidly adapting properties in the somatosensory system of primates are driven very effectively by periodic flutter stimuli; their evoked spike trains typically have a periodic structure with highly regular time differences between spikes. A long-standing conjecture is that, such periodic structure may underlie a subject's capacity to discriminate the frequencies of periodic vibrotactile stimuli and that, in primary somatosensory areas, stimulus frequency is encoded by the regular time intervals between evoked spikes, not by the mean rate at which these are fired. We examined this hypothesis by analyzing extracellular recordings from primary (S1) and secondary (S2) somatosensory cortices of awake monkeys performing a frequency discrimination task. We quantified stimulus-driven modulations in firing rate and in spike train periodicity, seeking to determine their relevance for frequency discrimination. We found that periodicity was extremely high in S1 but almost absent in S2. We also found that periodicity was enhanced when the stimuli were relevant for behavior. However, periodicity did not covary with psychophysical performance in single trials. On the other hand, rate modulations were similar in both areas, and with periodic and aperiodic stimuli, they were enhanced when stimuli were important for behavior, and were significantly correlated with psychophysical performance in single trials. Thus, the exquisitely timed, stimulus-driven spikes of primary somatosensory neurons may or may not contribute to the neural code for flutter frequency, but firing rate seems to be an important component of it.
Monkeys are able to discriminate the difference in frequency between two periodic mechanical vibrations applied sequentially to the fingertips. It has been proposed that this ability is mediated by the periodicity of the responses in the quickly adapting (QA) neurons of the primary somatosensory cortex (S1), instead of the average firing rates. We recorded from QA neurons of S1 while monkeys performed the vibrotactile discrimination task. We found that the periodic mechanical vibrations can be represented both in the periodicity and in the firing rate responses to varying degrees across the QA neuronal population. We then computed neurometric functions by using both the periodicity and the firing rate and sought to determine which of these two measures is associated with the psychophysical performance. We found that neurometric thresholds based on the firing rate are very similar to the animal's psychometric thresholds whereas neurometric thresholds based on periodicity are far lower than those thresholds. These results indicate that an observer could solve this task with a precision similar to that of the monkey, based only on the firing rate produced during the stimulus periods.
OBJECTIVE: To determine the enzymatic activity and cellular localization of matrix metalloproteinases (MMPs) 2, 3, and 9 in labial salivary glands from patients with different degrees of severity of primary Sjogren's syndrome (primary SS). METHODS: Gelatinase activity was determined by zymography and quantified by densitometry. The specificity of MMPs was determined using protease inhibitors and chelators, as well as activators of the latent forms of these enzymes. The cellular localization of MMPs was carried out using monoclonal antibodies that recognize their latent and active forms. RESULTS: Labial glands from control subjects and patients showed gelatinase activity for MMP-2 and MMP-9. Activation studies revealed that both enzymes were predominantly present in their latent forms. The highest levels of MMP-9 activity were detected in patients with severe, active, primary SS (except for patients with severe clinical symptoms for extended periods) and correlated with structural and functional glandular changes. MMP-2 activity was almost the same in patients and controls. MMPs were detected by immunolocalization only in acinar and ductal cells and were homogeneously distributed throughout patients' glands. MMP-2 and MMP-9 expression paralleled their gelatinase activity. MMP-3, detectable only with immunologic methods, was absent in control subjects but abundantly expressed in patients. Importantly, MMP protein levels in acinar and ductal cells were independent of either the presence or the proximity of mononuclear infiltrate cells. CONCLUSION: MMP-3 and MMP-9 expression, as well as MMP-9 catalytic activity, were increased in tissue samples from SS patients in a manner that correlated with the severity of the disease. Most important, increased MMP activity stemmed from exocrine epithelial cells and was not due to infiltrating lymphocytes. Thus, changes in salivary glands as a consequence of proteolysis may lead to severe glandular destruction.
Unequivocal proof that the activity of a localized cortical neuronal population provides sufficient basis for a specific cognitive function has rarely been obtained. We looked for such proof in monkeys trained to discriminate between two mechanical flutter stimuli applied sequentially to the fingertips. Microelectrodes were inserted into clusters of quickly adapting (QA) neurons of the primary somatosensory cortex (S1), and the first or both stimuli were then substituted with trains of current pulses during the discrimination task. Psychophysical performance with artificial stimulus frequencies was almost identical to that measured with the natural stimulus frequencies. Our results indicate that microstimulation can be used to elicit a memorizable and discriminable analog range of percepts, and shows that activation of the QA circuit of S1 is sufficient to initiate all subsequent neural processes associated with flutter discrimination.
Humans and monkeys have similar abilities to discriminate the difference in frequency between two mechanical vibrations applied sequentially to the fingertips. A key component of this sensory task is that the second stimulus is compared with the trace left by the first (base) stimulus, which must involve working memory. Where and how is this trace held in the brain? This question was investigated by recording from single neurons in the prefrontal cortex of monkeys while they performed the somatosensory discrimination task. Here we describe neurons in the inferior convexity of the prefrontal cortex whose discharge rates varied, during the delay period between the two stimuli, as a monotonic function of the base stimulus frequency. We describe this as 'monotonic stimulus encoding', and we suggest that the result may generalize: monotonic stimulus encoding may be the basic representation of one-dimensional sensory stimulus quantities in working memory. Thus we predict that other behavioural tasks that require ordinal comparisons between scalar analogue stimuli would give rise to monotonic responses similar to those reported here.
Combined psychophysical and neurophysiological experiments have revealed some of the neural codes associated with perception and processing of tactile information. Recently, intracortical microstimulation was used to demonstrate a causal link between primary cortical activity and perception. Evidence for a subsequent link, between a sensory decision process and its expression as a movement, has been found in motor areas.
The sensation of flutter is produced when mechanical vibrations in the range of 5-50Hz are applied to the skin. A flutter stimulus activates neurons in the primary somatosensory cortex (S1) that somatotopically map to the site of stimulation. A subset of these neurons-those with quickly adapting properties, associated with Meissner's corpuscles-are strongly entrained by periodic flutter vibrations, firing with a probability that oscillates at the input frequency. Hence, quickly adapting neurons provide a dynamic representation of such flutter stimuli. However, are these neurons directly involved in the perception of flutter? Here we investigate this in monkeys trained to discriminate the difference in frequency between two flutter stimuli delivered sequentially on the fingertips. Microelectrodes were inserted into area 3b of S1 and the second stimulus was substituted with a train of injected current pulses. Animals reliably indicated whether the frequency of the second (electrical) signal was higher or lower than that of the first (mechanical) signal, even though both frequencies changed from trial to trial. Almost identical results were obtained with periodic and aperiodic stimuli of equal average frequencies. Thus, the quickly adapting neurons in area 3b activate the circuit leading to the perception of flutter. Furthermore, as far as can be psychophysically quantified during discrimination, the neural code underlying the sensation of flutter can be finely manipulated, to the extent that the behavioural responses produced by natural and artificial stimuli are indistinguishable.
Movement triggered by sensory stimuli requires that the networks generating the motor commands receive an adequate driving input, which, in general, is a transformed version of the initial sensory signal. We investigated the nature of this transformation in a task in which monkeys categorize the speed of tactile stimuli as either low or high, reaching for one of two pushbuttons to indicate their choice. Extracellular recordings from primary motor cortex revealed two types of neurons selective for the speed categories: ones that fire at higher rates for low versus high speeds, and others that do the opposite. These differential responses are task-specific; no firing rate modulation was seen when identical arm movements were triggered by visual cues or when stimuli were delivered passively. Analyses using decoding and modeling techniques produced two main results. First, the neurons accurately encode the chosen category; an observer measuring their responses can exhibit a psychophysical performance during categorization identical to the monkey's. Second, by analyzing separately the trials in which hits and errors were scored, it is possible to distinguish purely sensory activity from activity exclusively related to arm motion. The recorded responses did not match either of these alternatives but were consistent with a model in which the category-tuned neurons are the link between the output of the sensory categorization process and the motor command used to indicate the animal's decision. Thus, the observed activity seems to encode a preprocessed version of the sensory stimulus and to participate in driving the arm motion.
Humans and monkeys have similar capacities to discriminate the frequencies of mechanical sinusoids delivered to their hands in the range that corresponds to the sense of flutter (10-50 Hz). Previous studies showed that monkeys can discriminate whether comparison stimuli are higher or lower in frequency than a base stimulus that does not vary from trial to trial during an experiment. We verified this result in two monkeys trained in this manner. To confirm that these animals were able to discriminate, we tested them in a variant of the task in which the frequency of the base stimulus changed randomly from trial to trial. The monkeys failed to discriminate in this new testing mode; instead they seemed to categorize the comparison stimuli, ignoring the base stimulus. After further training in the randomized base condition, the two monkeys learned to discriminate accurately. We then explored how the stimulation parameters affected performance. We found that animals could discriminate accurately with stimulus durations as short as 250 msec, with interstimulus intervals as long as 10 sec, with 50% differences between base and comparison stimulus amplitudes or when stimulated on a different finger. Performance did not degrade in these conditions, even though the monkeys had never been trained or tested under them. The results show that monkeys may try to categorize rather than discriminate when the task allows either strategy, although they are capable of performing true discriminations very robustly. These findings have important implications for investigating the neuronal processes underlying sensory discrimination.
We lesioned the right primary somatic sensory (S1) cortex in two monkeys trained to categorize the speed of moving tactile stimuli. Animals performed the task by pressing with the right hand one of two target switches to indicate whether the speed of a probe moving across the glabrous skin of the left hand was low or high. Sensory performance was evaluated with psychometric techniques and motor behavior was monitored by measuring the reaction (RT) and movement (MT) times before the experiment and throughout the 60 days after the ablation of SI cortex. After the lesion, there was a slight increase in the RTs but no change in the MTs, indicating that removal of SI cortex did not affect the animals' capacity to detect the stimuli. However, monkeys lost their ability to categorize the stimulus speeds. This effect was observed from the 1st day after the lesion until the end of the study. We conclude that somatosensory areas outside SI can by themselves process tactile information in a limited way and that the extraction of higher-order features that takes place during the categorization task requires the intervention of SI cortex.
In this paper we describe a type of neuron of the medial premotor cortex (MPC) that discharged differentially during a categorization task and reflected in their activity whether the speed of a tactile stimulus was low or high. The activity of these neurons was recorded in the MPC contralateral (right MPC, n = 88) and ipsilateral (left MPC, n = 103) to the stimulated hand of four monkeys performing this somesthetic task. Animals performed the task by pressing with the right hand one of two target switches to indicate whether the speed of probe movement across the skin of the left hand was low or high. Differential responses of MPC neurons occurred during the stimulus and reaction time period. We used an analysis based on signal detection theory to determine whether these differential responses were associated with the animal's decision. According to this analysis, 104 of the 191 neurons (right MPC, n = 48; left MPC, n = 56) coded the categorization of the stimulus speeds (categorical neurons). In a light instruction task, we tested the possibility that the categorical neurons (n = 71) were associated with the intention to press, or with the trajectory of the hand to one of the two target switches used to indicate categorization. In this situation, each trial began as in the somesthetic categorization task, but one of the two target switches was illuminated beginning with the skin indentation, continued during the delay period and turned off when the probe was lifted off from the skin. This condition instructed the animal which target switch was required to be pressed for reward. Very few neurons (14 of 71) maintained their differential responses observed in the categorization task. Some categorical neurons (n = 5) were also studied; the animal categorized the tactile stimulus speeds, but knew in advance whether the stimulus speed was low or high (categorization + light instruction). This was made by illuminating one of the two target switches which was associated with the stimulus speed. The categorical response was considerably attenuated in this condition. Interestingly, during the delay period, these neurons reflected in their activity whether the stimulus was low or high. A number of the categorical MPC neurons (n = 30) were studied when the same set of stimuli, used in the categorization, were delivered passively. None of these neurons responded in this condition. These results suggest that the MPC, apart from its well-known role in motor behavior, is also involved in the animal's decision during the execution of this learned somesthetic task.
We used psychometric techniques and neurophysiological recordings to study the role of the putamen in somesthetic perception. Four monkeys were trained to categorize the speed of moving tactile stimuli. Animals performed a task in which one of two target switches had to be pressed with the right hand to indicate whether the speed of probe movement across the glabrous skin of the left, restrained hand was low or high. During the task we recorded the activity of neurons in the putamen contralateral (right) and ipsilateral (left) to the stimulated hand. We found different types of neuronal responses, all present in the right and left putamen. Some neurons responded during the stimulus period, others responded during the hand-arm movement used to indicate categorization, and others responded during both of these periods. The responses of many neurons did not vary either with the speed of the stimuli or in relation to the categorization process. In contrast, neurons of a particular type responded differentially: their activity reflected whether stimulus speed was low or high. These differential responses occurred during the stimulus and hand-arm motion periods. A number of the nondifferential and differential neurons were studied when the same stimuli used in the categorization task were delivered passively. Few neurons with nondifferential discharges, and none of the differential neurons, responded in this condition. In a visually cued control task we studied the possibility that the differential responses were associated with the intention to press or with the trajectory of the hand to one of the target switches. In this condition, a light turned on instructed the animal which target switch to press for a reward. Very few neurons in both hemispheres maintained the differential responses observed during the categorization task. Those neurons that discharged selectively for low or high speeds were analyzed quantitatively to produce a measure comparable with the psychometric function. The thresholds of the resulting neurometric curves for the neuronal populations were very similar to the psychometric thresholds. The activity of a large fraction of these neurons could be used to accurately predict whether the stimulus speed was low or high. The results indicate that the putamen, both contralateral and ipsilateral to the stimulated hand, contains neurons that discharge in response to the somesthetic stimuli during the categorization task. Those neurons that respond irrespective of the stimulus speed appear to be involved in the general sensorimotor behavior of the animal during the execution of the task. The results suggest that the putamen may play a role in bimanual tasks. The recording of neurons in the right and left putamen whose activities correlate with the speed categories suggests that this region of the basal ganglia, in addition to its role in motor functions, is also involved in the animal's decision process.
We used psychometric techniques to study the sensorimotor performance of four monkeys trained to classify the speed of moving tactile stimuli. Animals performed the task by pressing one of two target switches to indicate whether the speed of probe movement across the glabrous skin of the hand was low or high. Psychometric curves indicated that animals classified the stimulus speeds irrespective of which finger was stimulated, traverse distance and direction. The mean values of the reaction (RT) and movement (MT) times during the correct categorization of low and high stimulus speeds were similar. However, a slight increase was detected in the mean values of the RT during the incorrect categorization but not in the MT. During the task, activity of single neurones (n = 45) was recorded in primary somatic sensory (SI) cortex. The results indicate that a class of neurones (n = 12) of SI cortex increased their impulse rates as a function of the stimulus speeds. However, the magnitude of their responses was similar during the correct and incorrect categorizations of stimuli. The same neurones also responded when the same set of stimuli used in the categorization task were delivered passively. Neurones of SI cortex responded with a latency of 25.8 +/- 0.6 ms (+/- s.e.m.) relative to the beginning of the moving tactile stimuli during the categorization task. The same neurones (n = 17) also responded with a similar latency (24.6 +/- 4.0 ms) when the stimuli were delivered passively. These results may suggest that, although this evoked neuronal activity may be important for the perception of the moving tactile stimuli, more central structures associated with SI cortex may determine the performance of this learned somaesthetic task.
We have studied neuronal activity in the putamen of two monkeys trained to discriminate the speed of moving tactile stimuli. Animals pressed one of two target switches to indicate whether the speed of the probe across the skin was low or high. The activity of single neurones was recorded in the putamen ipsilateral to the glabrous skin of the stimulated hand and contralateral to the responding arm. During the task, we recorded neurones in the putamen that showed responses confined exclusively to the stimulus period of all speeds. A second class of putamen neurones responded during the stimulus period but continued discharging during the reaction and movement time period. None of these two classes of putamen neurones discharged when the same set of stimuli were delivered passively. A third class of putamen neurones responded differentially in the discrimination task and predicted whether the speed of the stimulus was low or high. A number of these neurones, which responded differentially during the categorization task, were tested in a light instruction task. This tested the possibility that these differential responses were associated with the intention to move the arm to one of the two target switches. Few neurones responded in this situation. These results indicate that the putamen, in addition to its role in motor regulation, is also involved in higher order aspects of sensory-motor behaviour and in the sensory decision process in this learned somaesthetic task.
1. We have studied how neurons of primary somatic sensory (SI) cortex encode the direction and speed of moving tactile stimuli delivered to the glabrous skin of the contralateral hand. 2. From a total of 178 neurons recorded in SI cortex of 3 awake Macaca mulatta monkeys, 103 were selected for quantitative analysis. Forty-six neurons had slowly adapting (SA) responses, 43 quickly adapting (QA), and 14 mixed SA-QA properties. All possessed cutaneous receptive fields on the distal segments of digits 2, 3, or 4. Receptive fields were scanned with a metal probe (2 mm diam, hemispheric tip) in four different directions (0, 90, 180, and 270 degrees), over a fixed traverse distance of 6 mm, at a variety of speeds (4-100 mm/s), and with a static normal force of 20 g by means of a computer-controlled tactile stimulator. 3. Most neurons gave statistically significant differences in mean impulse rate during the moving stimuli (Wilcoxon, P < 0.01), in at least one of the four directions, compared with the control (nonstimulus) period. The Kruskal-Wallis test (P < 0.01) and the direction index (DI > 35%) determined that about one-half of SI cortical neurons showed significant differences in mean impulse rates associated with the direction of the stimuli at the speeds of 23, 50, and 100 mm/s, and about one-third at 4 mm/s. 4. We determined how the temporal covariance of the neural activity was associated with the parameters of the moving stimuli by calculating the coefficients of the Karhunen-Loève (KL) transform for each set of stimulus responses. Decomposition of the neural activity into principal components indicated that approximately 85% of the impulse train variance during the stimulus responses was contained in the 1st 10 coefficients of the KL transform for the speeds of 23, 50, and 100 mm/s, and approximately 75% at the speed of 4 mm/s. The line spectra calculated from the coefficients of the KL transform showed that the variance contained in the impulse trains in about one-half of the neurons is related to the stimuli. 5. We investigated how the temporal covariance of the neuronal activity was correlated with the direction of the stimulus, by fitting the first coefficient of the KL transform to a weighting function model. This analysis showed that the first coefficient of the KL transform varied as an orderly function of the direction of the moving stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)