Somatosensory disinhibition in dystonia.

Despite the fact that somatosensory processing is inherently dependent on inhibitory functions, only excitatory aspects of the somatosensory feedback have so far been assessed in dystonic patients. We studied the recovery functions of spinal N13, brainstem P14, parietal N20, P27, and frontal N30 somatosensory evoked potentials (SEPs) after paired median nerve stimulation in 10 patients with dystonia and in 10 normal subjects. The recovery functions were assessed (conditioning stimulus: S1; test stimulus: S2) at interstimuls intervals (ISIs) of 5, 20, and 40 ms. SEPs evoked by S2 were calculated by subtracting the SEPs of the S1 only response from the SEPs of the response to the paired stimuli (S1 + S2), and their amplitudes were compared with those of the control response (S1) at each ISI considered. This ratio, (S2/S1)*100, investigates changes in the excitability of the somatosensory system. No significant difference was found in SEP amplitudes for single stimulus (S1) between dystonic patients and normal subjects. The (S2/S1)*100 ratio at the ISI of 5 ms did not significantly differ between dystonic patients and normal subjects, but at ISIs of 20 and 40 ms, this ratio was significantly higher in patients than in normals for spinal N13 and cortical N20, P27, N30 SEPs. These findings suggest that in dystonia there is an impaired inhibition at spinal and cortical levels of the somatosensory system which would lead to an abnormal sensory assistance to the ongoing motor programs, ultimately resulting in the motor abnormalities present in this disease.     

Responses of human single motor units to transcranial magnetic stimulation

Transcranial electromagnetic brain stimuli elicit a complex response in the electromyogram of active human hand muscles. Relatively weak stimuli evoke a short-latency primary response via a presumably monosynaptic corticospinal path. This is followed by a silent period that is terminated by a second peak at a latency of 50–80 ms. The responses evoked in single motor units in flexor digitorum profundus (FDP) were recorded. Responses were elicited at the second-peak latency only in trials in which no primary response was elicited in that unit, and only when the stimulus was given during the first half of the interspike interval (ISI). When given during the second half of the ISI, the same stimulus evoked a primary response but no second peak response. Stronger stimuli suppressed the second peak by evoking a primary response in more trials. Having discharged at about 20 ms latency, the parent motoneurone was unable to discharge again at second-peak latency, 30–60 ms later. The response at second-peak latency was not modified by disengaging both FDP and the extensors of the distal interphalangeal joint. Hence, this response is not secondary to a stretch reflex provoked by activation of the finger extensors, nor is it the result of a cutaneous signal resulting from movement of the finger. The latencies suggest that the corticospinal volley evokes a β-motoneurone-mediated twitch in FDP muscle spindles, which elicits an afferent volley that activates the motoneurone reflexly. The first 100 ms or so of the silent period is due to the realignment of the first post-stimulus spike in most trials to corticospinal latency; i.e. this is not necessarily the result of an inhibitory or disfacilitatory process. Still stronger stimuli increase the duration of the ISI in which the stimulus is given, indicating the presence of an inhibitory/disfacilitatory process.     

Shortening of the cortical silent period following transcranial magnetic brain stimulation during an experimental paradigm for generating contingent negative variation (CNV).

OBJECTIVES: We investigated changes in the cortical silent period (CSP) following transcranial magnetic cortical stimulation (TCMS) during a standard paradigm which was designed to evoke contingent negative variation (CNV) in ten normal subjects. METHODS: We recorded the motor evoked potentials (MEP) and CSP during the inter-stimulus interval (ISI) of a CNV paradigm in ten normal subjects. The CNV paradigm consisted of a visual warning stimulus (S1) followed by a visual response stimulus (S2). The CSP following TCMS on the hand motor area was recorded from mildly contracted first dorsal interosseous muscles. RESULTS: The CSP was significantly shortened during the ISI (P < 0.01, t test) with a highly significant correlation with the TCMS timing during the ISI (P < 0.02, Spearman's correlation coefficient), while the MEP amplitude and latency were unchanged. CONCLUSIONS: The results suggested that shortening of the CSP was associated with neural processes related to preparation for voluntary movement during the paradigm.     

The correlation between physiological and psychological responses to odour stimulation in human subjects.

OBJECTIVES: To correlate physiological and psychological responses to odour stimulation. METHODS: Olfactory event-related potentials (OERP) were recorded from human subjects in response to different odour pulse protocols. Pulse duration and interstimulus interval (ISI) were varied while the subjects recorded pulse detection by a button press. RESULTS: There was a correlation between odour strength and OERP. The amplitude of the OERP (peak positive-peak negative) declined by 48% with repetitive stimulation for all stimulus strengths. The time constant for this decline (adaptation) was concentration dependent and varied from 10 to 4 s for increasing odorant strength (from 35 to 200 ms pulse of saturated amyl acetate vapour diluted 1:3 at 3 l min(-1) at 24 degrees C). The psychometric test score (cognitive odour perception) was also concentration dependent and increased with increasing stimulus strength at all ISIs except the lowest value; 2.5 s. At this ISI adaptation/habituation interfered with the dose-response. The decline of the psychometric test score with increasing stimulus frequency (decreasing ISI) was more rapid (tau approximately 2.5 s) than that of the OERP. The psychometric test score declined to zero at a constant rate and was not dependent upon stimulus strength. CONCLUSIONS: Continuous olfactory stimulation results in a shut-down of cognitive perception with a time constant of around 2.5 s while the response of the physiological system (receptors, transduction and relay system) declines by about 50% with a slower time course (> or = 4 s). This former process defines habituation in the olfactory system while the latter describes adaptation. Since the adaptation process is concentration dependent the rate of adaptation contains information about odour strength, thus both the amplitude of the OERP and the rate of adaptation could encode stimulus strength.     

Gamma and beta neural activity evoked during a sensory gating paradigm: effects of auditory, somatosensory and cross-modal stimulation.

OBJECTIVE: Stimulus-driven salience is determined involuntarily, and by the physical properties of a stimulus. It has recently been theorized that neural coding of this variable involves oscillatory activity within cortical neuron populations at beta frequencies. This was tested here through experimental manipulation of inter-stimulus interval (ISI). METHODS: Non-invasive neurophysiological measures of event-related gamma (30-50 Hz) and beta (12-20 Hz) activity were estimated from scalp-recorded evoked potentials. Stimuli were presented in a standard "paired-stimulus" sensory gating paradigm, where the S1 (conditioning) stimulus was conceptualized as long-ISI, or "high salience", and the S2 (test) stimulus as short-ISI, or "low salience". Three separate studies were conducted: auditory stimuli only (N = 20 participants), somatosensory stimuli only (N = 20), and a cross-modal study for which auditory and somatosensory stimuli were mixed (N = 40). RESULTS: Early (20-150 ms) stimulus-evoked beta activity was more sensitive to ISI than temporally-overlapping gamma-band activity, and this effect was seen in both auditory and somatosensory studies. In the cross-modal study, beta activity was significantly modulated by the similarity (or dissimilarity) of stimuli separated by a short ISI (0.5 s); a significant cross-modal gating effect was nevertheless detected. CONCLUSIONS: With regard to the early sensory-evoked response recorded from the scalp, the interval between identical stimuli especially modulates beta oscillatory activity. SIGNIFICANCE: This is consistent with developing theories regarding the different roles of temporally-overlapping oscillatory activity within cortical neuron populations at gamma and beta frequencies, particularly the claim that the latter is related to stimulus-driven salience.     

Dishabituation of laser-evoked EEG responses: dissecting the effect of certain and uncertain changes in stimulus modality

The repetition of nociceptive stimuli of identical modality, intensity, and location at short and constant interstimulus intervals (ISIs) determines a strong habituation of the corresponding EEG responses, without affecting the subjective perception of pain. To understand what determines this response habituation, we (i) examined the effect of introducing a change in the modality of the repeated stimulus, and (ii) dissected the relative contribution of bottom-up, stimulus-driven changes in modality and top-down, cognitive expectations of such a change, on both laser-evoked and auditory-evoked EEG responses. Multichannel EEG was recorded while participants received trains of three stimuli (S1-S2-S3, a triplet) delivered to the hand dorsum at 1-sec ISI. S3 belonged either to the same modality as S1 and S2 or to the other modality. In addition, participants were either explicitly informed or not informed of the modality of S3. We found that introducing a change in stimulus modality produced a significant dishabituation of the laser-evoked N1, N2, and P2 waves; the auditory N1 and P2 waves; and the laser- and auditory-induced event-related synchronization and desynchronization. In contrast, the lack of explicit knowledge of a possible change in the sensory modality of the stimulus (i.e., uncertainty) only increased the ascending portion of the laser-evoked and auditory-evoked P2 wave. Altogether, these results indicate that bottom-up novelty resulting from the change of stimulus modality, and not top-down cognitive expectations, plays a major role in determining the habituation of these brain responses.     

Paradigm-dependent modulation of event-related fMRI activity evoked by the oddball task

We have previously shown that event-related functional magnetic resonance imaging (ER-fMRI) may be used to record responses to the rapid, interleaved presentation of stimuli in the three-stimulus oddball task. The present study examined the sensitivity of ER-fMRI responses to variations in the range of inter-stimulus intervals (ISIs, calculated as the time from the offset of one stimulus to the onset of the next stimulus) and the type of behavioral response task used. ISIs were varied between a wide ISI range (550-2,050 msec) and a narrow ISI range (800-1,200 msec), while maintaining a similar mean ISI (approximately 1 stimulus per sec) between experiments. The response task was varied between button press and subvocal target counting. Gradient echo, echo planar images were acquired for each of three experiments (wide ISI with button press, narrow ISI with button press, and wide-ISI with counting) in five subjects. Target stimuli generated increased fMRI signal in a wide range of brain regions. The use of a narrow ISI range generated a greater volume of subcortical activity and a reduced volume of cortical activity relative to a wide ISI range. The counting task generated a larger amplitude and longer lasting evoked response in brain regions that responded during all three experiments. Rare distractor stimuli evoked fMRI signal change primarily in orbitofrontal, ventral-medial prefrontal and superior parietal cortex. These results illustrate that although ER-fMRI is relatively insensitive as a technique to small variations in the timing of stimulus-evoked responses, it is remarkably sensitive to consequences such variations have for the topographic location and amplitude of neural responses to stimuli.     

The Effect of Motor-Response-Deprivation on Contingent Negative Variation (CNV) II: Information of the Warning Stimulus

1) Using a single click as the warning stimulus (S1), a yellow-colored light as the imperative stimulus (S2) and a button-press as the motor-response (MR), conventional (paradigm of S1-S2-MR) and motor-response-deprived (S1-S2) CNVs were recorded in 16 normal subjects. 2) Motor-response-deprived CNV or MRD-CNV generated before the reinforcement seems to relate to the process of S1-information or S1-signalization. 3) The easiness of the conditioning, involving the reinforced conditioning and conditioned emotional response, was considered to relate to the development of CNV. 4) Because of higher amplitude of MRD-CNV in female subjects, we concluded that females may have the biological nature easier to be conditioned.     

The cumulative inhibitory effect of repetitively flashed stimuli on the recovery process of the human visual evoked potential to a test stimulus.

Cumulative inhibitory effects produced by visual response to flashed conditioning stimuli were measured by means of the amplitude reduction of the visual evoked potential (VEP) to a test stimulus. Four kinds of conditioning stimuli were used: a single conditioning stimulus and 3 repetitive conditioning stimuli with interstimulus intervals (ISIs) of 100, 200 and 400 msec, respectively. The VEP amplitude for the test stimulus was reduced most when the stimulus was paired with the single conditioning stimulus. It still remained small when the test stimulus was paired with the repetitive conditioning stimulus of 400 msec ISI, increased significantly when the ISI was shortened from 400 to 200 msec. Explanations of the VEP behaviors in terms of the stimulus relevance, task difficulty and the recovery rate of the cortical excitability were discussed.     

Habituation of the nociceptive flexion reflex is dependent on inter-stimulus interval and stimulus intensity

The nociceptive flexion reflex (NFR) has become a popular tool in experimental and clinical pain research. However, the gradual decrease of the reflex size during repeated application of stimuli, which is termed habituation, may reduce its validity and the comparability of studies. We investigated the degree of habituation at different inter-stimulus intervals (ISI) commonly used in clinical studies and the dependency of habituation on stimulus intensity. Thirty subjects each received 12 sets of 50 stimuli to elicit the NFR at ISI of 1, 3, 6 and 10 s, each at stimulus intensities of 1×, 1.5× and 2× the individual NFR-threshold. For each of the sets, the habituation was calculated as the relative size of the average of the last 10 reflexes compared to the average of the first 10 reflexes. The influence of the factors ISI and stimulus intensity, as well as the factor interaction, was tested using a two-way analysis of variance (ANOVA). Analysis proved that influences of ISI and stimulus intensity on reflex habituation were significant (p < 0.01, two-way ANOVA), while the interaction between the two factors had no significant influence (p = 0.99). We conclude that habituation of the NFR is dependent on ISI and stimulus intensity. Lower stimulus intensities and shorter ISI lead to stronger habituation. Therefore, to ensure habituation is avoided during repeated elicitation of the NFR, stimulation should be conducted according to the ISI for the respective stimulus intensities presented here.     

Dynamics of event-related potentials to trains of light and dark flashes: Responses to missing and extra stimuli in elasmobranch fish

To characterize the dependecies of event-related potentials (ERPs) in lower vertebrates and brain levels upon recent history and sequences of stimuli, trains of flashes were delivered at various frequecies to unanesthetized rays while recording in optic tectum and telencephalon. ERPs to repetitive stimuli cannot be understood in terms of simple refractoriness and recovery. Processes must be invoked such as simultaneous excitation and suppression, facilitation and its opposite, rebound and induced rhythms, each with development and decay times and non-linearities. Some of these processes are uncovered by omitting a stimulus from a train. Omitted stimulus potentials (OSPs) act as though the brain expects a stimulus within 5–7 msec of the interstimulus interval (ISI) of the train. Very few ISIs suffice. The effect upon visual evoked potential (VEP) form and duration of the number of stimuli in short trains, before the steady state response (SSR) is established, is complex. Alteration of the amplitude of successive VEPs (1 large every 2 VEPs, 1 in 3, 1 in 4) is one indication of complexities in the SSR. OSPs also alternate. A single extra stimulus interpolated into a regular train causes distinct effects according to its position. Sharp discontinuities in these effects appear with <5 msec shifts. Total power of the SSR decreases with stimulation frequency but there is a large peak of increased power at 7 Hz and another at 12 Hz. Induced rhythms are a labile, late phase of OSPs as well as of rested VEPs and of the off response to a long light pulse. Jittered ISI experiments show that the apparent expectation of the OSP is little affected and that the intervals in the last few hundred milliseconds are most influential. The OSP studied here (ISI < 0.5 s) is quite different from that so far studied in human subjects (ISI > 1 sec). We predict further similarities when each taxon is tested in the other ISI range.A major category of response characteristics, besides sensitivity, receptive fields and recovery times, is dependence upon recent history of iterative events, including intervals, delays, omissions and perhaps multiple facilitating and forgetting time constants. The variables examined parametrically in this study are only some of those available. Such dynamical characteristics are important neglected properties of afferent systems at each level.     

Long-latency event-related potentials in squirrel monkeys: further characterization of wave form morphology, topography, and functional properties

Event-related potentials (ERPs) were recorded from the brain surface of untrained monkeys exposed to sequences of auditory stimuli (2 kHz and 6 kHz tones of 40 msec duration). Stimulus probability and interstimulus interval (ISI) were systematically varied in different paradigms. In an oddball paradigm with a 1 sec ISI in which one stimulus constituted 90% of all trials and the other 10%, a 'monkey' late positive component (MLPC), characterized by two peaks (P248 and P369), was recorded prominently over lateral parietal areas in response to the unpredictable and infrequent shifts in pitch. The amplitude of this late positivity was found to be sensitive to stimulus probability and to exhibit trial-to-trial sequential dependencies similar to those described for the human P300. The amplitude of MLPC was also found to be larger following longer ISIs. In addition, a 'monkey' late negative component (MLNC), with characteristics similar to those of the human slow wave (SW), was recorded following the infrequent shifts in pitch and found to temporally overlap with MLPC. MLNC was recorded with maximal amplitude over frontal cortex and was sensitive to stimulus probability but not to trial-to-trial changes in stimulus sequence. Thus MLPC and MLNC which appear to reflect similar yet distinct processes exhibit several analogies to the human P3a and SW, respectively.     

Repetitive Paired-Pulse Transcranial Magnetic Stimulation Over the Visual Cortex Alters Visual Recovery Function

BackgroundSome repetitive transcranial magnetic stimulation (rTMS) techniques fail to facilitate cortical excitability in the human visual cortex. A more effective and facilitatory method is needed to increase the feasibility of rTMS to explore visual cortex function.ObjectiveThe present study aimed to develop a novel tool for modulating the visual cortex excitability and examined the influences of repetitive transcranial magnetic paired-pulse stimulation (rPPS) on the visual cortex.MethodsOptimal interstimulus intervals (ISIs) were determined to assess recovery function of visual evoked potentials (VEPs). Paired stimuli from checkerboard pattern reversals were presented at 11 ISIs from 50–200 ms. Each session consisted of control (S1) and paired (S1 + S2) epochs to extract the S2 response. The recovery function was calculated as the ratio of S2/S1 amplitudes. Subsequently, rPPS was utilized with a 1.5 ms ISI over the visual cortex at the stimulus intensity of the visual masking effect. Amplitudes and suppression ratios of the paired VEPs were compared before and after rPPS. The effect of single pulse TMS was also evaluated.ResultsPaired VEPs resulted in suppressive effects at ISIs up to 200 ms, with an optimal ISI of 90 ms due to small variability and moderate inhibitory effects. There was no significant effect of rPPS on N75-P100 with paired VEPs. Following rPPS, however, P100-N145 inhibition decreased up to 10 min. The single pulse protocol did not result in these effects.ConclusionsModulation of VEP recovery by rPPS suggested that rPPS exhibited a disinhibitory effect on the visual cortex.     

New concept for the recovery function of short-latency somatosensory evoked cortical potentials following median nerve stimulation.

OBJECTIVES: We investigated the recovery function of the cortical components of somatosensory evoked potentials (SEP) at a very short interstimulus interval (ISI, less than 10 ms) using an integrative computer system in 10 healthy subjects (age, 27-38 years). METHODS: The SEP and nerve action potentials were recorded at P3 with a reference of Fz in the International 10-20 System and the ipsilateral Erb's point, respectively. Double stimulation of the right median nerve with an ISI from 0.5 to 100 ms was performed to analyze the N20 and P30 components at less than 10 ms. RESULTS: The P30 component was recognized following the second stimulation at an ISI of over 1 ms, while N20 was not identified at an ISI of less than 9 ms. There appeared a sub-component of SEP at 1-12 ms ISI, which was not identified following a single stimulation under control conditions. CONCLUSIONS: The results indicated that the recovery function of given SEP components was not simply determined by the number of synapses interposed between the stimulus site and the generator source of the response in the central nervous system, but there might be a structural or functional process of low-cut filtering in the primary sensory cortex. We also considered that the final SEP waveform determined by the excitatory and inhibitory balance of the components, which could be changed with ISI, and that the existence of the sub-component might cause the complexity of the recovery curve and large inter-individual difference of the waveform.     

Auditory event-related potentials in the squirrel monkey: Parallels to human late wave responses

Event-related potentials (ERPs) were recorded from the brain surface in squirrel monkeys during the presentation of two auditory stimulus paradigms which have previously been utilized to elicit scalp-recorded ERPs in humans. In the first paradigm, inter-stimulus interval (ISI) was systematically varied during the presentation of a series of tone pips. The tones produced a negative (70 ms)-positive (130 ms) sequence of components similar in morphology to the human scalp-recorded N1-P2 'vertex' potential. The amplitude of the N70 and P130 components recorded from midline electrodes decreased with decreasing ISI, as previously shown for the human vertex potential. However, this amplitude change with ISI was not observed in ERPs recorded from lateral frontal and temporal electrodes. These results agree with previous studies of monkeys and humans which suggest at least two different sources contribute to N1-P2 components recorded in response to tones. The effects of stimulus probability and novelty on ERP morphology and amplitude were studied in the second paradigm. ERPs elicited by frequent (P = 0.92) and infrequent (P = 0.08) tone pips presented in an unpredictable order were compared. N70 - P130 components were produced by both stimuli, and the infrequent stimuli also elicited a broad, long latency (300 ms) positive complex that decreased in amplitude with repeated presentations. In humans the same infrequent auditory stimuli produce a frontally distributed late positive component that has been interpreted as indicating the activation of orientation mechanisms or of a 'mismatch detector'. These data suggest that in these paradigms squirrel monkeys exhibit ERPs which are similar in several respects to ERPs recorded to identical stimuli in humans.     

Lateral spread response elicited by double stimulation in patients with hemifacial spasm

In patients with hemifacial spasm (HFS), a lateral spread response (or abnormal muscle response) is recorded from facial muscles after facial nerve stimulation. The origin of this response is not completely understood. We studied the lateral spread responses elicited by double stimulation in 12 patients with HFS during microvascular decompression. The response was recorded from the mentalis muscle by electrical stimulation of the temporal branch of the facial nerve or from the orbicularis oculi muscles by stimulation of the marginal mandibular branch. The interstimulus intervals (ISIs) of double stimulation ranged from 0.5 to 7.0 ms. R1 was defined as the response elicited by the first stimulus, and R2 as the response elicited by the second stimulus. R1 had a constant latency and amplitude regardless of the ISI, whereas R2 appeared after a fixed refractory period without facilitation or depression in a recovery curve of latency and amplitude. From these findings, we consider that the lateral spread response is due to cross-transmission of facial nerve fibers at the site of vascular compression rather than arising from facial nerve motor neurons.     

Cingulate cortex activation and competing responses: the role of preparedness for competition

Regional cerebral blood flow (rCBF) was studied in a task, where a preparatory stimulus (S1) cued for an imperative second stimulus (S2) which was associated with a response. Two preparatory stimuli cued unequivocally each for one response. In contrast, a third preparatory stimulus cued for two response alternatives which appeared for the same ratio (each in 50% of all trials) introducing response competition. In a first experimental condition, non-arbitrary, unambiguous stimuli were used as S1 to enable the subjects to prepare their responses. In a second and third scan, arbitrary preparatory stimuli were used during different stages of awareness for the S1-S2 association. Subjects performed this task "naive" without knowledge about the S1-S2 association and also in an experimental condition being aware of the S1-S2 association. Button presses after unambiguous, non-arbitrary preparatory stimuli activated the right middle frontal gyrus and inferior parietal lobe if S1 was associated with a definite response. When the subjects did not know the S1-S2 relation, left prefrontal cortex activation was associated with trials including definite responses. Performing the same S1-S2 response condition after subjects knew their relation right prefrontal and left parietal areas became additionally engaged. However, in the first experimental condition using unambiguous, non-arbitrary stimuli and in the third, "aware" experimental condition when S1 was coupled with two response alternatives, the anterior cingulate cortex was activated. As these experimental conditions have in common, that the preparatory stimulus shares information about the upcoming competing response alternatives they highlight the evaluative role of the anterior cingulate cortex for competing actions.     

Neurophysiological mechanisms underlying motor evoked potentials in anesthetized humans. Part 1. Recovery time of corticospinal tract direct waves elicited by pairs of transcranial electrical stimuli.

Direct (D) corticospinal tract discharges were recorded epidurally in patients at anesthetic depths suppressing indirect (I) activity and were elicited by two equal transcranial electrical stimuli. The recovery of amplitude of the second D wave (D2) was a function of the interstimulus interval (ISI) and the stimulus duration. For example, with a 100 micros pulse, there was no response at an ISI of 1.1 ms, but partial recovery occurred with a 500 micros pulse. This indicates a relative refractory component at this ISI. Both D2 amplitude and conduction time recovered completely using a 4 ms ISI, with evidence of increased amplitude and reduced conduction time (supernormality) at longer ISIs. These findings are relevant in explaining high frequency D and I discharges and facilitation of motor responses by two transcranial magnetic pulses. Furthermore, these data help to understand why an ISI of 4 ms would be optimal in eliciting limb muscle responses when a short train of transcranial stimuli elicits only D waves in anesthetized patients (Deletis et al., Clin Neurophysiol 112 (2001) 445).     

Conditioned stimulus duration in classical trace conditioning: test of a real-time neural network model.

In classical trace conditioning, the interstimulus interval (ISI) is equal to the conditioned stimulus (CS) duration plus the trace interval (TI), the interval between CS offset and unconditioned stimulus (US) onset. The Sutton-Barto-Desmond neural-network model of classical conditioning predicts that, with a sufficiently long TI, conditioning will be faster with a CS of relatively long duration than with one of shorter duration. This prediction is illustrated with simulations and tested with the rabbit nictitating membrane response. Animals were trained with a tone CS of 350- or 700-ms duration. The TI was fixed at 300 ms, so that the ISI for the two durations was 650 or 1000 ms, respectively. Another factor in the experimental design was tone intensity (63 or 83 dB). Consistent with the model's prediction, conditioning was faster with the longer ISI, but only with the louder tone. The results have implications for computational models of classical conditioning.     

Purkinje cell activity during learning a new timing in classical eyeblink conditioning

During classical eyeblink conditioning, animals acquire adaptive timing of the conditioned response (CR) to the interstimulus interval (ISI) between the conditioned stimulus (CS) and the unconditioned stimulus (US). To investigate this coding of the timing by the cerebellum, we analyzed Purkinje cell activities during acquisition of new timing after we shifted the ISI. Decerebrate guinea pigs were conditioned to an asymptotic level of learning using a delay paradigm with a 250-ms ISI. A 350-ms tone and a 100-ms electrical shock were used as the CS and US, respectively. As reported previously in other species, Purkinje cells in the simplex lobe exhibited three types of responses to the CS: excitatory, inhibitory, or a combination of the two. After we increased the ISI to 400 ms, the frequency of the CR stayed at an asymptotic level, but the latency of the CR peak became gradually longer. Two types of cells were observed, based on changes in the nature of their response to the CS; one changed its type of response in parallel with learning the new timing, while the other did not. There was no correlation between the type of response before and after we changed the ISI. In some cells, the peak latency of activities became longer or shorter, while the type of response did not change. These results suggest that some Purkinje cells code the timing of the CR, but do not play a consistent role in shaping the CR over a range of ISIs.