Temporal discrimination thresholds (TDT) for recognition of paired sensory (tactile, auditory and visual) stimuli given over a wide range of time intervals were assessed in 44 patients with Parkinson's disease (PD) and 20 age-matched normal subjects. A significant increment in TDT for all three sensory modalities was found in PD patients compared with controls. This abnormality was greatly attenuated for about 2 h by a single levodopa/carbidopa (250/25 mg) tablet. A significant correlation was found between disease severity as assessed clinically and TDT. Patients with more severe PD had higher TDT values. The study of the peripheral median nerve and cortical somatosensory evoked potential recovery curves following double electrical stimulation of the index finger showed no differences between patients and control subjects, nor changes from 'off' to 'on' motor state which could explain the findings. These results indicate the existence of an abnormality of timing mechanisms in PD.

We compared the performance of 44 patients with Parkinson's disease (PD), tested 12-24 h after withdrawal of dopaminergic medication, with 20 age-matched controls, on a verbal test for time estimation and in several time reproduction tasks. Patients with PD underestimated the duration of a time interval in the verbal time estimation task and showed overproduction of time intervals when required to reproduce a short time sample. Absolute errors were greater in the reproduction of longer time intervals in both control and PD patients, but especially in the latter. The presentation of time markers at faster rates had a detrimental effect on the performance of the patients but not of the controls. Patients with more severe PD performed worse on the time estimation and reproduction tasks compared with those with milder disease. Administration of levodopa-carbidopa (205/25 mg, p.o.) significantly reduced absolute errors in time estimation and reproduction in conditions where time markers were presented at the two faster rates of 5 Hz and 3.3 Hz. Performance in these two latter tests best discriminated patients and controls and had a positive significant association with simple reaction time and movement time. These results lead us to suggest that time estimation, i.e. the 'internal clock', is abnormally slow in PD.

Flicker stimuli of variable frequency (2-90 Hz) elicit a steady-state visual-evoked response (SSVER) in the electroencephalogram (EEG) with the same frequency as the stimulus. In humans, the amplitude of this response peaks at approximately 15 Hz, decreasing at higher stimulation frequencies. It was not known whether this peak response corresponds to increased synaptic activity in the visual cortex or to other mechanisms [for instance, the temporal coherence (phase summation) of evoked responses]. We studied the SSVER in 16 normal volunteers by means of visual stimulation at 14 different frequencies (from 5 to 60 Hz) while recording the EEG. In nine subjects of the group, we measured regional cerebral blood flow (rCBF) with positron emission tomography (PET)-H2(15)O at rest and during visual stimulation at five different frequencies: 5, 10, 15, 25, and 40 Hz. We confirmed that the amplitude of the SSVER in occipital regions peaks at 15 Hz stimulation. Applying to the PET rCBF data a contrast weighted by the amplitude of the SSVER, we determined that the primary visual cortex rCBF follows an activation pattern similar to the SSVER. This finding suggests that the amplitude of the SSVER corresponds to increased synaptic activity, specifically in Brodmann's area 17. Additionally, this study showed that visual stimulation at 40 Hz causes selective activation of the macular region of the visual cortex, and that a region in the dorsal aspect of the Crus I lobule of the left cerebellar hemisphere is activated during repetitive visual stimulation.

1. We have studied the effects of changes in posture on the motor response to galvanic vestibular stimulation (GVS). The purpose of the experiments was to investigate whether the function of the GVS-evoked response is to stabilize the body or the head in space. Subjects faced forwards with eyes closed standing with various stance widths and sitting. In all cases the GVS-evoked response consisted of a sway of the body towards the anodal ear. 2. In the first set of experiments the response was measured from changes in (i) electromyographic activity of hip and ankle muscles, (ii) the lateral ground reaction force, and (iii) lateral motion of the body at the level of the neck (C7). For all measurements the response became smaller as the feet were placed further apart. 3. In the second set of experiments we measured the GVS-evoked tilts of the head, torso and pelvis. The basic response consisted of a tilt in space (anodal ear down) of all three segments. The head tilted more than the trunk and the trunk tilted more than the pelvis producing a leaning and bending of the body towards the anodal ear. This change in posture was sustained for the duration of the stimulus. 4. The tilt of all three segments was reduced by increasing the stance width. This was due to a reduction in evoked tilt of the pelvis, the bending of the upper body remaining relatively unchanged. Changing from a standing to a sitting posture produced additional reductions in tilt by reducing the degree of upper body bending. 5. The results indicate that the response is organized to stabilize the body rather than the head in space. We suggest that GVS produces a vestibular input akin to that experienced on an inclined support surface and that the function of the response is to counter any threat to balance by keeping the centre of mass of the body within safe limits.Passing a small current across the mastoid processes stimulates the vestibular system and in standing subjects evokes a sway of the body. This 'galvanic vestibular stimulation' (GVS) acts by modulating the spontaneous firing of vestibular afferents, increasing their firing frequency on

Arterial Spin Labeling (ASL) can be implemented by combining different labeling schemes and readout sequences. In this study, the performance of 2D and 3D single-shot pulsed-continuous ASL (pCASL) sequences was assessed in a group of young healthy volunteers undergoing a baseline perfusion and a functional study with a sensory-motor activation paradigm. The evaluated sequences were 2D echo-planar imaging (2D EPI), 3D single-shot fast spin echo with in-plane spiral readout (3D FSE spiral), and 3D single-shot gradient-and-spin-echo (3D GRASE). The 3D sequences were implemented with and without the addition of an optimized background suppression (BS) scheme. Labeling efficiency, signal-to-noise ratio (SNR), and gray matter (GM) to white matter (WM) contrast ratio were assessed in baseline perfusion measurements. 3D acquisitions without BS yielded 2-fold increments in spatial SNR, but no change in temporal SNR. The addition of BS to the 3D sequences yielded a 3-fold temporal SNR increase compared to the unsuppressed sequences. 2D EPI provided better GM-to-WM contrast ratio than the 3D sequences. The analysis of functional data at the subject level showed a 3-fold increase in statistical power for the BS 3D sequences, although the improvement was attenuated at the group level. 3D without BS did not increase the maximum t-values, however, it yielded larger activation clusters than 2D. These results demonstrate that BS 3D single-shot imaging sequences improve the performance of pCASL in baseline and activation studies, particularly for individual subject analyses where the improvement in temporal SNR translates into markedly enhanced power for task activation detection.

We used functional brain imaging with positron emission tomography (PET)-H 2 15 O to study a remarkable neurophysiological finding in the normal brain. Auditory stimulation at various frequencies in the gamma range elicits a steady-state scalp electroencephalographic (EEG) response that peaks in amplitude at 40 Hz, with smaller amplitudes at lower and higher stimulation frequencies. We confirmed this finding in 28 healthy subjects, each studied with monaural trains of stimuli at 12 different stimulation rates (12, 20, 30, 32, 35, 37.5, 40, 42.5, 45, 47.5, 50, and 60 Hz). There is disagreement as to whether the peak in the amplitude of the EEG response at 40 Hz corresponds simply to a superimposition of middle latency auditory evoked potentials, neuronal synchronization, or increased cortical synaptic activity at this stimulation frequency. To clarify this issue, we measured regional cerebral blood flow (rCBF) with PET-H 2 15 O in nine normal subjects at rest and during auditory stimulation at four different frequencies (12, 32, 40, and 47 Hz) and analyzed the results with statistical parametric mapping. The behavior of the rCBF response was similar to the steadystate EEG response, reaching a peak at 40 Hz. This finding suggests that the steady-state amplitude peak is related to increased cortical synaptic activity. Additionally, we found that, compared with other stimulation frequencies, 40 Hz selectively activated the auditory region of the pontocerebellum, a brain structure with important roles in cortical inhibition and timing. Key words: steady-state auditory evoked potentials; gamma oscillatory activity; regional cerebral blood flow; positron emission tomography; cerebellum; auditory cortexIn humans, auditory stimulation at different gamma frequencies elicits an electroencephalographic (EEG) steady-state response (SSR) that cycles at the stimulation frequency and has the greatest amplitude when the stimulus is given at 40 Hz (Galambos et al., 1981). Lower or higher frequencies produce a response of smaller amplitude. These oscillatory responses seem to be generated at the level of the auditory cortex, although modulated by thalamocortical systems (Makela and Hari, 1987;Steriade et al., 1991). The significance and origin of the steady-state potentials continue to be debated (Basar et al., 1987;Santarelli et al., 1995;Gutschalk et al., 1999). It is unclear whether the power increment of the steady-state auditory response at 40 Hz results merely from the temporal coherence (phase summation) of "middle latency" evoked responses, phase synchronization of a pool of cortical neurons, or a true increase in cortical synaptic activity at 40 Hz. Synaptic activity causes an increment in regional cerebral blood flow (rCBF). To test the hypothesis that the enhanced response at 40 Hz reflects increased synaptic cortical activity, we measured rCBF with positron emission tomography (PET) in the auditory cortex and other brain regions during auditory stimulation at different frequencies. A rise in rCBF at 40 Hz stimulatio...

Two identical stimuli, such as a pair of electrical shocks to the skin, are readily perceived as two separate events in time provided the interval between them is sufficiently long. However, as they are presented progressively closer together, there comes a point when the two separate stimuli are perceived as a single stimulus. Damage to posterior parietal cortex, peri-supplementary motor area (peri-SMA), and basal ganglia can disturb this form of temporal discrimination. Our aim was to establish, in healthy subjects, the brain areas that are involved in this process. During functional magnetic resonance imaging scanning, paired electrical pulses, separated by variable interstimulus intervals (5-110 msec), were delivered to different sites on one forearm (8 -64 mm from the midline). Subjects were required to simply detect the stimulus (control task) or to identify a stimulus property. For temporal discrimination (TD), subjects reported whether they felt one or two stimuli. For spatial discrimination, they reported whether the stimuli were located on the right or left side of the forearm. Subjects reported their choice by pressing a button with the opposite hand. Our results showed that discrimination, as opposed to simply detection, activated several brain areas. Most were common to both discrimination tasks. These included regions of prefrontal cortex, right postcentral gyrus and inferior parietal lobule, basal ganglia, and cerebellum. However, activation of pre-SMA and anterior cingulate was found to be specific to the TD task. This suggests that these two frontal regions may play a role in the temporal processing of somatosensory events.

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