Peter Praamstra

Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations

A Dutch family with autosomal recessive early-onset parkinsonism showed a heterozygous missense mutation in combination with a heterozygous exon deletion in the parkin gene. Although the main clinical syndrome consisted of parkinsonism, the proband clinically had additional mild gait ataxia and pathologically showed neuronal loss in parts of the spinocerebellar system, in addition to selective loss of dopaminergic neurons in the substantia nigra pars compacta. Lewy bodies and neurofibrillary tangles were absent, but tau pathology was found.

Brain activity correlates differentially with increasing temporal complexity of rhythms during initialisation, synchronisation, and continuation phases of paced finger tapping.

Activity in parts of the human motor system has been shown to correlate with the complexity of performed motor sequences in terms of the number of limbs moved, number of movements, and number of trajectories. Here, we searched for activity correlating with temporal complexity, in terms of the number of different intervals produced in the sequence, using an overlearned tapping task. Our task was divided into three phases: movement selection and initiation (initiate), synchronisation of finger tapping with an external auditory cue (synchronise), and continued tapping in absence of the auditory pacer (continue). Comparisons between synchronisation and continuation showed a pattern in keeping with prior neuroimaging studies of paced finger tapping. Thus, activation of bilateral SMA and basal ganglia was greater in continuation tapping than in synchronisation tapping. Parametric analysis revealed activity correlating with temporal complexity during initiate in bilateral supplementary and pre-supplementary motor cortex (SMA and preSMA), rostral dorsal premotor cortex (PMC), basal ganglia, and dorsolateral prefrontal cortex (DLPFC), among other areas. During synchronise, correlated activity was observed in bilateral SMA, more caudal dorsal and ventral PMC, right DLPFC and right primary motor cortex. No correlated activity was observed during continue at P<0.01 (corrected, cluster level), though left angular gyrus was active at P<0.05. We suggest that the preSMA and rostral dorsal PMC activities during initiate may be associated with selection of timing parameters, while activation in centromedial prefrontal cortex during both initiate and synchronise may be associated with temporal error monitoring or correction. The absence of activity significantly correlated with temporal complexity during continue suggests that, once an overlearned timed movement sequence has been selected and initiated, there is no further adjustment of the timing control processes related to its continued production in absence of external cues.

Dipole source analysis suggests selective modulation of the supplementary motor area contribution to the readiness potential

The readiness potential preceding voluntary movement is modulated by the mode of movement selection, i.e. it has a higher amplitude preceding freely selected than before prescribed movements (Praamstra, P., Stegeman, D.F., Horstink, M.W.I.M., Brunia, C.H.M. and Cools, A.R. Movement-related potentials preceding voluntary movement are modulated by the mode of movement selection. Exp. Brain Res., 1995, 103: 429-439). One cortical area that is likely to be involved in this modulation is the supplementary motor area (SMA). Recent attempts to elucidate the neural generators of the readiness potential using spatiotemporal dipole source analysis, however, failed to establish a significant SMA contribution to the readiness potential. This might be explained by a failure of the proposed analyses to discriminate between SMA and motor cortex contributions to the readiness potential. We applied a dipole source analysis approach that better separates these overlapping source activities. The resulting source model includes an SMA source generating pre-movement activity consistent with evidence from intracranial recordings in humans. The SMA source accounts almost completely for the modulation of the readiness potential by different modes of movement selection. On the basis of these results, the relation between scalp-recorded movement-related activity, intracranially recorded potentials, and findings from functional imaging studies of voluntary movement, appears more transparent than suggested by previous dipole source analyses of premovement potentials.

Failed Suppression of Direct Visuomotor Activation in Parkinson's Disease

The response times in choice-reaction tasks are faster when the relative spatial positions of stimulus and response match than when they do not match, even when the spatial relation is irrelevant to response choice. This spatial stimulusresponse (S-R) compatibility effect (i.e., the Simon effect) is attributed in part to the automatic activation of spatially corresponding responses, which need to be suppressed when the spatial location of stimulus and correct response do not correspond. The present study tested patients with Parkinsons disease and healthy control subjects in a spatial S-R compatibility task in order to investigate whether basal ganglia dysfunction in Parkinsons disease leads to disinhibition of direct visuomotor activation. High-density event-related brain potential recordings were used to chart the cortical activity accompanying attentional orientation and response selection. Response time measures demonstrated a failure to inhibit automatic response activation in Parkinson patients, which was revealed by taking into account a sequence-dependent modulation of the Simon effect. Event-related potential (ERP) recordings demonstrated that visuospatial orientation to target stimuli was accompanied by signal-locked activity above motor areas of the cortex, with similar latencies but an enhanced amplitude in patients compared to control subjects. The results suggest that inhibitory modulation of automatic, stimulus-driven, visuomotor activation occurs after the initial sensory activation of motor cortical areas. The failed inhibition in Parkinsons disease appears therefore related to a disturbance in processes that prevent early attention-related visuomotor activation, within motor areas, from actually evoking a response.

Neurophysiology of Implicit Timing in Serial Choice Reaction-Time Performance

Neural representations of time for the judgment of temporal durations are reflected in electroencephalographic (EEG) slow brain potentials, as established in time production and perception tasks. Here, we investigated whether anticipatory processes in reaction-time procedures are governed by similar mechanisms of interval timing. We used a choice reaction task with two different, temporally regular stimulus presentation regimes, both with occasional deviant interstimulus intervals. Temporal preparation was shown in the form of adjustments in time course of slow brain potentials, such that they reached their maximum amplitude just before a new trial, independent of the duration of the interstimulus interval. Preparation was focused on a brief time window, demonstrated by a drop in amplitude of slow potentials as the standard interval had elapsed in deviant interstimulus intervals. Implicit timing influencing perceptual processing was shown in reduced visual-evoked responses to delayed stimuli after a deviant interstimulus interval and in a reduction of EEG α power over the visual cortex at the time when the standard interval had elapsed. In contrast to explicit timing tasks, the slow brain potential manifestations of implicit timing originated in the lateral instead of the medial premotor cortex. Together, the results show that temporal regularities set up a narrow time window of motor and sensory attention, demonstrating the operation of interval timing in reaction time performance. The divergence in slow brain potential distribution between implicit and explicit timing tasks suggests that interval timing for different behaviors relies on qualitatively similar mechanisms implemented in distinct cortical substrates.

Neurophysiological manifestations of phonological processing: Latency variation of a negative erp component timelocked to phonological mismatch

Two experiments examined phonological priming effects on reaction times, error rates, and event-related brain potential (ERP) measures in an auditory lexical decision task. In Experiment 1 related prime-target pairs rhymed, and in Experiment 2 they alliterated (i.e., shared the consonantal onset and vowel). Event-related potentials were recorded in a delayed response task. Reaction times and error rates were obtained both for the delayed and an immediate response task. The behavioral data of Experiment 1 provided evidence for phonological facilitation of word, but not of nonword decisions. The brain potentials were more negative to unrelated than to rhyming word-word pairs between 450 and 700 rnsec after target onset. This negative enhancement was not present for word-nonword pairs. Thus, the ERP results match the behavioral data. The behavioral data of Experiment 2 provided no evidence for phonological Facilitation. However, between 250 and 450 msec after target onset, i.e., considerably earlier than in Experiment 1, brain potentials were more negative for unrelated than for alliterating Word-word and word-nonword pairs. It is argued that the ERP effects in the two experiments could be modulations of the same underlying component, possibly the N400. The difference in the timing of the effects is likely to be due to the fact that the shared segments in related stimulus pairs appeared in different word positions in the two experiments.

The Neurophysiology of Response Competition: Motor Cortex Activation and Inhibition following Subliminal Response Priming

Some widely used tasks in cognitive neuroscience depend on the induction of a response conflict between choice alternatives, involving partial activation of the incorrect response before the correct response is emitted. Although such conflict tasks are often used to investigate frontal-lobe-based conflict-monitoring processes, it is not known how response competition evolves in the motor cortex. To investigate the dynamics of motor cortex activation during response competition, we used a subliminal priming task that induced response competition while bypassing preresponse stage processing conflict. Analyses of movement-related EEG potentials supported an interaction between competing responses characterized by reciprocal inhibition. Inhibitory interactions between response channels contribute to the resolution of response conflict. However, the reciprocal inhibition at motor cortex level seemed to operate independent of higher level conflict-monitoring processes, which were relatively insensitive to response conflict induced by subliminal priming. These results elucidate how response conflict causes interference as well as the conditions under which frontal-lobe-based interference control processes are engaged.

Phonological effects on the auditory N400 event-related brain potential

We report 3 experiments exploring the responsiveness of the auditory N400 event-related potential to the phonological relations between word or non-word targets and preceding prime words. When subjects had to decide whether primes and targets rhymed, non-rhyming words produced greater negativity in the N400 time range than rhyming words. The same effect was obtained when these targets were spoken by another voice than the prime words, suggesting that the effect is determined by phonological factors, and not merely by a physical-acoustic mismatch (Experiment 1). In the rhyming task, the differential N400 for non-rhyming vs. rhyming words was equally pronounced for non-rhyming vs. rhyming non-words (Experiment 2). In a lexical decision task on the same stimuli, a difference between non-rhyming and rhyming targets was obtained for words, but not for non-words (Experiment 3). The results show that the auditory N400 is sensitive to phonological variables. It is further proposed that phonological effects on the auditory N400 are not manifestations unique to phonological processes that demand conscious attention, but may also reflect operations that are performed automatically during auditory word recognition.

Comparing neural correlates of configural processing in faces and objects: an ERP study of the Thatcher illusion.

In the Thatcher illusion, a face with inverted eyes and mouth looks abnormal when upright but not when inverted. Behavioral studies have shown that thatcherization of an upright face disrupts perceptual processing of the local configuration. We recorded high-density EEG from normal observers to study ERP correlates of the illusion during the perception of faces and nonface objects, to determine whether inversion and thatcherization affect similar neural mechanisms. Observers viewed faces and houses in four conditions (upright vs. inverted, and normal vs. thatcherized) while detecting an oddball category (chairs). Thatcherization delayed the N170 component over occipito-temporal cortex to faces, but not to houses. This modulation matched the illusion as it was larger for upright than inverted faces. The P1 over medial occipital regions was delayed by face inversion but unaffected by thatcherization. Finally, face thatcherization delayed P2 over occipito-temporal but not over parietal regions, while inversion affected P2 across categories. All effects involving thatcherization were face-specific. These results indicate that effects of face inversion and feature inversion (in thatcherized faces) can be distinguished on a functional as well as neural level, and that they affect configural processing of faces in different time windows.

Intermediate CAG repeat lengths (53,54) for MJD/SCA3 are associated with an abnormal phenotype

We report on a Dutch family in which 4 members in 2 generations have intermediate repeat lengths (53 and 54) for Machado‐Joseph Disease/ Spinocerebellar Ataxia (MJD/SCA3). All but the youngest have a restless legs syndrome with fasciculations and a sensorimotor axonal polyneuropathy. Central neurological abnormalities are only present in 2. This family shows that intermediate repeat lengths can be pathogenic and may predispose for restless legs and peripheral nerve disorder.