Do eye movement impairments in patients with small vessel cerebrovascular disease depend on lesion load or on cognitive deficits? A video-oculographic and MRI study.

Small vessel cerebrovascular disease (SVCD) is one of the most frequent vessel disorders in the aged brain. Among the spectrum of neurological disturbances related to SVCD, oculomotor dysfunction is a not well understood symptom- in particular, it remains unclear whether vascular lesion load in specific brain regions affects oculomotor function independent of cognitive decline in SVCD patients or whether the effect of higher brain function deficits prevails. In this study, we examined a cohort of 25 SVCD patients and 19 healthy controls using video-oculographic eye movement recording in a laboratory environment, computer-based MRI assessment of white matter lesion load (WMLL), assessment of extrapyramidal motor deficits, and psychometric testing. In comparison to controls, the mean WMLL of patients was significantly larger than in controls. With respect to eye movement control, patients performed significantly worse than controls in almost all aspects of oculomotion. Likewise, patients showed a significantly worse performance in all but one of the neuropsychological tests. Oculomotor deficits in SVCD correlated with the patients' cognitive dysfunctioning while there was only weak evidence for a direct effect of WMLL on eye movement control. In conclusion, oculomotor impairment in SVCD seems to be mainly contingent upon cognitive deterioration in SVCD while WMLL might have only a minor specific effect upon oculomotor pathways.

Eye movement impairments in Parkinson's disease: possible role of extradopaminergic mechanisms.

BACKGROUND: The basal ganglia (BG) are thought to play an important role in the control of eye movements. Accordingly, the broad variety of subtle oculomotor alterations that has been described in Parkinson's disease (PD) are generally attributed to the dysfunction of the BG dopaminergic system. However, the present study suggest that dopamine substitution is much less effective in improving oculomotor performance than it is in restoring skeletomotor abilities. METHODS: We investigated reactive, visually guided saccades (RS), smooth pursuit eye movements (SPEM), and rapidly left-right alternating voluntary gaze shifts (AVGS) by video-oculography in 34 PD patients receiving oral dopaminergic medication (PD-DA), 14 patients with deep brain stimulation of the nucleus subthalamicus (DBS-STN), and 23 control subjects (CTL);In addition, we performed a thorough review of recent literature according therapeuthic effects on oculomotor performance in PD by switching deep brain stimulation off and on in the PD-DBS patients, we achieved swift changes between their therapeutic states without the delays of dopamine withdrawal. In addition, participants underwent neuropsychological testing. RESULTS: Patients exhibited the well known deficits such as increased saccade latency, reduced SPEM gain, and reduced frequency and amplitude of AVGS. Across patients none of the investigated oculomotor parameters correlated with UPDRS III whereas there was a negative correlation between SPEM gain and susceptibility to interference (Stroop score). Of the observed deficiencies, DBS-STN slightly improved AVGS frequency but neither AVGS amplitude nor SPEM or RS performance. CONCLUSIONS: We conclude that the impairment of SPEM in PD results from a cortical, conceivably non-dopaminergic dysfunction, whereas patients' difficulty to rapidly execute AVGS might be related to their BG dysfunction.

Human spatial orientation in non-stationary environments: relation between self-turning perception and detection of surround motion.

We investigated the relative weighting of vestibular, optokinetic and podokinetic (foot and leg proprioceptive) cues for the perception of self-turning in an environment which was either stationary (concordant stimulation) or moving (discordant stimulation) and asked whether cue weighting changes if subjects (Ss) detect a discordance. Ss (N = 18) stood on a turntable inside an optokinetic drum and turned either passively (turntable rotating) or actively in space at constant velocities of 15, 30, or 60°/s. Sensory discordance was introduced by simultaneous rotations of the environment (drum and/or turntable) at ±{5, 10, 20, 40, 80}% of self-turning velocity. In one experiment, Ss were to detect these rotations (i.e. the sensory discordance), and in a second experiment they reported perceived angular self-displacement. Discordant optokinetic cues were better detected, and more heavily weighted for self-turning perception, than discordant podokinetic cues. Within Ss, weights did not depend on whether a discordance was detected or not. Across Ss, optokinetic weights varied over a large range and were negatively correlated with the detection scores: the more perception was influenced by discordant optokinetic cues, the poorer was the detection score; no such correlation was found among the podokinetic results. These results are interpreted in terms of a "self-referential" model that makes the following assumptions: (1) a weighted average of the available sensory cues both determines turning perception and serves as a reference to which the optokinetic cue is compared; (2) a discordance is detected if the difference between reference and optokinetic cue exceeds some threshold; (3) the threshold value corresponds to about the same multiple of sensory uncertainty in all Ss. With these assumptions the model explains the observed relation between optokinetic weight and detection score.

Comparison of smooth pursuit eye movement deficits in multiple system atrophy and Parkinson's disease.

Because of the large overlap and quantitative similarity of eye movement alterations in Parkinson's disease (PD) and multiple system atrophy (MSA), a measurement of eye movement is generally not considered helpful for the differential diagnosis. However, in view of the pathophysiological differences between MSA and PD as well as between the cerebellar (MSA-C) and Parkinsonian (MSA-P) subtypes of MSA, we wondered whether a detailed investigation of oculomotor performance would unravel parameters that could help to differentiate between these entities. We recorded eye movements during sinusoidal pursuit tracking by means of video-oculography in 11 cases of MSA-P, 8 cases of MSA-C and 27 cases of PD and compared them to 23 healthy controls (CTL). The gain of the smooth pursuit eye movement (SPEM) component exhibited significant group differences between each of the three subject groups (MSA, PD, controls) but not between MSA-P and MSA-C. The similarity of pursuit impairment in MSA-P and in MSA-C suggests a commencement of cerebellar pathology in MSA-P despite the lack of clinical signs. Otherwise, SPEM gain was of little use for differential diagnosis between MSA and PD because of wide overlap. However, inspection of the saccadic component of pursuit tracking revealed that in MSA saccades typically correct for position errors accumulated during SPEM epochs ("catch-up saccades"), whereas in PD, saccades were often directed toward future target positions ("anticipatory saccades"). The differences in pursuit tracking between PD and MSA were large enough to warrant their use as ancillary diagnostic criteria for the distinction between these disorders.

Deriving angular displacement from optic flow: a fMRI study.

Using fMRI we wished to identify brain areas subserving the conversion of velocity signals into estimates of self-displacement (velocity-to-displacement integration, VDI), a function which is a prerequisite for the ability to navigate without landmarks. As real self-motion is not feasible in an fMRI environment, we presented subjects with a ride along a circular path in virtual reality devoid of usable landmarks. We asked subjects to try and feel as if actually moving in the scene and to either detect and count changes in driving speed (V-task) or to estimate the angular displacement achieved during a ride (D-task). We examined the contrast between these two tasks with regard to two hypothesised key functions for VDI: (1) evoking an internal image of the self in space and (2) manipulating this image in proportion to perceived velocity at the pace of a time base. The BOLD-responses during both tasks were fairly similar showing activity with right hemispheric dominance in a large parieto-temporo-occipital area as well as in frontal and prefrontal areas. Contrast D-V revealed a mainly parieto-hippocampal network comprising precuneus and inferior parietal cortex, posterior parieto-occipital cortex, retrosplenial cortex and the hippocampal region, but also right superior frontal gyrus and right cerebellum. It can be viewed as a blend of networks known to be involved in mental rotation and in navigation, except for the lack of ventral premotor and prefrontal activity. A tentative interpretation proposes a scenario where precuneus, together perhaps with posterior parieto-occipital cortex, provides the postulated mental image of the self in space and uses it to interpret results computed in the hippocampal region. In the hippocampal region, VDI proper would take place based on a map of spatial orientation, with the appropriate time scale being an intrinsic property. In addition, a dedicated time keeping system in inferior parietal cortex appears to be involved.

Signs of impaired selective attention in patients with amyotrophic lateral sclerosis.

The evidence for involvement of extramotor cortical areas in non-demented patients with amyotrophic lateral sclerosis (ALS) has been provided by recent neuropsychological and functional brain imaging studies. The aim of this study was to investigate possible alterations in selective attention, as an important constituent part of frontal brain function in ALS patients. A classical dichotic listening task paradigm was employed to assess event-related EEG potential (ERPs) indicators of selective attention as well as preattentive processing of mismatch, without interference by motor impairment.A total of 20 patients with sporadic ALS according to the revised El Escorial criteria and 20 healthy controls were studied. Additionally a neuropsychological test battery of frontotemporal functions was applied. Compared with the controls, the ALS patients showed a distinct decrease of the fronto-precentral negative difference wave (Nd), i.e., the main ERP indicator of selective attention. Analysis of the P3 component of the ERPs indicated an increased processing of non-relevant stimuli in ALS patients confirming a reduced focus of attention. We conclude impaired selective attention reflects a subtle variant of frontotemporal dementia frequently observed in ALS patients at a relatively early stage of the disease.

Differential diagnostic value of eye movement recording in PSP-parkinsonism, Richardson's syndrome, and idiopathic Parkinson's disease.

Vertical gaze palsy is a highly relevant clinical sign in parkinsonian syndromes. As the eponymous sign of progressive supranuclear palsy (PSP), it is one of the core features in the diagnosis of this disease. Recent studies have suggested a further differentiation of PSP in Richardson's syndrome (RS) and PSP-parkinsonism (PSPP). The aim of this study was to search for oculomotor abnormalities in the PSP-P subset of a sample of PSP patients and to compare these findings with those of (i) RS patients, (ii) patients with idiopathic Parkinson's disease (IPD), and (iii) a control group. Twelve cases of RS, 5 cases of PSP-P, and 27 cases of IPD were examined by use of video-oculography (VOG) and compared to 23 healthy normal controls. Both groups of PSP patients (RS, PSP-P) had significantly slower saccades than either IPD patients or controls, whereas no differences in saccadic eye peak velocity were found between the two PSP groups or in the comparison of IPD with controls. RS and PSP-P were also similar to each other with regard to smooth pursuit eye movements (SPEM), with both groups having significantly lower gain than controls (except for downward pursuit); however, SPEM gain exhibited no consistent difference between PSP and IPD. A correlation between eye movement data and clinical data (Hoehn & Yahr scale or disease duration) could not be observed. As PSP-P patients were still in an early stage of the disease when a differentiation from IPD is difficult on clinical grounds, the clear-cut separation between PSP-P and IPD obtained by measuring saccade velocity suggests that VOG could contribute to the early differentiation between these patient groups.

Perception of angular displacement without landmarks: evidence for Bayesian fusion of vestibular, optokinetic, podokinesthetic, and cognitive information.

The perception of angular displacement during self turning is generally based on a combination of redundant signals from different sources. For example, during active turning in a visually structured environment devoid of landmarks, podokinesthetic, vestibular, and optokinetic velocity signals are fused and integrated over time to yield a unitary percept of the ongoing change in angular position ('podokinesthetic' refers to proprioceptive and corollary signals related to leg and foot movement). Previously we have shown that the fusion of two of these afferents improves perceptual accuracy and reliability in comparison to when only one is available. For example, with only a single modality available, slow rotations are perceived to be significantly larger than fast ones, whereas the combination of two modalities greatly reduces this difference. These observations spurred the hypothesis that displacement perception results from a weighted average of bottom-up (sensory) signals and top-down signals (a priori knowledge or expectation), with the weight of the latter decreasing the more sensory information is available. We now ask (1) whether the accuracy of angular displacement estimation can be further improved if it can draw on all three sensory modalities instead of only two, and (2) whether bottom-up sensory and top-down a priori information is combined for displacement estimation in a statistically optimal way. To this end 12 healthy subjects (Ss) standing on a turning platform surrounded by a rotatable optokinetic pattern were exposed to 6 different sensory conditions: pure podokinesthetic (P), vestibular (V), or optokinetic (O) stimulation, and combined podokinesthetic-vestibular (PV), vestibular-optokinetic (VO), or podokinesthetic-vestibular-optokinetic (PVO) stimulation. Stimuli had constant angular velocities of either 15, 30, or 60 degrees /s. Subjects were to press a signal button when they felt that angular displacement had reached a previously instructed magnitude (150-900 degrees ). In agreement with earlier observations, the combination of two sensory signals improved the accuracy of displacement perception by reducing both the variance of subjects' displacement estimates and their dependence on turning velocity. Adding a third sensory signal (condition PVO) led to a further reduction of variance and almost eliminated the effect of velocity. We show that these experimental results are compatible with a probabilistic fusion mechanism based on Bayes' law. This mechanism would operate on logarithmic representations of turning velocity and proceed in two stages. A first stage fuses all available bottom-up information to create a unitary representation of the velocity signalled by the different sensory modalities. A second stage then fuses this sensory information with top-down a priori information; the latter creates a bias in favour of a 'default velocity' that grows as the uncertainty of the sensory information increases. Our experimental data agree with the relation between (1) the variance of displacement estimates and (2) their modulation by velocity predicted by this scheme.

Emotional responding in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal disease, leaving the patient in a partially or completely deafferented state. In an explorative study, we investigated responses to visual socio-emotional stimuli in ALS patients. Pictures from the International Affective Picture System (IAPS) were verbally judged by 12 moderately affected ALS patients with a spinal onset and a slow progression and 18 age-matched controls, and data were compared with psychophysiological responses. Verbal emotional judgments of patients were more positive than ratings of controls. Regarding arousal, patients neutralized extreme pictures, in that they rated calm pictures as more exciting than controls and exciting pictures as more calm. These changes of emotional processing were unrelated to depression or frontal lobe dysfunction. There were no major differences between patients and controls concerning physiological responses to emotional stimuli. We conclude that emotional responses of ALS patients tend to be altered towards positive valence and towards a more balanced arousal state in early stages of the disease. These findings contradict assumptions of a generally negative impact of the disease on the emotional disposition and may indicate compensatory cognitive or neuroplastic changes.

Maintaining spatial body alignment on a rotating platform by means of active counter-circling: role of vestibular and podokinesthetic afferents.

We investigated the behaviour of vision-deprived human subjects who try to maintain their horizontal alignment in space on a rotating platform by stepping about their own axis in counter-direction ('podomotor counter-rotation'), and we ask which of two alternative hypotheses best explains this behaviour. (1) The feedback hypothesis assumes that the podomotor counter-rotation is controlled by negative feedback of vestibular signals from the horizontal canals. (2) The reconstruction hypothesis holds that the vestibular cue first is combined with leg proprioceptive afferents signalling the individual's rotation on the platform ('podokinesthetic cue') in a way that reconstructs the platform's motion in space for internal representation; a negative (direction-inverted) copy of this representation then would drive the counter-rotation. Subjects were exposed to three different velocity profiles of platform rotation: VC, constant velocity rotation with sudden onset and offset; VS, sinusoidal rotation; VN, pseudorandom noise sequences. The subjects' response (i.show $132#e., their active self-rotation on the platform) to the onset and offset of VC rotations was reminiscent of a first-order lead system. Specifically, after rotation onset subjects immediately began to step on the platform in opposite direction; initially, the velocity of this response matched that of platform rotation, leading to a fairly good stabilisation of subjects' alignment in space. However, this response declined exponentially; consequently, subjects began to increasingly rotate in space along with the platform, ultimately stepping in place on the platform. After rotation offset, subjects immediately began to step around on the now stationary platform so as to continue their previous rotation in space; this response again declined exponentially until subjects became gradually stable again with respect to space. Within subjects, the time constant (tau) of these responses was similar for onset and offset. Across subjects it exhibited a conspicuous variability, ranging from 7 s to virtually infinity. The responses to VS and VN rotations were closely correlated to what could be predicted for each individual from his tau during VC on the assumption of a first-order lead system. We conclude that the mechanism stabilising body orientation basically is linear (no prediction with sinusoidal rotation, no extrapolation of constant velocity rotation). A comparison of the experimental results with simulations of the feedback hypothesis and of the reconstruction hypothesis suggests that the reconstruction hypothesis is a more likely description of the underlying processing of the vestibular and podokinesthetic cues.

Musicians versus nonmusicians. A neurophysiological approach.

The ability to perceive sounds and correctly categorize them within a scale is the result of the interaction between inherited capabilities and acquired rules. If a subject listens to a melody, occasional and unexpected endings of the melody typically evoke characteristic auditory evoked responses in the latency range of 300-400 ms (P300). Also, earlier stages of auditory information processing have been exhaustively investigated by means of mismatch negativity (MMN), a deflection that occurs in the auditory evoked response at a latency of about 200 ms, whenever a deviance is randomly inserted in a series of otherwise equal stimuli. Conceivably, perceptual deviations could also be detected against expectancies that are based on abstract rules; introspective experience suggests that such deviations may also elicit fast intuitive responses that typically initiate processes of analytical reasoning for confirmation. In music, the physical features of the stimulus are, in fact, always changing, because the melodic contour consists of a series of notes with different pitch characteristics. In such a condition, a typical mismatch negativity would not be evoked on the basis of physical deviance, but rather of criteria involving the musical contour of the stimulus. In this study, 20 healthy subjects (10 nonmusicians and 10 musicians) underwent auditory stimulation (tone, chord, chord sequence, Mozart and Bach melodies) and both electrical and magnetic recordings. Clear N1 was recorded for all paradigms, in all subjects; MMN and P300 were also recorded, and their amplitudes and latencies were significantly correlated with the musicality score and with the paradigm's difficulty.

Vestibular, optokinetic, and cognitive contribution to the guidance of passive self-rotation toward instructed targets.

We ask how vestibular and optokinetic information is combined ("fused") when human subjects who are being passively rotated while viewing a stationary optokinetic pattern try to tell when they have reached a previously instructed angular displacement ("targeting task"). Inevitably such a task entices subjects to also draw on cognitive mechanisms such as past experience and contextual expectations. Specifically, because we used rotations of constant angular velocity, we suspected that they would resort, consciously or unconsciously, to extrapolation strategies even though they had no explicit knowledge of this fact. To study these issues, we presented the following six conditions to subjects standing on a rotatable platform inside an optokinetic drum: V, pure vestibular (passive rotation in darkness); O, pure optokinetic (observer motionless, drum rotating); VO, combined (passive rotation while viewing stationary drum); Oe, optokinetic extrapolation (similar to O, but drum visible only during first 90 degrees of rotation; thereafter subjects extrapolate the further course in their minds); VOe, combined extrapolation (similar to VO, but drum visible only during first 90 degrees ); AI, auditory imagination (rotation presented only metaphorically; observers imagine a drum rotation using the rising pitch of a tone as cue). In all conditions, angular velocities ( v(C)) of 15, 30, or 60 degrees /s were used (randomized presentation), and observers were to indicate when angular displacement (of the self in space or relative to the drum) had reached the instructed magnitude ("desired displacement", D(D); range 90-900 degrees ). Performance was analyzed in terms of the targeting gain ( G(T) = physical displacement at time of subjects' indication / D(D)) and variability (% E(R) = percentage absolute deviation from a subject's mean gain). In all six conditions, the global mean of G(T) (across v(C) and D(D)) was remarkably close to veracity, ranging from 0.95 (V) to 1.06 (O). A more detailed analysis of the gain revealed a trend of G(T) to be larger with fast than with slow rotations, reflecting an underestimation of fast and an overestimation of slow rotation. This effect varied significantly between conditions: it was smallest in VO, had intermediate values with the monomodal conditions V and O, and also with VOe, and was largest in Oe and AI. Variability was similar for all velocities, but depended significantly on the condition: it was smallest in VO, of intermediate magnitude in O, VOe, Oe, and largest in V and AI. Additional experiments with conditions V, O, and VO in which subjects repetitively indicated displacement increments of 90 degrees, up to a subjective displacement of 1080 degrees, yielded similar results and suggest, in addition, that the displacement perceptions measured at the beginning and during later phases of the rotation are correlated. With respect to the displacement perception during optokinetic stimulation, they also show that the gain and its variability are similar whether subjects feel stationary and see a rotating pattern, or feel rotated and see a stationary pattern (circular vection). We conclude that the vestibular and optokinetic information guiding the subjects' navigation toward an instructed target is not fused by straightforward averaging. Rather the subjects' internal velocity representation (which ultimately determines G(T)) appears to be a weighted average of (1) whatever sensory information is available and of (2) a cognitive default value reflecting the subjects' experiences and expectations. The less secure the sensory information (only one source as in V or O, additional degrading as in Oe or AI), the larger the weight of the default value. Vice versa, the better the information (e.g., two independent sources as in VO), the more the actual velocity and not the default value determines displacement perception. Moreover, we suggest that subjects intuitively proceeded from the notion of a constant velocity rotation, and therefore tended to carry on the perception built up during the beghe perception built up during the beginning of a rotation or, in the case of vestibular navigation, to compensate for the decaying vestibular cue by means of an internal recovery mechanism.

Fusion of vestibular and podokinesthetic information during self-turning towards instructed targets.

When observers step about their vertical axis ("active turning") without vision they dispose of essentially two sources of information that can tell them by how much they have turned: the vestibular cue which reflects head rotation in space and the "podokinesthetic" cue, a compound of leg proprioceptive afferents and efference copy signals which reflects the observer's motion relative to his support. We ask how these two cues are fused in the process leading to the perception of self-displacement during active turning. To this end we compared the performance of observers in three angular navigation tasks which differed with regard to the number and type of available motion cues: (1) Passive rotation, vestibular cue ( ves) only; observers are standing on a platform which is being rotated. (2) Treadmill stepping, podokinesthetic cue ( pod) only; observers step counter to the rotating platform so as to remain stable in space. (3) Active turning, ves and pod available; observers step around on the stationary platform. In all three tasks, angular velocity varied from trial to trial (15, 30, 60 degrees /s) but was constant during trials. Perception was probed by having the observers signal when they thought to have reached a previously instructed angular displacement, either in space or relative to the platform ("target"; range 60-1080 degrees ). Performance was quantified in terms of the targeting gain (displacement reached by the observer divided by target angle) and of the random error ( E(r)), which records an observer's deviation during single trials from his average performance. Confirming previous observations, E(r) was found to be significantly smaller during active turning than during passive turning, and we now complement these observations by showing that it is also significantly smaller than during treadmill stepping. This behaviour of E(r) is compatible with the idea that ves and pod be averaged during active turning. On the other hand, the observed characteristics of the targeting gain ( G(T)) support this idea only for the case of fast rotations (60 degrees /s); at lower velocities, the gain found during active turning was clearly not the average of the G(T) values recorded in the passive and the treadmill modes. We therefore also discuss alternative scenarios as to how ves and pod could interact, among these one based on the concept of a vestibular eigenmodel. A common denominator of these scenarios is that ves assumes the role of a prerequisite for an optimal use of pod during turning on a stationary support, without itself entering the calculation of displacement perception; this perception would be based exclusively on pod. Finally, it was a consistent observation that during passive rotations cognitive mechanisms fill in for the decaying vestibular signal in the context of the present navigation task, enabling observers to achieve large displacements surprisingly well although the duration of these movements exceeds by far the conventionally cited value of the central vestibular time constant (=20 s).

Circular vection during voluntary suppression of optokinetic reflex.

Optokinetic circular vection (CV) was investigated in 12 subjects using an optokinetic pattern rotating at 15 degrees /s, 30 degrees /s, or 60 degrees /s, and four viewing conditions: FOL, subjects attentively followed details of pattern; STA, subjects stared at the pattern; SUP, subjects suppressed their optokinetic reflex (OKR) voluntarily (this was facilitated by a white, featureless band at eye level which separated the pattern in an upper and lower half); FIX, subjects suppressed OKR by fixating at a stationary fixation point (FP). To quantify CV, subjects pressed a signal button each time they felt rotated by a further 90 degrees; OKR was recorded by electro-oculography. Voluntary suppression of OKR was achieved during 2-70% of stimulus duration. Total apparent self-displacement (cumulated 90 degrees indications) was smallest during FOL, increasing gradually in the order FOL < STA < SUP < FIX (all inequalities significant); CV latency decreased in the same order. Slow eye velocity was identical during FOL and STA, and was reduced by 70-30% during SUP. We conclude from these results: (1) the effect of eye movements on CV depends on whether these are intentional (FOL) or not (STA); (2) the increase in CV during voluntary OKR suppression without FP suggests that afferent motion cues (retinal slip) are processed with larger gain than efferent motion cues (eye movement); hence (3) the enhancement of CV during fixation of FP is not, or not solely, the result of the apparent motion of the FP counter to the direction of pattern movement (Duncker illusion).