Remodeling of the fovea in Parkinson disease.

To quantify the thickness of the inner retinal layers in the foveal pit where the nerve fiber layer (NFL) is absent, and quantify changes in the ganglion cells and inner plexiform layer. Pixel-by-pixel volumetric measurements were obtained via Spectral-Domain optical coherence tomography (SD-OCT) from 50 eyes of Parkinson disease (PD) (n = 30) and 50 eyes of healthy control subjects (n = 27). Receiver operating characteristics (ROC) were used to classify individual subjects with respect to sensitivity and specificity calculations at each perifoveolar distance. Three-dimensional topographic maps of the healthy and PD foveal pit were created. The foveal pit is thinner and broader in PD. The difference becomes evident in an annular zone between 0.5 and 2 mm from the foveola and the optimal (ROC-defined) zone is from 0.75 to 1.5 mm. This zone is nearly devoid of NFL and partially overlaps the foveal avascular zone. About 78 % of PD eyes can be discriminated from HC eyes based on this zone. ROC applied to OCT pixel-by-pixel analysis helps to discriminate PD from HC retinae. Remodeling of the foveal architecture is significant because it may provide a visible and quantifiable signature of PD. The specific location of remodeling in the fovea raises a novel concept for exploring the mechanism of oxidative stress on retinal neurons in PD. OCT is a promising quantitative tool in PD research. However, larger scale studies are needed before the method can be applied to clinical follow-ups.

Cortical control of saccades in Parkinson disease and essential tremor.

A number of studies suggest that some features of essential tremor (ET) and Parkinson disease (PD) overlap. Besides tremor, also some cognitive features have been implicated in ET and PD. There is recent evidence that a common genetic mutation occurs in ET and PD. Saccadic eye movements could provide an easily quantifiable procedure to help in the differential diagnosis in early PD and ET. Being able to distinguish early on the two diseases may help in tailoring therapy. Cortical control of saccades and antisaccades as they pertain to the potential discrimination of PD and ET is reviewed. Imaging and electrophysiological studies are highlighted; however, there are still few studies. Hopefully this review will stimulate further research, in particular in the direction of differences and similarities in the neural circuits involved in PD and ET.

Cortical control of voluntary saccades in Parkinson's disease and pre-emptive perception.

Gamma range EEG has been associated with cognition. Bodis-Wollner et al. [Ann NY Acad Sci 2002;956:464-7] and Forgacs et al. [Perception 2008;37:419-32] described posterior perisaccadic gamma (35-45 Hz) modulation associated with voluntary saccades. Voluntary impairment is a hallmark of Parkinson's disease (PD). We have done correlational analysis of frontally and posteriorly (posterior-parietal) recorded intrasaccadic gamma (ISG) powers, to understand cortical control of voluntary saccades in PD and healthy controls. Fifteen PD patients (55-71 years, 4 females) and 17 healthy controls (54-72 years, 9 females) participated in the study. The EEG was recorded over frontal and posterior-parietal scalp sites. Saccades were recorded with electro-oculogram and infra-red ISCAN camera. Subjects executed horizontal voluntary saccades to a mark; 15 degree distance rightwards or leftwards (centrifugal CF) from the central fixation, then back to the center (centripetal CP) and so on, for 2 minutes. Perisaccadic EEG segments were wavelet transformed followed by Hilbert transform to obtain ISG (35-45 Hz) powers. ISG power was trial-averaged, separately for the 4 possible saccade types; CP and CF, rightwards and leftwards. The perisaccadic EEG revealed disorganization in the intrasaccadic period. The correlations between frontal and posterior ISG power are high in PD (correlation coefficient >0.6) while low in controls (correlation coefficient <0.02). We interpret these results as lack of modulatory coupling between frontal and posterior intrasaccadic mechanisms in PD. Impaired volition in PD may be due to impaired circuitry of preemptive perception (PEP). Interareal phase coupling analysis will help in investigating the cortical voluntary saccade control with greater temporal precision.

Perisaccadic gamma modulation in Parkinson disease patients and healthy subjects.

We quantified the anterior-posterior distribution of the gamma modulation index (GMI), an index of perisaccadic phasic modulation of the gamma (35-45 Hz) range electroencephalogram (EEG), in healthy human subjects and Parkinson disease (PD) patients. The EEG was recorded over the frontal, parietal, temporal and occipital sites in 11 idiopathic PD patients (age 50-70 years, four females), 4 age matched healthy volunteers (1 female) and 17 young healthy controls (age 21-30 years, four females) Eye movements were recorded with EOG and ISCAN camera. Subjects executed saccades to a mark at right and back to fixation point and vice versa. The saccades directed away from center/fixation (centrifugal CF) were analyzed. Two minutes of EEG were obtained from each subject for the two possible saccade types (centrifugal rightwards and leftwards at 15 degrees). Each perisaccadic EEG segment was analyzed using continuous wavelet transform for quantifying the power and time course of gamma EEG ranges for each saccade type. A three way ANOVA was used for statistical analysis. Perisaccadic GMI (peak intrasaccadic power divided by mean power) in healthy subjects was higher over the contralateral hemisphere to the saccade direction, for both centrifugal saccades at anterior, posterior and occipital recording sites. Contrary to the healthy subject GMI remained near one in PD, i.e., there was no evidence of intrasaccadic gamma power increase in PD patients.

Getting around and communicating with the environment: visual cognition and language in Parkinson's disease.

Vision in PD. In PD an impairment of dopaminergic neurons of the preganglionic retina and a defect of the retinal nerve fibers (axons of the retinal ganglion cells) has been demonstrated and a correlation of loss of spatial contrast sensitivity, with the progression of motor impairment in PD has been described. These low level visual deficits contribute but do not directly explain behavioural visual deficits in PD involving spatial cognition, internal representation, space navigation and visual categorization. Language deficits in non-demented PD patients can include impairments in comprehension, verbal fluency, and naming. Comprehension deficits become evident when patients are required to process sentences with non-canonical, irregular grammatical structures. Semantic memory deficits may result in the impairments in category fluency and confrontational naming. Selective language deficits may be due to impaired dynamics of the "phonological loop" connecting the pre-frontal cortex and the basal ganglia. A more encompassing linguistic and functional model of PD specific language impairments would be useful for evaluating language deficits in the context of motor dysfunction.

Role of the calcarine cortex (V1) in perception of visual cues for saccades.

OBJECTIVE: To determine the initial level at which the pathways for cue perception, saccades and antisaccades diverge. METHODS: Two procedures: single pulse transcranial magnetic stimulation (sTMS) over posterior occiput and backward masking were used. A visual cue directed saccades to the left or right, either a pro-saccade (to the side of the cue but beyond it) or an antisaccade, i.e., contraversive saccade. No visual target was presented. RESULTS: Latencies of the two types of saccades did not differ. Focal sTMS applied unilaterally over V1 suppressed both perception of a cue flashed 80-90ms earlier contralaterally (but not ipsilaterally) and the appropriate saccade. Masking at a delay of 100ms abolished the appropriate saccade and cue perception. CONCLUSIONS: V1 is essential for the perception of a flashed cue and for executing appropriate pro- and contraversive saccades. Masking may occur beyond V1, where the pathways for perception and for saccades at least to the next visual processing level start separating. SIGNIFICANCE: VI is needed for rapid, accurate perceptual and motor responses to the crudest (left versus right) cues. It is unlikely that the "where" system can have a major direct input bypassing V1.

Nicotinic receptors and cognition in Parkinson's Disease: the importance of neuronal synchrony.

Parkinson's Disease (PD) is associated with cognitive deficits. The earliest impairment is evident for executive abilities, visuospatial orientation and memory. Dopamine deficiency is unlikely to be singly responsible for all cognitive changes in PD. Acetyl-choline has an essential role in cognition, thus cholinergic transmission may have an important role in non-dopaminergic cognitive changes. If so, some cognitive defects could possibly be treated with choline-esterase inhibitors. A concern is the potential negative motor effect of cholinergic medication in PD. Surprisingly, these are reported only in a few patients studied. Establishing the relationship between select cognitive deficits and nicotinic neurotransmission may lay the foundation for rational pharmacotherapy of cognitive dysfunction in PD. We summarize anatomical, physiological and pharmacological aspects of nicotinic receptor function. The focus is on those nicotine receptor dependent cognitive dysfunctions which are likely to contribute to motor impairment. Lastly, we discuss hypotheses concerning cholinergic involvement in neuronal synchrony and sensorimotor integration in PD.

The visuo-cognitive and motor effect of amantadine in non-Caucasian patients with Parkinson's disease. A clinical and electrophysiological study.

It has been reported that non-Caucasian populations often suffer from an atypical type of Parkinson's disease (PD) characterized by poor levodopa response, early cognitive impairment and autonomic dysfunction. We tested the effect of a well known antiparkinsonian compound, amantadine, in 23 Afro-American patients with PD in a time-limited (six months), open-label, clinical and electrophysiological (simultaneously recorded primary and cognitive visual evoked potentials) trial. Patients were given amantadine either as monotherapy (first group) or added to levodopa treatment (second group). Amantadine produced a significant (p < 0.05) shortening of the latency of the event related potential (P300) obtained in a visual discrimination paradigm, while the timing of primary visual evoked potentials was little or not at all affected. Amantadine also showed significant beneficial effects (p < 0.01) on the motor score of both groups as assessed by the Rated Parkinson's Disease Neurological Exam, including items related to autonomic dysfunction. These findings suggest that amantadine alone and as adjuvant to levodopa can significantly improve both the speed of visual cognitive processing and the clinical score in non caucasian patients with PD. For these populations amantadine can be thus considered a helpful therapeutical option.

Wavelet transform of the EEG reveals differences in low and high gamma responses to elementary visual stimuli.

Multiunit electrophysiological studies indicate that oscillatory activity is common in the awake mammalian central nervous system. Synchronous 20-80 Hz oscillations, so called gamma rhythms, have been proposed as a possible fundamental physiological mechanism of binding neuronal activity underlying object recognition. The purpose of this study was to determine whether or not gamma band oscillatory activity in the human brain is modulated by attributes of elementary visual stimulation. The experiment was performed on 7 normal subjects. Sinusoidal gratings were presented over a range of spatial frequencies. Evoked potentials were recorded over 5 surface electrodes placed in a horizontal occipital chain across the back of the head. Discrete wavelet transform was performed on the first 200 msec following stimulus onset on the average data of 256 sweeps. Power was analyzed with ANOVA across conditions. In our previous studies we have separated a "low" (14-28 Hz) and "high" (28-55 Hz) gamma band. The current results indicate that both gamma bands to full-field stimulation have the highest power at the midline (inion) electrode to a spatial frequency of 5.5 cpd, which is the peak spatial frequency from foveal psychophysical data. However, the spatial frequency bandwidth is considerably narrower in the HG than in the LG band. Occipital spatial frequency tuning of the massed high gamma response is narrower than the tuning of individual cortical neurons. The bandwidth difference between low and high gamma band suggests that different frequency gamma range oscillations may represent not only different functional properties of visual processing, but may also reflect underlying differences in excitatory and postsynaptic inhibitory circuits shaping the contrast sensitivity of the human observer. Our study emphasizes the importance of elementary visual filter properties for gamma responses and the need to subdivide gamma frequency ranges according to functional properties.

The paracentral visual field in multiple sclerosis: evidence for a deficit in interneuronal spatial summation?

A visual complaint such as blurred or "washed-out vision" can be one of the early signs of multiple sclerosis (MS). Although visual deficits are commonly attributed to optic nerve demyelination even with preserved visual acuity, the results of a considerable number of visual studies are inconsistent with this interpretation [Camisa, Mylin, & Bodis-Wollner, Annals of Neurology 10 (1981) 532-539; Regan & Neima, British Journal of Ophthalmology 68 (1984) 310-315]. However, a retinal axonal (nerve fiber layer) defect can be detected in some eyes, this is not the rule. Routine visual field (VF) tests, with a low sampling rate may also be non-informative in MS and optic neuritis, possibly because the VF abnormalities may be small and spotty or they can be found between tested points. The present study combined the advantages of VF and contrast sensitivity (CS) testing by applying contrast perimetry (CP), to the central 16 degrees of the VF. Four paracentral VF quadrants were tested in clinically affected and unaffected eyes of 31 MS patients and 26 controls. The stimuli were vertical Gaussian apertured sinusoidal gratings (Gabors) of 1 cpd. CS was obtained as a function of the diameter of the Gábor ranging from 1 to 7.4 degrees. The CP data of controls and definite and probable MS groups were significantly different for each pattern size, but the largest difference was found at diameters 2.5-3.7 degrees. Our study adds to previous evidence showing that optic nerve pathology does not explain "subclinical" and manifest visual dysfunction in MS. Given previous studies revealing orientation dependent monocular visual deficits and our study results, parsimony suggests that MS affects a network relying on myelinated lateral axonal branches of the visual cortex, binding monocular columns of neurons with like-with-like specificity.

Retinocortical gain in the foveal pathway: the effect of spatial frequency and stimulus size.

The amplitude and the phase of the simultaneously recorded steady-state pattern electroretinogram (PERG) and visual evoked potential (VEP) were evaluated in humans as a function of the vertical diameter (D) of unidimensional Gabor stimuli. In the other dimension, parallel to the horizontal gratings, the patterns all had constant diameter (see Methods and Materials). Spatial frequencies (SFs) of 1 cycle per degree (cpd) and 5.3 cpd were counterphase modulated at a rate of 6.8 Hz. After off-line artifact rejection, the response was subject to Fast Fourier Transformation (FFT). Amplitude and phase of the first and second harmonics of both ERG and VEP were displayed for each SF and stimulus diameter. Both ERG and VEP amplitude were found to increase as a function of D. Using trend analysis we found that ERG amplitude increased linearly as a function of D. VEP amplitude was found to be both linear and cubic, as a function of D. We calculated the ratio of VEP amplitude and ERG amplitude at each D and termed it retinocortical gain (G). G normalized to stimulus area was high for small D and decreased with D independently of SF. Unity gain occurred at stimulus sizes of 6 degrees to 7 degrees. ERG phase was found to be more negative at 5.3 cpd than at 1 cpd. Although no significant difference was found between VEP phases at the two SFs tested, neither ERG nor VEP phase changed as a function of D. The results suggest that retinocortical gain is highest for the foveally centered low spatial frequency small patch Gabors. The results provide support for the notion of the "foveal window" in human vision.

Parkinson's disease changes the balance of onset and offset visual responses: an evoked potential study.

OBJECTIVES: We investigated whether the transient pattern onset and offset visual evoked potential (VEP) can distinguish between patients with Parkinson's disease (PD) and normal subjects. METHODS: Two horizontal sinusoidal gratings differing in spatial frequency, i.e. 1 and 4 cycles per degree, were presented to 17 patients with PD and 16 age-matched control subjects. We analyzed the responses in the time-domain and measured the latencies and amplitudes of N1 and P1 to the onset and the offset of the stimulus; we also derived the measures of offset N1 and P1 amplitude responses 'normalized' to onset N1 and P1 amplitude values, respectively (amplitude ratios). RESULTS: Absolute and normalized offset P1 amplitude is a distinguishing feature of PD patients from controls. Offset P1 amplitude was significantly larger in PD patients than in controls, particularly to the lower spatial frequency stimulus (P<0.01 for absolute and P<0.001 for normalized values, respectively). CONCLUSIONS: We conclude that the pattern onset/offset VEP amplitude provides a simple measure to evaluate visual processing deficits in PD and could contribute to an understanding of the pathophysiology of these changes.

Psychophysical examination of paracentral defects in glaucoma.

More than 50% of ganglion cells may be damaged before visual field loss is measurable by conventional methods in primary open angle glaucoma. There is general agreement on the need to improve early diagnosis of visual field loss in primary open angle glaucoma. In this article, new techniques that enlist measurement of paracentral regions are discussed, and the ability of each method to detect visual field loss prior to perimetric loss is described.

Functional properties of sub-bands of oscillatory brain waves to pattern visual stimulation in man.

The scalp recorded transient visual evoked potential (VEP) represents the massed activity of a large number of neurons of the human visual cortex. Animal studies show that intracerebrally-recorded high frequency electrical activity represents binding between neurons participating in a cooperative response. We evaluated the relationship between scalp recorded high frequency activity and transient VEPs elicited by a repetitive (grating) pattern. Stimuli were 1 and 4 cycles/degree sinusoidal gratings, presented in an on/off mode. Following conventional averaging, the discrete wavelet transform (DWT) was applied. Multi-resolution decomposition was used to divide the responses into 6 orthogonal frequency bands. The results show that high frequency oscillatory activity in the beta and gamma frequency range is closely related in time to the N70 peak of the simultaneous VEP. Power in both bands is modulated by spatial frequency. Beta range response to hemifield stimulation recorded over a chain of electrodes over the occipital area lateralizes in the same manner as N70, while gamma range activity is insensitive to lateralization and is more closely linked to foveal stimulation. This dissociation between beta and gamma range activity suggests that different bands of high frequency oscillatory activity in humans, linked to visual stimulation, may represent different aspects of visual processing.

Cortical activation patterns during voluntary blinks and voluntary saccades.

OBJECTIVE: To investigate the activation of frontal, parietal, and occipital areas in normal volunteers during voluntary blinks and during voluntary saccades using functional MRI (fMRI). BACKGROUND: A previous fMRI study revealed the activation of the precentral and posterior middle frontal gyrus ("frontal eye field" [FEF]), the medial part of the superior frontal gyrus ("supplementary eye field" [SEF]), and the visual cortex. The parietal cortex was not included in this study. Frontal and occipital cortical areas involved in voluntary blinking have not been shown previously using fMRI. METHODS: A 1.5-T standard clinical scanner was used for both anatomic and functional studies in 12 observers. To conduct data analyses the authors used voxel-by-voxel cross-correlation. RESULTS: Voluntary blinks led to the activation (p < 0.05) of the FEF, the SEF, the posterior parietal cortex ("parietal eye field" [PEF]), and the visual cortex. Voluntary blinking produced activity in the same cerebral structures as voluntary saccades. However, the number of activated voxels was smaller during voluntary blinking than during voluntary saccades in the visual cortex and in the FEF (p < 0.01). In contrast, the extent of activation was significantly higher (p < 0.003) in the SEF and in the PEF during voluntary blinking. CONCLUSIONS: Voluntary blinks and saccades are associated with similar loci of activation patterns; however, the quantitative distribution of activation suggests that the middle part of the frontal gyrus and posterior parietal cortex are of special significance for voluntary blinks. The results argue for the importance of considering quantitative distributional properties of parallel cortical activities associated with saccades and blinks.

A mixed D1 and D2 antagonist does not replay pattern electroretinogram alterations observed with a selective D2 antagonist in normal humans: relationship with Parkinson's disease pattern electroretinogram alterations.

The human retina produces a tuned response to stimuli of increasing spatial frequency reversed at a steady state. The peak amplitude response, at medium spatial frequencies, is decreased in Parkinson's disease and in normal subjects (n = 18) treated with a D2 dopaminergic antagonist (l-sulpiride). Here, we report that a mixed D1-D2 receptor antagonist (haloperidol) in normal subjects (n = 18) does not produce an amplitude decrease of medium spatial frequencies (SFs) responses but it decreases low-frequency response. It could argued that the increased dopamine release produced by the presynaptic D2 antagonistic action of haloperidol is subsequently counteracted at postsynaptic level by its D1 antagonistic effect, producing a net counterbalance at medium SFs. These data suggest that the two dopamine receptors may play different roles in the retinal function and in the origin of visual alterations in Parkinson's disease.

L-alpha-glycerylphosphorylcholine enhances the amplitude of the pattern electroretinogram in rhesus monkeys. A pilot study.

The effects of L-alpha-glyceryl-phosphorylcholine (LGPC), a putative acetylcholine precursor, were studied on the pattern electroretinogram (PERG) in two rhesus monkeys. In the time interval 10-30 min after LGPC administration (85 mg/kg i.m.), the amplitude of the PERG increased significantly. In both monkeys the amplitude enhancement was more pronounced for low spatial frequency stimuli (1 cycle/degree) than for medium spatial frequency gratings (5 cycles/degree). This result suggests that besides the general facilitatory properties, LGPC may have specific spatial frequency tuning effects at the level of retinal information processing.