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.

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.

Visual acuity and contrast sensitivity in patients with cerebral lesions.

Spatial contrast sensitivity as a function of spatial frequency was measured in patients with cerebral lesions. In most of these patients visual acuity, as measured by the Snellen chart, was 20/30 or better, yet marked departures from normal contrast sensitivity were found. The greatest loss in contrast sensitivity occurred at high frequencies, but in one patient the loss was greatest in the midfrequency range. This finding lends support to the channel hypothesis of spatial contrast discrimination.

Visual association cortex and vision in man: pattern-evoked occipital potentials in a blind boy.

In a 6-year-old child who had been blind since the age of 2 years, occipital potentials of normal amplitude and waveform could be evoked not only by diffuse light flashes but also by alternating checkerboard ans sinusoidal grating patterns of low spatial frequency. Computerized tomography demonstrated destruction of the occipital lobes except of the primary visual projection area. Thus, in man, destruction of visual association cortices may result in loss of vision with partial preservation of pattern-evoked occipital potentials.

Visual deficits related to dopamine deficiency in experimental animals and Parkinson's disease patients.

In patients affected by Parkinson's disease, and in the monkey model of this disease, visual defects have been shown using psychophysical and electrophysiological measures of spatial and temporal contrast sensitivity. These studies imply an essential role for dopamine in primate vision. There is electrophysiological and neurochemical evidence to suggest that at least part of the problem is impaired retinal processing caused by systemic dopaminergic deficiency. Some of the deficits that have been demonstrated, consistent with physiological studies, suggest that center-surround interaction of neurons may suffer as a consequence of dopaminergic deficiency. The role of the regulation of retinal dopamine (D1 and D2) receptors in primate vision and of the balance of these receptors in presynaptic dopaminergic deficiency is not yet determined. Using sinusoidal grating stimuli in cognitively loaded tasks may increase understanding of the behavioral consequences of visual deficits seen in dopamine deficiency syndromes.

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.

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.

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.

Nitrous oxide: clinical and electrophysiologic investigation of neurologic complications.

Prolonged exposure to nitrous oxide produces a recognized neurologic syndrome. We report clinical and electrophysiologic studies of nervous system involvement in a 25-year-old student who abused nitrous oxide. He developed signs of a sensorimotor polyneuropathy and of myelopathy. Routine blood studies, CSF examination, and myelogram were normal. Clinical electrophysiologic studies were performed serially. Nerve conduction studies demonstrated reduced amplitude and slowed sensory potentials, and mildly prolonged late responses. Sensory evoked potentials revealed prolonged latency of scalp-evoked potentials from tibial nerve stimulation with normal median nerve values. The foveal visual evoked potential was delayed in the right eye, with normal visual acuity, funduscopic examination, and spatial contrast sensitivity. Repeat electrophysiologic studies demonstrated improvement. Nitrous oxide produces multifocal reversible dysfunction within the nervous system similar to that described in patients with vitamin B12 deficiency.

Functional MRI mapping of occipital and frontal cortical activity during voluntary and imagined saccades.

We investigated the activation of frontal and occipital cortical areas in 14 normal volunteers during voluntary saccades in light or dark and during imagined saccades using functional magnetic resonance imaging (FMRI) with electro-oculogram monitoring. Voluntary saccades in light or dark and imagined saccades led to a significant activation (p < 0.005) of the precentral and posterior medial frontal gyrus (frontal eye field). The medial part of the superior frontal gyrus (supplementary eye field) also showed significant activity during voluntary saccades in all subjects, but only in four subjects during imagined saccades. In addition to frontal activity we found an activated primary visual cortex during voluntary saccades, both in light and in dark. In contrast to executed saccades, imagined eye movements revealed to occipital response under either condition. Our FMRI study supports the concept of frontal eye fields during voluntary saccades and demonstrates that occipital areas are associated with the generation of voluntary eye movements. However, the primary visual cortex is not active when eye movement is only imagined.

VEPs in humans reveal high and low spatial contrast mechanisms.

The effect of contrast on visual evoked potential (VEP) amplitude was examined in nine observers. A 6.0 cycles/deg (cpd) grating was modulated in an "on-off" mode at 7.5 Hz. The VEP response contains significant first and second harmonic components: their growth with contrast is parallel, each function consisting of two limbs. The data are consistent with the hypothesis that the pattern VEP obtained with "on-off" presentation may reflect the contributions of "low" and "high" contrast neuronal populations demonstrated in physiological studies of the primate.

Visual evoked potentials in macular disease.

Although a delayed visual evoked potential is considered to be the hallmark of optic nerve disease, relatively little has been published about VEP delays in macular disease. In this study, 20 patients with either acquired unilateral maculopathy or bilateral maculopathy in which one eye was more affected than the other were evaluated. VEP amplitudes and peak latencies were compared between eyes when recordable. Nine patients (45%) exhibited significant interocular delays in the affected or more affected eye while only four patients (20%) exhibited significant interocular attenuations in amplitude. In the nine patients exhibiting delays, three patients had a visual acuity of 20/30 or better in the affected eye or more affected eye. In the patients exhibiting amplitude attenuations, no patient had a visual acuity better than 20/50 in the affected or more affected eye. Although the mechanism of VEP delays in maculopathy is not clear, a VEP delay, in isolation of other tests, should not be used in the differential diagnosis of macular vs optic nerve disease. The clinician should specifically rule out macular disease in any patient with a delayed VEP before presuming the presence of a visual pathway dysfunction.

Flicker threshold and pattern VEP latency in ocular hypertension and glaucoma.

Latency of the pattern visual-evoked potential (PVEP) was measured in 24 ocular hypertensive (OHT) patients, eight open-angle glaucoma (OAG) patients, and 37 control subjects. The PVEP stimulus was a 2.3 cycle/degree sinusoidal grating, counterphase-modulated at 1 Hz. Field size was 9 degrees and mean luminance 1.7 log ft-lamberts. For 22 of the 32 patients, a psycholphysical measure of dynamic contrast sensitivity at 8 Hz (DRC) was obtained with a 4 degrees diameter stimulus, by determining the mean value for the contrast sensitivities to a homogeneous flickering field and to a 1.2 cycle/degree counterphase-flickering grating. Patient DRC values were compared with previously published control data from 21 subjects. Mean PVEP latencies of both the OHT and the OAG patients were greater than normal (P less than 0.001), with the OAG value larger than the OHT value (P less than 0.001). Mean DRCs were lower than normal (P less than 0.002) for both patient groups, with the OAG value lower than the OHT value (P less than 0.025). DRC correlated with PVEP latency for these patients (r = -0.66, P less than 0.001).

Flash and pattern electroretinograms in normal and laser-induced glaucomatous primate eyes.

Experimental glaucoma was produced in one eye of five cynomolgus monkeys with the argon laser delivering 100-200 50-mu spots at 1200-1500 mW power and 0.5 sec to 360 degrees of the mid-trabecular meshwork. Monocular electroretinograms (ERGs) were recorded prior to and 2, 3, and 4 mo following the laser treatment. In the laser-treated (glaucoma) eyes, normal flash ERGs were observed using 1-Hz stimulation; however, pattern ERGs (PERGs) elicited using steady-state counterphase modulation of a 0.51 cpd square wave grating showed statistically significant reductions of amplitude. Only small reductions of PERG amplitude were seen with a 1.25 cpd grating. In three animals, abnormalities of the PERG occurred prior to clinically significant cupping of the optic nervehead. Moreover, reductions of PERG amplitude were progressive and associated with the magnitude of cupping of the optic nervehead and elevation of intraocular pressure. PERG amplitude did not change following acute reductions in intraocular pressure in the glaucoma eyes. Several control experiments were conducted to insure that results were not due to alterations in pupil size, refractive state, or accommodation in the glaucoma eyes. The authors believe they now have a monkey model for the electrophysiologic study of glaucoma.

Electrophysiological and psychophysical testing of vision in glaucoma.

Electrophysiological testing in patients with early glaucoma and in glaucoma suspects reveals defects of central or foveal vision. Most studies suggest that glaucomatous eyes are best separated from normal eyes by use of stimuli with a spatial frequency below the peak of the human contrast sensitivity curve and a relatively high temporal frequency. The stimulus-dependent abnormalities in glaucoma are generally consistent with contrast sensitivity data The stimulus-dependent visual changes are related to the physiology of parallel processing in the primate retinogeniculate pathway.

Responses of complex cells in the visual cortex of the cat as a function of the length of moving slits.

(1) As a step towards specifying the spatial selectivity characteristics of complex cells with spatially periodic substructures, we have studied single cell responses to narrow slits of variable length moved across the receptive field in the preferred direction. In general, the length-response curves were linear over a considerable and sometimes full range until an optimal slit length was reached. (2) In those cells in which the rate of rise of the slit length-response functions decreased before the optimal length was reached, at least 3 factors contribute to the shape of the curve. First, the receptive field shapes of some complex cells are more ovoid or rounded than rectangular, and the summation of responses from excitatory zones of varying optimal lengths itself results in a nonlinear slit length-response function at long slit lengths. Second, central regions may contribute more to cell response than do more lateral regions along the length dimension. Third, a nonlinearity in the slit length-response curve may occur in the upper range of slit lengths as a saturation effect because discharge rates may reach 600/sec, which appears to be close to a limiting firing rate. (3) Some cells believed to be complex during preliminary receptive field testing showed weak inhibitory regions beyond the region of the optimal slit length. Many of these cells also displayed periodic average response histograms to moving slits. The extent and magnitude of the inhibition were variable from cell to cell. In terms of receptive field properties, these cells and 'regular' complex cells seem part of a continuum.

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.

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.

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.

Dopamine D2 receptor blockade alters the primary and cognitive components of visual evoked potentials in the monkey, Macaca fascicularis.

The effects of sulpiride, a dopamine D2 receptor antagonist, were studied on visual event-related potentials in a monkey performing in a visual oddball task in order to investigate receptor specific mechanisms in visuo-cognitive processes. Following the injection of 0.35 mg/kg sulpiride i.m., the amplitude and latency of the primary (P100) and cognitive (P300) components did not change significantly. When 1.05 mg/kg sulpiride was administered, the latency of the primary and cognitive components increased. The amplitude of the P100 component decreased, while that of the P300 component increased. These data suggest that D2 receptors play an important role in visuo-cognitive processes in both physiological and pathological conditions such as Parkinson's disease and schizophrenia.