Primary Visual Impairments In Pd

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Parkinson Diseases Manual By Lianna Marie

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The Role of Dopamine in Retinal Processing

In the last decades pharmacological studies related to the electroretinogram (ERG) in normal human volunteers and in PD patients have suggested a specific role of dopamine (DA) in retinal processing of visual input.21 3793 99 Going beyond the limitations of human studies, extensive neu-ropharmacological and neurotoxicological studies affecting the dopaminergic system in the monkey and lower vertebrates have led to a more detailed understanding of visual impairment in PD. (For a review, see References 17 and 21.) Various types of DA receptors, broadly classified into D1 and D2 subtypes, are located on different neurons of the retina.59 The dual physiologic action of DA on distal D1 and D2 receptors located on neuronal structures has been studied in detail only in the retina of lower vertebrates with larger neurones.36 However, studying the effects of selective DA receptor ligands on massed elec-trophysiological retinal responses (ERG) in the monkey22 has led to an understanding of the final retinal output in primates due to DA-s push-pull role in mediating center-surround interaction for establishing the receptive field structure of ganglion cells.26 Visual electrophysiological and psychophysical abnormalities, originally observed in

PD patients,151662 have also been reported in neuroleptic treated normal volunteers,12 in neuroleptics-induced parkinsonism in humans,53,64 and also in parkinsonian animal models.42-44 Taken together, the results of these studies suggest that dopaminergic deficiency, irrespective of the cause, results in characteristic visual impairment of spatial processing. The deficits are similar in experimental models and in idiopathic PD.

Evidence for Retinal and Cortical Dopaminergic Dysfunction in PD

It was originally reported by Bodis-Wollner and Yahr15 that more than half of the examined PD patients had delayed visual evoked potentials (VEPs) (see Figure 23.1). This finding remained controversial until it became clear that the appropriate visual stimuli, preferentially Gabor filtered stimulus containing only one spatial frequency, should be used. The widely distributed checkerboard pattern, still ideal because of its robustness for a variety of patients, usually fails to reveal abnormalities in PD. (For reviews, see References 21, 25, and 26.) Now it is apparent that the VEP and pattern ERG (PERG) abnormality in PD is most evident for foveal stimuli of medium and high spatial frequencies (SFs) [above 2 cycles/degree (cpd)] where normal observers are most sensitive for the visual stimuli (see Figure 23.2).18,95,100 Consistent with the results of the electrophysiological studies, in PD, contrast sensitivity (CS) is most reduced above 2 cpd.19,21,29,33,34,70,88,95,102 However, reduced CS in PD goes undocumented in the majority of patients, as many vision care specialists are not aware of testing for a potentially profound CS deficit in a patient with near normal VA.

Contrast sensitivity loss in PD becomes more profound when the stimulus grating is temporally modulated at 4 to 8 Hz,206888 suggesting that a dopaminergic deficiency state also affects distal temporal processing.67 It has been shown, however, that increasing stimulus strength can normalize some select temporal deficits seen in PD patients.8 In summary, the spatial and temporal selectivity of visual losses detected with CS in PD is consistent with the results of electrophysiological tests (PERG and VEP). The interpretation of visual deficits in PD suggests that the disease process causes progressive, select pathology of dopaminergic neuronal processing in the human retina, leading to loss of spatio-temporal tuning and distorted retinal input to higher visual centers. An essential proof of visual system involvement in PD and the relationship of visual and motor changes was recently provided by a longitudinal study of visual dysfunction in PD patients: CS impairs in parallel with the worsening of motor score.34 These results therefore suggest that the visual system shares with the motor system progressive degeneration of dopaminergic neurons and/or progressive failure of the effect of L-dopa therapy.

FIGURE 23.1 Scatter plot showing the latency of the major positive VEP deflection in 35 patients with PD (triangles) and 26 control subjects (dots). Numerals indicate the number of measurements falling on the same locus. Values for the left and right eye are shown on the ordinate and abscissa, respectively. An ellipse has been drawn within which 95% of the normal population would be expected to fall, based on the statistics of the control group (dark dots). Over two-thirds of the PD patients are outside the ellipse. (Source: Bodis-Wollner and Yahr,15 with permission of Brain.)

FIGURE 23.1 Scatter plot showing the latency of the major positive VEP deflection in 35 patients with PD (triangles) and 26 control subjects (dots). Numerals indicate the number of measurements falling on the same locus. Values for the left and right eye are shown on the ordinate and abscissa, respectively. An ellipse has been drawn within which 95% of the normal population would be expected to fall, based on the statistics of the control group (dark dots). Over two-thirds of the PD patients are outside the ellipse. (Source: Bodis-Wollner and Yahr,15 with permission of Brain.)

The delay of the P100 component is observed in both de novo and also in treated PD patients using stimuli at middle (2 to 6 cpd) spatial frequencies.49,75,80 It was reported that treated patients can exhibit longer delays.75 This apparently paradoxical result is likely due to the more advanced disease in treated patients, which per se results in worse retinal visual responses.34,100 While both ERG and VEP can improve with therapy, there is an apparent difference: levodopa therapy improves PERG abnormalities to a higher degree than it does VEP deficits.80 One possible interpretation is that VEP changes in PD are secondary to retinal pathology and, at the cortical level, represent chronic and not exclusively dopaminergic alterations in visual processing. However, there is evidence of visual cortical dopaminergic innervation, even in the absence of retinal visual input.86

The question emerges: Is the visual dysfunction really an integral part of PD? It has been observed that the deficit fluctuates with motor symptoms in "on-off' patients19 and worsens with the progression of motor symptoms.34 While the role of DA deficiency is strongly implied by the above-mentioned studies, DA deficiency may not be exclusively responsible for visual changes in PD. For example, a higher onset/offset VEP amplitude ratio was found in PD patients compared to controls using sinusoidal grating as visual stimuli in on-off mode.10 It is known that onset versus offset retinal responses may be separated using selective glutamate receptor blockers.91 The relevance of dopaminergic deficiency or other neurotransmit-ter alteration, such as the involvement of selective glutamate receptor subtypes in the retina and beyond, in generating the "supernormal" offset VEP in PD is not yet

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Spatial Frequency (c/d) Spatial Frequency (c/d)

FIGURE 23.2 (a) The PERG tuning function in PD: PERG spatial transfer function obtained in patients (squares) and age-matched subjects (diamonds). The functions are parallel at lower SF and very close at the higher SF tested (6.9 cpd). Note lack of tuning of the PERG transfer function in PD. (Source: Tagliati et al.100 with permission of Clinical Neurophysiology.) (b) Effects of L-dopa therapy on PERG amplitude. PERG amplitude obtained in age-matched subjects (triangles), PD patients receiving (squares) and not receiving (diamonds) L-dopa are plotted as a function of SF. PD patients receiving L-dopa show higher values and better tuning compared to untreated patients, although they rarely achieve normal values. The dashed line represents the mean noise level during recordings. Error bars indicate SE. (Source: Tagliati et al.100 with permission of Clinical Neurophysiology.)

established. Although the findings appear robust and intriguing, no other studies have yet compared onset with offset responses on PD.

Are Visual Deficits in PD Solely Determined by Retinal Dopaminergic Dysfunction?

PERG changes in PD are definitely caused by retinal dopaminergic deficiency.2557 However, a retinal abnormality may passively cause visual deficits in subsequent processing, or other anatomical areas may also, independently of the retina may be affected in PD. The LGN1 and the visual cortex also have dopaminergic innervation.79,82,86,87 Asymmetrically lateralized primary visual cortex glucose hypometabolism has been demonstrated in PD with the most severe abnormalities contralateral to the most severe motoric dysfunction.28 Although more confirmatory evidence is needed, it is possible that occipital hypometabo-lism indirectly reflects basal ganglia dysfunction or intrinsic cortical pathology.

Pattern orientation dependent CS losses have been reported in PD88 more severe for horizontal than for vertical patterns29 (see Figure 23.3). This finding cannot be due to retinal dopaminergic deficiency; rather, the deficit suggests the presence of intrinsic cortical pathology. However, contrast adaptation, which has a cortical origin, is spared in PD.103

Visuocognitive Processing in PD

A correlation between cortical DA innervation and expression of cognitive capacities has been claimed (Nieoullon, 2002).74 Impaired cognitive processing in PD is not surprising, due to the connections and loops110 between the basal ganglia and various sensory cortical areas. However, DA is apparently involved in a more specific manner than just "gating" bottom up visual information flow. Several aspects of consciously controlled information processing, such as planning, problems solving, decision making, and response selection, are associated with the functions of fronto-striatal circuits.41,46,50,65,76,77 A dopaminergic dysreg-

FIGURE 23.3 Effect of orientation on visual contrast sensitivity. Ordinates plot CS for flicker perception (filled dots) and for pattern perception (open dots) versus grating orientation (abscissa). Vertical is = deg. and 180 deg. on the abscissa, and horizontal is 90 deg. The vertical bars show the upper normal limits for orientational tuning, and the horizontal arrows show lower normal limits for absolute sensitivities (99% limits). The grating had a spatial frequency of 2 cpd and a temporal frequency of 8 Hz. A = left eye, B = right eye. (Source: Regan and Maxner,88 with permission of Brain.)

FIGURE 23.3 Effect of orientation on visual contrast sensitivity. Ordinates plot CS for flicker perception (filled dots) and for pattern perception (open dots) versus grating orientation (abscissa). Vertical is = deg. and 180 deg. on the abscissa, and horizontal is 90 deg. The vertical bars show the upper normal limits for orientational tuning, and the horizontal arrows show lower normal limits for absolute sensitivities (99% limits). The grating had a spatial frequency of 2 cpd and a temporal frequency of 8 Hz. A = left eye, B = right eye. (Source: Regan and Maxner,88 with permission of Brain.)

ulation of this subcortico-cortical system in PD leads to higher-level cognitive dysfunctions.31'41'69'77,78 Recent electrophysiological, neurophysiological, and functional imaging studies attempt to link cognitive symptoms and specific neuronal circuits of the basal ganglia and its connections.

ELECTROPHYSIOLOGY: THE RELATIONSHIP OF PRIMARY VEP-S AND THE CONCURRENTLY OBTAINED P300

Identifiable positive and negative deflections of event-related potentials (ERPs) provide indices for the timing in information processing including stimulus evaluation, response selection, and context updating.63 ERPs are recorded in response to an external stimulus or event to which the subject is consciously paying attention. They are often elicited when the subject distinguishes one stimulus (target) from other stimuli (nontargets). The most extensively studied ERP component is the P300, appearing 300 to 400 ms after the onset of the target stimulus.96 P300 amplitude is maximal at the midline electroenceph-alographic (EEG) electrodes (Cz and Pz) and is inversely related to the probability of the eliciting event.

Many visual ERP studies yielded a delayed P300 only in demented PD patients,48,94,98,106,109 although other studies reported a delayed P300 in nondemented PD patients.7,23,24,89,97 This suggests that the slowness of visual information processing may be independent or that it precedes global dementia.

Latency

Comparing the P100 and P300 of the concurrently obtained visual ERP resulted in a somewhat surprising finding in two independent and ethnically different groups of PD patients. A prolongation of the normalized P300 latency (P300-P100 latency difference, called central processing time) differentiated younger PD patients from controls.7,89 These data suggest that younger PD patients could be differentiated from other types of PD using a concurrent VEP and visual P300 recording. Amantidine also shortened the latency of the visual P300 in PD with little or no effect on the primary VEP component.11

Amplitude

Few studies have examined P300 amplitude in PD. In general, P300 amplitude increases when more attention is allocated, as in the case of unexpected or in complex tasks. However, it is conceivable that the interpretation of raw amplitude can be misleading, since a nonspecific, age-related, low-voltage EEG recording could cause low P300 amplitude.7 Measuring the P300/P100 amplitude ratio therefore gives a more reliable measure on the nature of amplitude alterations.7 This individually normalized P300 amplitude provided a significant distinction of younger nondemented PD patients from older patients and from age matched control subjects.7,89

N200 of the Visual ERP in PD

Apparently, P100 and P300 are independently affected in PD. To localize the stage of visual processing at which this independence becomes established, earlier cognitive ERP components such as N200 were analyzed and showed that this component is also independently changing from P300.7 The visual N200 probably represents a visual form of the auditory mismatch negativity.101 This component is more negative for the infrequent stimuli and distributed over the extrastriate visual areas and the posterior-temporal cortex. N200 latency was delayed in nondemented PD patients, even when P300 was not prolonged using a simple visual paradigm.7 In a semantic discrimination task, a similar result was found.97 These data further suggest that visual deficits and processes indexed by the P300 may reflect processing that is either parallel to or well beyond the interface of bottom-up and top-down visual inputs.32,60

The Pharmacology of P300: Does the P300 Abnormality Represent only Dopaminergic Dysfunction?

A study in MPTP-treated monkeys suggests that levodopa therapy alone does not affect the visual P300,44 however D2 receptor blockade can influence the visual P300 in monkeys (see Figure 23.4).6 Cellular electrophysiological evidence shows however that D1 receptors are involved in visual working memory in the prefrontal area (for a review, Reference 47), which was also identified as one of the generators of P300.51 It is therefore conceivable that the synergistic action of D1 and D2 receptors is necessary to improve the visual P300.

Levodopa treatment shortens the latency of P300 in PD.92,94 However, some investigators have described a prolonged P300 latency in medicated patients.52,85 One

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