Saccadic Eye Movements in Young-Onset Parkinson’s Disease - A BOLD fMRI Study

ABSTRACT

The objective of the present study was to understand control of saccadic eye movements in patients with young onset Parkinson’s disease (YOPD) where onset of disease symptoms appears early in life (<40 years of age). Functional magnetic resonance imaging (fMRI) was performed in patients with YOPD and control subjects while they performed saccadic tasks, which consisted of a reflexive task and another task that required inhibitory control of eye movements (Go-NoGo task). Functional imaging related to saccadic eye movements in this group of patients has not been widely reported. A 1.5T MR scanner was used for structural and functional imaging. Analysis of blood-oxygen-level-dependent (BOLD) fMRI was performed using Statistical Parametric Mapping (SPM) software and compared in patients and controls. In patients with YOPD greater activation was seen significantly in the middle frontal gyrus, medial frontal gyrus, angular gyrus, cingulate gyrus, precuneus and cerebellum, when compared with the control group, during the saccadic tasks. Gap and overlap protocols revealed differential activation patterns. The abnormal activation during reflexive saccades was observed in the overlap condition, while during Go-NoGo saccades in the gap condition. The results suggest that impaired circuitry in patients with YOPD results in recruitment of more cortical areas. This increased frontal and parietal cortical activity possibly reflects compensatory mechanisms for impaired cognitive and saccadic circuitry.

Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative disorder associated with motor and/or non-motor symptoms. Young onset PD (YOPD) is less prevalent than late onset PD.^1–5 Age of onset for YOPD is below 40 years of age unlike late onset PD where age of onset is around 60 years.⁶ Although the disease course in YOPD is long with slow progression, the disease symptoms and pathology are similar in YOPD and PD and are mainly associated with tremors and movement impairments like gait abnormalities and postural instability.⁷

Saccadic eye movements have also been found to be affected in PD.^8–10 The saccadic system is a very useful system to understand motor and cognitive changes in movement disorder patients. Brain imaging studies have shown similar neural circuit being involved with tasks associated with attentional and saccadic shift, indicating an overlap between the saccadic and cognitive circuitry.

Functional neuroimaging has proved useful in exploring the saccadic circuitry and its intersection with cognitive circuitry.¹¹ Furthermore, imaging studies have reported that saccadic tasks which involve inhibition of saccades versus simple visually guided saccades show different activation patterns. Greater blood-oxygen-level-dependent (BOLD) activity in the Frontal eye field (FEF) is attributed to saccadic initiation and reaction time.¹² The supplementary eye field (SEF), a part of the medial frontal cortex is linked to saccadic tasks, which require performance monitoring.¹³ The frontal eye fields have been found to be activated more during response selection and saccadic goals.¹⁴ The frontal eye field is functionally distinct within itself where the lateral and medial FEF are involved in reflexive and volitional saccades respectively. The parietal eye field (PEF) and superior colliculus (SC) are also closely associated with reflexive saccades.¹² The dorsolateral prefrontal cortex (DLPFC) is involved in the decision- making process by inhibiting undesirable reflexive saccades and therefore provides top down control of saccades.¹⁵ Error monitoring and saccadic inhibition are associated with anterior cingulate (ACC) activity as seen in antisaccades.¹²

The aim of this study was to further our understanding regarding the neural correlates of saccadic control in patients with YOPD. Saccade related brain changes have not been well established in this rare group of patients. This study investigated brain changes associated with motor and inhibitory control in patients with YOPD while performing saccadic eye movements.

Materials and methods

Participants

After ethical approval from our institute’s ethical committee, YOPD patients (n = 14) were recruited from the movement disorder clinic of the neurology department of our institute (AIIMS, New Delhi, India) and control subjects (n = 13) were recruited from among the institute population. Controls were age and gender matched to patients.

Patients were tested during the “On” medication condition. All participants gave informed written consent to participate in the study. The patient group consisted of males with YOPD with mild to moderate PD (Hoehn and Yahr stages: 1–3) and PD symptom onset was below 40 years of age. YOPD is more common in males.^16–18 We wanted a homogenous group and since male patients were much more frequent clinic attenders as compared with females, we decided to recruit only males. Patients with YOPD had a mean disease duration of 6 ± 3 years. All participants had a best-corrected visual acuity >6/12 in their better seeing eye. Patients with YOPD were diagnosed by a board certified neurologist who specialised in movement disorder in the Neurology department, AIIMS. Detailed inclusion and exclusion criteria are given below:

Inclusion criteria were:

a) Patients with YOPD diagnosed on the basis of standard diagnostic criteria (UKPDBB)

b) Patients with YOPD with age of onset <40 years

Exclusion criteria were:

a) Patients with co-morbid neurological illness i.e. stroke, dementia etc.

b) Patients with known history of coexisting mental illness

c) Patients with visual impairment

Saccadic eye movement tasks

All participants performed reflexive and Go-NoGo saccadic paradigms (Figure 1a,b). Both tasks were designed to elicit horizontal saccades to the left or to the right of the central fixation point. A 17-degree visual angle was made between the fixation point in the centre and the peripheral target/stimulus which were presented either to the left or right of the fixation point. Training trials were given to the participants outside of the scanner to familiarise them with the tasks and testing was done when they were comfortable with the tasks. Participants were instructed tto press a button when the target appeared. In order to understand effects of early fixational disengagement on the BOLD activity in saccadic tasks, a gap condition and overlap conditions were introduced in the reflexive as well as the Go-NoGo saccadic paradigms.

Figure 1.

A. Schematic representation of stimulus presentation in the reflexive saccadic task. Participants executed saccades in response to the onset of a peripheral target, 200–300ms after the disappearance of the fixation point (Gap) and also when the fixation point was visible throughout target presentation (Overlap). B. Schematic representation of stimulus presentation in the Go-NoGo saccadic task. Participants executed saccades in response to the onset of a peripheral target when the colour of the target matched the colour of the stimulus presented at an eccentric position above the fixation point. Participants executed saccades in response to the onset of a peripheral target, 200–300ms after the disappearance of the fixation point (Gap) and also when the fixation point was visible throughout target presentation (Overlap).

Reflexive saccadic task

In the reflexive saccade task, participants were instructed to make horizontal saccades at the onset of the peripheral target to the left or to the right of the central fixation point (Figure 1a). They were instructed to fixate on the green plus (+) sign at the centre of the computer screen and to move their eyes as quickly as they could towards the red circles in the periphery when they appeared. Participants were instructed to move their eyes accurately towards the red circles.

Gap reflexive saccade task

In this task, the target appeared at a variable interval of 200–300 ms after central fixation point disappearance (Figure 1a).

Overlap reflexive saccade task

This task was similar to the Gap task except that the central fixation point remained continuously visible during target presentation (Figure 1a).

Go-NoGo saccadic task

Participants were instructed to make saccades to the peripheral target when the colour of the peripheral target matched the red circle, which was at an eccentric position above the central fixation point, i.e. when the colour of the peripheral target was red. Participants were supposed to inhibit saccades when the colour of target did not match the red circle at the eccentric position. In this task, the peripheral stimulus was either a red or a yellow circle either to left or right of the central fixation point (Figure 1b). Participants were instructed to ignore the red circle above the central green plus (+) sign in the centre of the computer screen and only move their eyes as quickly as possible towards the coloured circle in the periphery as it appeared.

Gap Go-NoGo saccade task

In this task, the target appeared at a variable interval of 200–300 ms after central fixation point disappearance (Figure 1b).

Overlap Go-NoGo saccade task

This task was similar to the Gap Go-NoGo saccade task. The only difference in the Overlap Go-NoGo saccade task was that the central fixation point remained continuously visible during target presentation (Figure 1b).

Task design and data acquisition

The task design involved a block design having alternating cycles of task of 20s (Reflexive saccadic tasks with Gap and Overlap conditions) and a baseline (20s, blank screen) and alternating cycles of task (Go-NoGo saccadic tasks with Gap and Overlap conditions). A baseline (blank screen) as a control condition was also used (Figure 2).

Figure 2.

Schematic representation of the stimulation protocol (block Design) depicting active and rest (baseline) periods.

The functional magnetic resonance imaging (fMRI) tasks were designed using the Superlab software (ver 4.0, Cedrus Corporation, CA, USA). These were projected to the subjects with MR compatible binocular LCD goggles with an eye tracker (Nordic Neuro Lab, Norway) mounted on an eight channel head coil of a 1.5 T MR scanner (Magnetom Avanto, M/s Siemens Healthineers, Germany). Arrington software (Arrington Viewpoint eye tracker, Arrington Research Inc., AZ, USA) was used to monitor real time location of the pupil to assure participants’ task performance. Whole brain T1 weighted anatomical (three dimensional [3D] T1 MPRage, 176 slices, 1 mm thickness) images were acquired. T2* weighted functional (BOLD) images were acquired using a gradient echo based- echo planar imaging (GE-EPI) sequence with 31 contiguous slices of thickness 5 mm, echo train length acquisition matrix of 64 × 64, TR = 2 s, TE = 24 ms, flip angle of 90° and 180 dynamics.

Image analysis

Pre, post-processing and statistical analyses of the BOLD data were performed using statistical parametric mapping¹⁹ software (SPM8, Wellcome Department of Cognitive Neurology, London, UK) implemented in MATLAB 7.10 (The Mathworks, Natick, USA). Functional MR images were transformed into a standard space, using transformation parameters determined from the anatomical image through an automatic non-linear stereotaxic normalisation procedure. The template image was based on average data provided by the Montreal Neurological Institute (MNI) template and conformed to a standard coordinate referencing system. Functional images were then spatially smoothed using an isotropic Gaussian kernel (6 mm full-width at half maximum). A design matrix was created with onset time, duration of trials and baseline blocks incorporated into it. Block-related changes in brain activity were estimated by general linear model. Active regions for each cognitive process were obtained by applying specific contrast. Individual contrast results of participants were then grouped together, and the significance in-group analysis was assessed through one-way analysis of variance (ANOVA).

VBM analysis

Voxel based morphometry was carried out on the 3D T1-weighted images using the CAT12 toolbox of SPM12, using the standard pipeline. The segmented grey matter images were compared between patient and control groups using a two sample t-test, with p < 0.05, FDR correction for whole brain. A Desikan-Killiany atlas or DK40 template was used.

Statistical analysis

The data were analysed statistically for significance (p ≤ 0.001). Paired t-tests were used to compare Overlap and Gap conditions. Group analysis for comparing the patient and control groups was performed using one-way ANOVA.

Results

Compared with control subjects, patients with YOPD had significantly greater activation (BOLD activity) in the reflexive saccadic task (Overlap condition). Similarly, in the Go-NoGo saccadic task (Gap condition), patients had significantly greater activation when compared with controls. Patients showed significantly greater activation than controls in the Reflexive saccadic task (Overlap condition) mainly in the middle frontal gyrus, medial frontal gyrus, angular gyrus, cingulate gyrus and precuneus (Figures 3, 4, Table 1).

Figure 3.

Maximum intensity projection (MIP) of patients with YOPD with respect to controls in (a). the reflexive saccadic task (Overlap condition) and (b). the Go-NoGo saccadic task (Gap condition).

Figure 4.

BOLD activation rendered images of patients with YOPD with respect to controls in (a). the reflexive saccadic task (Overlap condition) and (b). the Go-NoGo saccadic task (Gap condition).

Table 1.

BOLD brain activation in the reflexive saccadic task (Overlap condition) from the group analysis (one way ANOVA) of patients with YOPD with respect to controls (p < 0.001).

Equivk	T	EquivZ	x,y,z {mm}	Hemisphere	Area activated	Broadmann area
131	4.85	4.37	4 −80 −14	Right Cerebellum	Declive of Vermis
122	3.77	3.52	−4 −80 −18	Left Cerebellum	Declive
252	4.84	4.36	6 −60 62	Right Cerebrum	Precuneus	Brodmann area 7
64	4.38	4.01	46 −72 −22	Right Cerebellum	Declive
44	4.05	3.75	2 −32 18	Left Cerebrum	Posterior Cingulate	Brodmann area 23
11	3.87	3.60	−38 −82 −28	Left Cerebellum	Tuber
31	3.81	3.55	4 −8 20	Right Cerebrum	Thalamus
48	3.32	3.14	−4 −10 16	Left Cerebrum	Thalamus
16	3.80	3.55	4 −16 54	Right Cerebrum	Medial Frontal Gyrus	Brodmann area 6
28	3.77	3.52	38 −56 44	Right Cerebrum	Angular Gyrus	Brodmann area 39
23	3.37	3.19	12 0 44	Right Cerebrum	Cingulate Gyrus	Brodmann area 24
13	3.57	3.35	34 6 44	Right Cerebrum	Middle Frontal Gyrus	Brodmann area 6

Similarly, in the Go-NoGo saccadic task (Gap condition), which required subjects to inhibit saccades, patients with YOPD had significantly greater activation in the anterior cingulate, middle frontal gyrus and medial frontal gyrus, when compared with the control group (Figures 3, 4, Table 2). The cerebellum and thalamus were activated in patients with YOPD in the reflexive saccadic task (Overlap condition) when compared with controls (Table 1).

Table 2.

BOLD brain activation in the Go-NoGo saccadic task (Gap condition) from the group analysis (one way ANOVA) of patients with YOPD with respect to controls (p < .001).

Equivk	T	EquivZ	x,y,z {mm}	Hemisphere	Area activated	Brodmann area
22	3.69	3.45	−22 52 4	Left Cerebrum	Medial Frontal Gyrus	Brodmann area 10
29	3.80	3.54	−14 36 10	Left Cerebrum	Anterior Cingulate	Brodmann area 32
10	3.58	3.36	−16 30 32	Left Cerebrum	Cingulate Gyrus	Brodmann area 32
22	3.69	3.45	14 28 30	Right Cerebrum	Cingulate Gyrus	Brodmann area 32
10	3.64	3.42	−4 −2 58	Left Cerebrum	Medial Frontal Gyrus	Brodmann area 6
13	3.56	3.34	−12 48 24	Left Cerebrum	Medial Frontal Gyrus	Brodmann area 9
49	3.64	3.41	−26 38 26	Left Cerebrum	Middle Frontal Gyrus	Brodmann area 9
7	3.39	3.20	40 36 26	Right Cerebrum	Middle Frontal Gyrus	Brodmann area 9

No significant changes (p < 0.001) in BOLD activity were found in patients in the Gap condition of the reflexive saccadic task and the Overlap condition of the Go-NoGo saccadic task.

Grey matter volume changes were compared between patients and controls. Patients showed grey matter atrophy in many frontal cortical areas (especially in the inferior and middle frontalgyri). Atrophy was also observed in the superior temporal gyrus, precuneus, inferior parietal lobule, cingulate gyrus, claustrum and insula in patients with respect to controls (Table 3, Figure 5).

Table 3.

Brain areas showing significant difference in grey matter among patients and controls.

Cluster	Peak	Peak	Peak
Equivk	T	EquivZ	p(unc)	x,y,z {mm}	x,y,z {mm}	x,y,z {mm}	Level 1	Level 2	Level 3	Level 5	Range (mm)
478	6.30	4.80	8.11E-07	31.5	31.5	−4.5	Right Cerebrum	Sub-lobar	Insula	Brodmann area 13	4
648	5.72	4.50	3.36E-06	−54	−9	−15	Left Cerebrum	Temporal Lobe	Superior Temporal Gyrus	Brodmann area 21	3
1868	5.54	4.40	5.3E-06	−31.5	28.5	4.5	Left Cerebrum	Sub-lobar	Insula, Claustrum	Brodmann area 13	2
979	4.10	3.53	0.000206	39	0	−28.5	Right Cerebrum	Temporal Lobe	Superior Temporal Gyrus	Brodmann area 38	3
218	5.21	4.22	1.22E-05	−37.5	1.5	−31.5	Left Cerebrum	Temporal Lobe	Superior Temporal Gyrus	Brodmann area 38	3
435	4.93	4.06	2.48E-05	67.5	−51	40.5	Right Cerebrum	Parietal Lobe	Supramarginal Gyrus	Brodmann area 40	0
1371	4.39	3.72	9.91E-05	−52.5	−19.5	12	Left Cerebrum	Temporal Lobe	Transverse Temporal Gyrus	Brodmann area 41	1
907	4.85	4.01	3.07E-05	60	−31.5	−25.5	Right Cerebrum	Temporal Lobe	Inferior, Middle Temporal Gyrus	Brodmann area 20, 21	1
63	4.72	3.93	4.25E-05	57	43.5	−6	Right Cerebrum	Frontal Lobe	Inferior Frontal Gyrus	Brodmann area 46	0
496	4.17	3.58	0.000169	24	−63	31.5	Right Cerebrum	Parietal Lobe	Precuneus	Brodmann area 7	3
311	4.36	3.70	0.000106	36	39	18	Right Cerebrum	Frontal Lobe	Middle Frontal Gyrus	Brodmann area 9	2
294	4.58	3.85	5.99E-05	−24	−30	−16.5	Left Cerebrum	Limbic Lobe	Parahippocampal Gyrus	Brodmann area 35, 36	0
17	4.55	3.83	6.53E-05	45	−25.5	−40.5	Right Cerebrum	Temporal Lobe	Inferior Temporal Gyrus	Brodmann area 20	3
49	4.54	3.82	6.77E-05	6	22.5	1.5	Right Cerebrum	Sub-lobar	Caudate	Caudate Head	2
83	4.42	3.74	9.07E-05	10.5	18	15	Right Cerebrum	Sub-lobar	Caudate	Caudate Body	2
325	3.86	3.37	0.000375	−1.5	31.5	−9	Left Cerebrum	Limbic Lobe	Anterior Cingulate	Brodmann area 24	1
79	4.36	3.70	0.000107	25.5	−12	−12	Right Cerebrum	Sub-lobar	Lentiform Nucleus	Lateral Globus Pallidus	1
146	4.33	3.69	0.000114	18	34.5	36	Right Cerebrum	Frontal Lobe	Sub-Gyral	Brodmann area 8	0
25	4.27	3.64	0.000134	55.5	−34.5	63	Right Cerebrum	Parietal Lobe	Inferior Parietal Lobule	Brodmann area 40	1
110	4.22	3.61	0.00015	−55.5	−27	49.5	Left Cerebrum	Parietal Lobe	Inferior Parietal Lobule	Brodmann area 40	0
17	4.20	3.60	0.000158	37.5	31.5	7.5	Right Cerebrum	Sub-lobar	Insula	Brodmann area 13	3
46	4.07	3.51	0.00022	24	−22.5	−16.5	Right Cerebrum	Limbic Lobe	Parahippocampal Gyrus	Brodmann area 35, 28	1
120	4.05	3.50	0.000232	−51	−37.5	33	Left Cerebrum	Parietal Lobe	Inferior Parietal Lobule	Brodmann area 40	4
117	4.04	3.50	0.000236	6	−55.5	21	Right Cerebrum	Limbic Lobe	Posterior Cingulate	Brodmann area 23	0
28	4.01	3.47	0.000258	−21	13.5	55.5	Left Cerebrum	Frontal Lobe	Sub-Gyral	Brodmann area 6	0
41	4.01	3.47	0.000258	−13.5	−66	−7.5	Left Cerebellum	Anterior Lobe	Culmen	*	0
30	3.98	3.45	0.000275	−37.5	−58.5	28.5	Left Cerebrum	Temporal Lobe	Middle Temporal Gyrus	Brodmann area 39	2
219	3.70	3.26	0.000553	30	10.5	1.5	Right Cerebrum	Sub-lobar	Lentiform Nucleus, Caudate	Putamen, Caudate Body	0
62	3.82	3.35	0.000411	16.5	1.5	−15	Right Cerebrum	Sub-lobar	Lentiform Nucleus	Medial Globus Pallidus	2
16	3.82	3.34	0.000413	−15	48	24	Left Cerebrum	Frontal Lobe	Superior Frontal Gyrus	Brodmann area 9	2
14	3.81	3.34	0.00042	−22.5	19.5	−15	Left Cerebrum	Sub-lobar	Lentiform Nucleus	Putamen	1
13	3.79	3.32	0.000449	27	−69	52.5	Right Cerebrum	Parietal Lobe	Superior Parietal Lobule	Brodmann area 7	1
10	3.78	3.32	0.000458	0	54	43.5	Left Cerebrum	Frontal Lobe	Superior Frontal Gyrus	Brodmann area 8	1
51	3.72	3.27	0.000534	−7.5	−7.5	42	Left Cerebrum	Limbic Lobe	Cingulate Gyrus	Brodmann area 24	0
55	3.69	3.25	0.000577	−9	46.5	39	Left Cerebrum	Frontal Lobe	Superior Frontal Gyrus	Brodmann area 8	1
33	3.66	3.23	0.000615	48	−9	19.5	Right Cerebrum	Sub-lobar	Insula	Brodmann area 13	4
16	3.64	3.22	0.000651	31.5	21	−36	Right Cerebrum	Frontal Lobe	Inferior Frontal Gyrus	Brodmann area 47	3
23	3.62	3.20	0.000677	63	−24	−7.5	Right Cerebrum	Temporal Lobe	Middle Temporal Gyrus	Brodmann area 21	0
15	3.61	3.19	0.000701	−63	−42	3	Left Cerebrum	Temporal Lobe	Middle Temporal Gyrus	Brodmann area 21	0

Figure 5.

Brain areas showing significant difference in grey matter among patients and controls.

Discussion

Response to sensory stimuli can be reflexive or goal-directed. Goal directed responses may involve suppression of compelling but incorrect responses with initiation of responses towards a goal. Reflexive saccades involve initiation of saccades towards a peripheral stimulus. Go-NoGo-related saccades involve suppression of unwanted saccades and initiation of saccades towards the goal. There is a key role for the frontal and parietal cortices in the control of saccades that are reflexive as well as those that require inhibitory control.¹²

Greater cortical activity in YOPD

In PD, due to basal ganglia dysfunction, saccadic circuitry has been reported to be affected.^20–23 In the present study, fMRI was used to investigate the underlying neural mechanisms of saccadic eye movements in YOPD patients during simple reflexive saccades and Go-NoGo saccades. The results suggest significantly greater cortical activity in the patients with YOPD compared with controls. This greater activation may be ascribed to the possible compensatory mechanism for attentional and executive dysfunction caused by PD. Delving into the individual cortical areas activated, and their significance, the following points merit consideration.

Patients exhibited more activation in the angular gyrus when compared with controls in the reflexive overlap task, which may be attributed to exogenous saccadic orienting, spatial cognition and attention.^24–26 Similarly, the precuneus has more activation in patients. Since the precuneus is related to the processing of spatial attention,^27–29 it reflects impaired attention in patients and top down control of reflexive saccades.

SEF (Brodmann area 6), which is a part of supplementarymotor area (SMA), has more activation in patients during the Go-NoGo saccadic task in the Gap condition. The SEF plays a key role in implementing control when there is conflict between several, ongoing competing saccadic responses.³⁰ There is an impairment of such control in YOPD patients and thus compensatory changes can be seen, which are reflected by higher activation of the SEF.

Patients with YOPD showed significantly greater activation in the middle frontal gyrus (part of DLPFC) when compared with controls. This part of the frontal cortex is involved in the preparation of saccadic eye movements and in the directional decision to be made for the forthcoming saccade.^31–33 Greater activation in the middle frontal gyrus suggests that patients are impaired in the saccadic decision-making process. Similarly, the medial frontal gyrus (or FEF) showed significantly greater activation in patients with PD when compared with controls.

The anterior cingulate cortex (ACC) showed greater activation in patients. The ACC is involved in executive functions which monitor performance.^34,35 The ACC is considered to be involved in intentional saccadic control where it prepares frontal motor areas for the future motor response and is not involved in the control of reflexive saccades.^36–38 It suggests that the ACC plays a major role in the Go-NoGo saccadic task where it acts in the early preparatory phase for the future saccade. Greater activation of the ACC in patients suggests more activity is required to compensate for the impaired neural circuitry.

To summarise, our findings illustrate significantly greater activations in the ACC and middle frontal gyrus in patients with YOPD in the task that involved inhibitory control of saccades (Go-NoGo task). This is suggestive of impaired inhibitory control in YOPD patients. The reflexive saccadic task showed greater activation in the angular gyrus and precuneus in patients reflecting impaired saccadic orienting.

Differential activation seen with gap and overlap conditions

The gap task involved removal of the central fixation point 200 ms before the appearance of the peripheral target. Saccadic reaction was reduced in this case compared with when the central fixation point was present with the peripheral target. This effect is called the Gap effect, and it has been considered to be related to attention disengagement³⁹ and oculomotor readiness.⁴⁰ Studies have shown that the FEF is involved in fixation disengagement,⁴¹ so we chose to perform saccadic tasks under Gap and Overlap conditions with the idea that the Gap condition would show greater BOLD modulation in frontal areas in YOPD considering attentional disengagement in the Gap condition. We, unexpectedly, got greater activations in the reflexive saccadic task in the Overlap condition in YOPD and not in the Gap condition. Go-NoGo tasks showed greater activations in the Gap condition when compared with the Overlap condition, as expected. It may be possible that BOLD modulations due to the Gap condition (Gap effect) when compared with the Overlap condition is more evident when a more complicated task is performed. The Go-NoGo task requires inhibition of saccades at a certain level unlike in the reflexive saccadic task. This differential activation pattern in Gap and Overlap conditions in patients with YOPD when compared with controls could be due to impaired motor preparedness or impaired attentional disengagement. Future experiments could focus on correlating saccadic reaction times in Gap and Overlap conditions with the activation pattern in patients with YOPD.

Reflexive saccades elicit hyperactivity not hypoactivity in YOPD

Few studies^42,43 in PD patients have shown hypoactivation in frontal and parietal areas during voluntary tasks like antisaccades. Tasks performed in the current study (simple reflexive and Go-NoGo tasks) do not truly reflect voluntary saccades, making it difficult to cross compare our results with these studies.

Specific areas show grey matter atrophy in YOPD

Saccadic eye movement changes in PD have been associated with decreased GM volume.^44,45 In the current study VBM analysis was performed to highlight GM atrophy areas in YOPD patients. GM atrophy was found in various brain areas mainly in frontal areas such as the inferior and middle frontal gyrus, parietal areas such as the inferior parietal lobule and temporal areas such as the superior temporal gyrus. All these areas are known to be involved in saccadic eye movements. Our results suggest that YOPD is associated with grey matter atrophy in the cortical and parietal areas. The BOLD activation changes in YOPD during saccadic tasks might be associated with these grey matter changes.

Limitations and future directions

The YOPD patients recruited in the current study were on a levodopa equivalent daily dose. fMRI was performed in the “on” state only. Thus, the influence of dopaminergic medication on the parameters cannot be commented upon. The current study was a block design and lacked robustness compared with an event related design. Analysis in terms of haemodynamic response to different trials was not possible with such a design. The current study did not characterise the clinical behaviour of saccades like direction errors, anticipatory errors, or saccade reaction time. In the absence of these data, it is difficult to dogmatically conclude the pathophysiology associated with the increased activation seen in certain cortical areas. If saccade behaviour (patient’s performance on the given task) was optimum in the patient group, then abnormal increases in activation may be interpreted as compensatory mechanisms. However, if saccadic performance was not optimum, it could even suggest an overdosing effect of medication, failed compensation, or aberrant activation associated with worse performance.

Future studies that comprehensively assess the clinical and imaging data and their correlation could shed better light on the pathophysiology of saccadic and cognitive abnormalities in YOPD patients.

We did not perform any detailed cognitive testing to assess any cognitive decline in the patients. YOPD patients were recruited based on clinical features and genetic testing was not carried out for the diagnosis.

Conclusion

Results of the reflexive and Go-Go-NoGo saccades in this study suggest impairment of fronto-parietal circuitry in patients with YOPD. This circuitry is thought to be related to the planning of saccadic eye movements that involves attentional control. Significantly greater activations in the ACC, middle frontal gyrus, angular gyrus and precuneus in patients reflect compensatory activity for the impaired frontal-parietal circuitry. If similar BOLD modulations are seen very early in disease progression there is a possibility of using saccadic behavioural assessments as early biomarkers for YOPD. This becomes important since in the early stages of the disease there are higher chances of successfully employing disease modifying treatment strategies, which could ultimately be helpful in changing the natural course of the disease.

Declaration of interest

The authors declare that there are no conflicts of interest. The authors alone are responsible for the writing and content of the article.