Changes of visual pathway and brain connectivity in glaucoma: A systematic review

published: 29 May 2018 doi: 10.3389/fnins.2018.00363

Edited by: Francesca Trojsi, Università degli Studi della Campania “Luigi Vanvitelli” Naples, Italy Reviewed by: Yang Hu, Stanford University, United States Antonio Giorgio, University of Siena, Italy Sandra Hanekamp, Harvard University, United States *Correspondence: Raffaele Nuzzi prof.nuzzi_raffaele@hotmail.it

Specialty section: This article was submitted to Neurodegeneration, a section of the journal Frontiers in Neuroscience Received: 18 January 2018 Accepted: 09 May 2018 Published: 29 May 2018 Citation: Nuzzi R, Dallorto L and Rolle T (2018) Changes of Visual Pathway and Brain Connectivity in Glaucoma: A Systematic Review. Front. Neurosci. 12:363. doi: 10.3389/fnins.2018.00363

Changes of Visual Pathway and Brain

Connectivity in Glaucoma: A

Systematic Review

Raffaele Nuzzi*, Laura Dallorto and Teresa Rolle

Eye Clinic, Department of Surgical Sciences, University of Torino, Turin, Italy

Background: Glaucoma is a leading cause of irreversible blindness worldwide. The increasing interest in the involvement of the cortical visual pathway in glaucomatous patients is due to the implications in recent therapies, such as neuroprotection and neuroregeneration.

Objective: In this review, we outline the current understanding of brain structural, functional, and metabolic changes detected with the modern techniques of neuroimaging in glaucomatous subjects.

Methods: We screened MEDLINE, EMBASE, CINAHL, CENTRAL, LILACS, Trip

Database, and NICE for original contributions published until 31 October 2017. Studies with at least six patients affected by any type of glaucoma were considered. We included studies using the following neuroimaging techniques: functional Magnetic Resonance Imaging (fMRI), resting-state fMRI (rs-fMRI), magnetic resonance spectroscopy (MRS), voxel- based Morphometry (VBM), surface-based Morphometry (SBM), diffusion tensor MRI (DTI).

Results: Over a total of 1,901 studies, 56 case series with a total of 2,381 patients were included. Evidence of neurodegenerative process in glaucomatous patients was found both within and beyond the visual system. Structural alterations in visual cortex (mainly reduced cortex thickness and volume) have been demonstrated with SBM and VBM; these changes were not limited to primary visual cortex but also involved association visual areas. Other brain regions, associated with visual function, demonstrated a certain grade of increased or decreased gray matter volume. Functional and metabolic abnormalities resulted within primary visual cortex in all studies with fMRI and MRS. Studies with rs-fMRI found disrupted connectivity between the primary and higher visual cortex and between visual cortex and associative visual areas in the task-free state of glaucomatous patients.

Conclusions: This review contributes to the better understanding of brain abnormalities in glaucoma. It may stimulate further speculation about brain plasticity at a later age and therapeutic strategies, such as the prevention of cortical degeneration in patients with glaucoma. Structural, functional, and metabolic neuroimaging methods provided evidence of changes throughout the visual pathway in glaucomatous patients. Other brain areas, not directly involved in the processing of visual information, also showed alterations.

INTRODUCTION

Rationale

Glaucoma is a leading cause of irreversible blindness worldwide (Tham et al., 2014) and is characterized by the death of retinal ganglion cells (RGC) and their axons (Weinreb et al., 2014). The global incidence of primary open angle glaucoma (POAG) is anticipated to increase to 65 million by 2020 (Kapetanakis et al., 2016).

Numerous studies showed brain changes, especially in the visual pathway in glaucoma (Gupta and Yücel, 2003; Davis et al., 2016). The neurodegenerative process has been established in glaucomatous damage (Gupta et al., 2007; Chang and Goldberg, 2012). As a matter of fact, POAG presents important analogies with other neurodegenerative diseases: it has been shown that RGC share the same cell death mechanisms with Alzheimer’s disease, AD (McKinnon, 2012). Protein misfolding is one of the identified mechanisms capable of triggering the apoptotic cascade in glaucomatous pathogenesis (Wostyn et al., 2009). Indeed, the β-amyloid deposits, characteristic of Alzheimer’s disease, have recently been implicated in the pathogenesis of glaucoma (Wostyn et al., 2010). The incidence of glaucoma is increased in patients with AD compared to controls with the same age (Bayer et al., 2002; Tamura et al., 2006). Furthermore, the progression of visual field defects is accelerated in patients with open-angle glaucoma and AD compared to patients with open-angle glaucoma without AD (Bayer and Ferrari, 2002).

Moreover, nowadays, new treatments targeted visual pathway. Several neuroprotective strategies and drugs have been studied and some of them are used in the clinical practice. Neuroprotection consist in the prevention of neurons death (Jutley et al., 2017; Sena and Lindsley, 2017). Molecules that have passed through clinical test are memantine (NMDA glutamate receptor antagonist) and brimonidine (alpha2-adrenergic agonist). Neuroprotection is not effective for RGCs which have already been injured, thus neuroenhancement is also proposed as a therapeutic approach. Axon regeneration is the aim of neurotrophic factors such as nerve growth factor (NGF) and ciliary neurotrophic factor (CNTF). Human trials using these exogenous neurotrophic factors showed promising results but of limited duration and with the inconvenient of repeated injections. In recent years, stem cells have been widely studied as potential source of cell replacement. Several types and methods of administration (subtenionan, retrobulbar, and intravitreal) have been proposed and experimented in clinical trials even in humans. Another approach, still limited to murine examples, is the RGC transplantation. Preliminary data showed promising approach in retinas with degenerating RGCs (Venugopalan et al., 2016). Finally, retinal implants provide electrical stimulation of different targets but their clinical application is limited due to limited visual perception (Mathieson et al., 2012).

The efficacy of these modern approaches impose a deep knowledge of, cortical reorganization, neuroplasticity, and rearrangement of the visual pathways in glaucoma. Almost all approaches targeted RGCs of optic nerve require the integrity of posterior visual pathway or the adaptation of nervous system through plastic capacity. Moreover, new insights into

brain changes in glaucoma may stimulate new therapeutic strategies.

The advent of non-invasive brain-imaging techniques has led to a rapid growth in studies investigating the brain damage in glaucomatous patients. Newer techniques and protocols enable the study of anatomical gray and white matter changes through structural techniques, brain connectivity and functional responses after stimulation through functional magnetic resonance imaging (fMRI) and changes in brain metabolite levels through metabolic technique (Fiedorowicz et al., 2011; Mastropasqua et al., 2015; Brown et al., 2016; Prins et al., 2016).

Structural brain techniques include diffusion MRI (diffusion tensor imaging, DTI) which can reveal abnormalities in white matter structure and brain connectivity through diffusivity of water molecules along the axons (Alexander et al., 2007). Voxel-based morphometry analysis (VBM) which is computed on MRI, quantifies the tissue concentration of gray and white matter volume (Ashburner and Friston, 2000). Surface-based morphometry (SBM), throughT1-weighted morphometric analysis, provides data about the brain structure, such as thickness, curvature, and surface area of brain cortex (Clarkson et al., 2011).

Functional magnetic resonance imaging (fMRI) is a neuroimaging procedure capable to detect functional brain activities after a stimulus through detecting changes in blood flow (Miki et al., 2001, 2002; Kollias, 2004). It is also used to evaluate interactions between brain areas in a resting subject without any visual stimulus, the so-called “resting state fMRI” (Smitha et al., 2017). Finally, metabolic method such as the proton magnetic resonance spectroscopy (MRS) is able to detect and quantify certain biochemical compounds in brain tissue (Boucard et al., 2007).

Objective

This systematic review focuses on brain changes detected with the modern techniques of neuroimaging (structural, functional, and metabolic methods) in glaucomatous subjects.

Research Question

What have studies on neuroimaging in glaucomatous patients found thus far?

When do brain changes occur and what is the cause of these changes in the glaucomatous patients?

METHODS

We adopted the Preferred Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Search Strategy

We searched: MEDLINE (Ovid), CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register), EMBASE (Ovid), Latin American and Caribbean Literature on Health Sciences (LILACS), CINAHL (EBSCO), Trip Database, and The National Institute for Health and Care Excellence (NICE). The construction of search strategies was performed using

database specific subject headings and keywords. The MEDLINE search strategy was provided as Supplementary Material (Supplementary Data 1). These searches were supplemented by hand searching the bibliographies of all the included studies.

Gray literature was not considered. Accepted languages of publication were: English, German, French, Spanish, Portuguese and Italian. Articles published until October 31, 2017 were included.

Study Design

Randomized controlled trials (RCT), clinical trials, non-randomized comparative studies, cohort studies, and case series (CS) were included.

Case report, case series with <6 patients and article with absence of outcome data were excluded.

Participants, Interventions, Comparators

We included studies on patients affected by POAG, primary angle closure glaucoma (PACG), and normal tension glaucoma (NTG). Glaucomatous damage could be both unilateral and bilateral. Stages of glaucoma were not exclusion criteria.

We included studies using the following neuroimaging techniques:

- Diffusion tensor MRI (DT MRI/ DTI) - Voxel- based Morphometry (VBM) - Surface-based Morphometry (SBM)

- Functional Magnetic Resonance Imaging (fMRI) - Resting-state fMRI (rs-fMRI)

- Magnetic resonance spectroscopy (MRS)

Data Sources, Studies Sections, and Data

Extraction

According to the PRISMA flow diagram screening of titles and abstracts was carried out. Not pertinent articles were rejected. Duplicates were removed using EPPI reviewer (by EPPI-Center, Social Science Research Unit, the Institute of Education, the University of London, UK). After this initial selection, full texts were independently judged for eligibility.

Data Analysis

The main outcome of this systematic review was the current understanding of brain changes in glaucomatous subjects. Structural, functional, and metabolic neuroimaging results were separately analyzed and presented, but their interaction was nonetheless studied. Differences between various types of glaucoma and various stages of disease were analyzed.

Specifically, characterizing parameters of each neuroimaging method are listed below:

- DTI: fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD). They all are measures of white matter damage.

- VBM: gray matter and white matter volume.

- SBM: thickness, curvature, and surface area of brain cortex. - fMRI: Blood oxygenation level dependent (BOLD) evaluation.

It detects changes in the blood flow of local brain regions

through changes in hemoglobin and unoxygenated

hemoglobin in the blood. In the manuscript we referred to fMRI for “task-fMRI,” which measures responses during visual tasking

- rs-fMRI: Voxel-wise degree centrality (DC), that is the direct connections for a given voxel in the voxel-wise connectome, and functional connectivity (FC) between areas in resting conditions, without any visual tasks

- MRS: concentrations of the metabolites such as N-acetylaspartate (NAA), creatinine (Cr), and Choline (Cho)

RESULTS

Study Selection

A total of 1,901 studies were screened using the described search strategy. At the end of the selection process, 56 case series were included in the systematic review. Prisma flow diagram (Figure 1) gives details on screening process.

Thirty-one out of 56 (55%) studies examined brain changes in terms of structural parameters (19 studies used DTI, 6 studies VBM, 4 studies SBM, one single study both VBM and SBM, and one single study both VBM and DTI). Nineteen out of fifty-six studies, (34%) used functional techniques to evaluate brain changes following glaucomatous degeneration (10 studies used the fMRI and 9 studies the rs-fMRI). Metabolic methods (MRS) are used in 2 studies (4%). Four studies (7%) used both structural and functional techniques on the same group of patients: three studies used rs-fMRI, VBM, and DTI, one study used VBM and fMRI.

Study Characteristics

A total of 1,326 patient and 1,055 controls were considered in this systematic review. Forty-nine studies included POAG patient (41 studies only POAG patients, 7 studies included both POAG and NTG, one single study had both POAG and PACG). A total of 1,061 patient, corresponding to 80% of the total number had POAG. 154 out of 1326 (12%) patients were affected by PACG (they are included in seven studies, one of these studies included both POAG and PACG patients). NTG was the less studied type, corresponding to 8% (111 patients) of the total. Eight studies included NTG patients, 7 studies had both NTG and POAG patients, one single study had NTG patients).

Patients characteristics of included studies are reported in

Table 1. Patients included in this review show high heterogeneity

in mean age ranging from 25 (Dai et al., 2013) to 76 (Bogorodzki et al., 2014) years. Severity of glaucoma damage varies from early to severe and some authors included different stages in the same study. Method of severity classification was not consistent throughout all studies, even though the most used is the Hodapp– Parrish–Anderson (HPA) classification.

Outcomes of Structural Analysis

Results of studies analyzing structural brain changes in glaucomatous patients are reported in Table 2.

Diffusion tensor imaging methodology has been extensively used to investigate differences in white matter tracts of visual pathway within glaucoma (19 out of 56 studies, 34% of all

FIGURE 1 | Prisma flow diagram.

included studies). Decreased fractional anisotropy (FA) and increased mean diffusivity (MD) and radial diffusivity (RD) are sign of axon injury. Differences of microstructure in white matter structures have been found in the optic nerve, optic tracts, optic chiasm, optic radiations, and occipital lobe. These results were obtained in studies including POAG (Garaci et al., 2009; El-Rafei et al., 2011, 2013; Engelhorn et al., 2011; Bolacchi et al., 2012; Nucci et al., 2012; Zhang et al., 2012; Zikou et al., 2012; Chen Z. et al., 2013; Lu et al., 2013; Michelson et al., 2013; Frezzotti et al., 2014, 2016; Kaushik et al., 2014; Omodaka et al., 2014; Schoemann et al., 2014; Sidek et al., 2014; Murai et al., 2015; Tellouck et al., 2016; Zhou et al., 2017a; Giorgio et al., 2018), NTG (Boucard et al., 2016) and PACG (Wang et al., 2013) patients.

Some of the studies using DTI methodology found alterations of white matter integrity not limited to the primary visual pathway. Boucard et al. (2016) revealed damage of corpus

callosum and parietal lobe in NTG,Frezzotti et al. (2016)found alterations in the longitudinal fascicle, supramarginal gyrus, and superior parietal lobule of early stage open angle glaucoma. In addition, according to Giorgio et al study (Giorgio et al., 2018), superior longitudinal fascicle, white matter adjacent to precuneus, inferior frontal gyrus, and superior parietal lobe had microstructural alterations in both normal tension and open angle glaucoma compared to healthy subjects (Giorgio et al., 2018). Such white matter structures are related to higher aspects of visual and cognitive process. Furthermore, significant decreased FA was found in glaucomatous compared to healthy subjects in the inferior fronto-occipital fasciculus (implied in visuospatial function), longitudinal and inferior frontal fasciculi (related to visual memory), putamen, caudate nucleus, anterior, and posterior thalamic radiations and anterior and posterior limbs of the internal capsule (implied in direction, color, and orientation;Zikou et al., 2012).

T A B L E 1 | D e m o g ra p h ic a n d c lin ic a lc h a ra c te ris tic s. A u th o r, y e a r G ty p e N p a ti e n ts A g e (y e a rs ) M e a n ± S D S e x M /F (% ) C li n ic a l c h a ra c te ri s ti c s G H G H G H B o g o ro d zk ie t a l., 2 0 1 4 P O A G 1 4 1 2 7 6 ± 7 .5 6 6 .5 ± 9 .8 5 7 /4 3 2 5 /7 5 A d va n c e d u n ila te ra lP O A G (n o lig h t p e rc e p tio n to h a n d m o ve m e n t, C D R 0 .9 –1 ), fe llo w e ye a ff e c te d le ss th a n M D > − 2 0 d B B o la c c h ie t a l., 2 0 1 2 P O A G 2 4 1 5 5 9 (M ) 5 5 (F ) 6 2 (M ) 6 0 (F ) 7 9 /2 1 8 0 /2 0 P O A G p a tie n ts a re d iv id e d in e a rly (s ta g e 1 a n d 2 o f H o d a p p c la ss ific a tio n ) a n d se ve re (s ta g e 4 a n d 5 ) st a g e B o rg e s e t a l., 2 0 1 5 P O A G 9 4 7 0 ± 8 .7 5 9 ± 8 .2 8 9 /1 1 7 5 /2 5 U n ila te ra lP O A G (a t le a st M D < − 1 0 d B , p a ra c e n tr a ls c o to m a o f d ia m e te r> 1 0 ◦ w ith in th e c e n tr a l2 0 ◦) fo r a t le a st 3 yr s B o u c a rd e t a l., 2 0 0 7 P O A G 7 1 2 7 3 6 2 8 6 /1 4 6 7 /3 3 H o m o n ym o u s sc o to m a > 1 0 ◦ fo r a t le a st 3 yr s. A g ro u p o f 7 p a tie n ts w ith A M D w a s a ls o c o n si d e re d B o u c a rd e t a l., 2 0 0 9 P O A G 8 1 2 7 2 6 6 8 8 /1 2 7 5 /2 5 H o m o n ym o u s sc o to m a > 1 0 ◦ fo r a t le a st 3 yr s. A g ro u p o f 9 p a tie n ts w ith A M D w a s a ls o c o n si d e re d B o u c a rd e t a l., 2 0 1 6 N T G 3 0 2 1 5 2 ± 1 0 .7 5 2 .3 ± 1 5 .3 7 7 /2 3 4 8 /5 2 In g la u c o m a to u s e ye s, m e a n M D R E = − 8 .9 d B , L E = − 6 .8 d B C a ie t a l., 2 0 1 5 P A C G 2 3 2 3 4 9 .5 ± 1 4 .4 4 8 .2 ± 9 .4 3 5 /6 5 3 5 /6 5 P A C G e ye s m e a n IO P = 3 9 m m H g . A ll p a tie n ts u n d e rw e n t g la u c o m a su rg e ry . 9 /2 3 u n d e rw e n t M R Ia ft e r su rg e ry C h e n Z . e t a l., 2 0 1 3 P O A G 2 5 2 4 3 4 .5 3 3 .6 7 6 /2 4 7 5 /2 5 P O A G su b je c ts w e re d iv id e d o n th e b a si s o f vi su a lfie ld se ve rit y in 6 g ro u p s C h e n W . W . e t a l., 2 0 1 3 P O A G 1 5 1 5 4 3 .3 ± 4 .1 4 3 .9 ± 3 .8 6 0 /3 0 6 0 /3 0 B ila te ra la d va n c e d P O A G (C D R > 0 .9 , M D < − 1 5 d B ). C h e n e t a l., 2 0 1 7 P A C G 2 0 2 0 5 4 .4 ± 9 .5 5 3 .8 ± 9 .2 5 0 /5 0 5 0 /5 0 N S D a ie t a l., 2 0 1 3 P O A G 2 2 2 2 2 5 3 6 7 7 /2 3 7 7 /2 3 N S D u n c a n e t a l., 2 0 0 7 a P O A G 6 * 0 6 9 .3 ± 7 .7 N A 5 0 /5 0 N A A sy m m e tr ic P O A G w ith o n e g la u c o m a to u s e ye a n d a le ss a ff e c te d c o n tr o la te ra l e ye D u n c a n e t a l., 2 0 0 7 b P O A G 6 * 0 6 9 .3 ± 7 .7 N A 5 0 /5 0 N A A sy m m e tr ic P O A G w ith o n e g la u c o m a to u s e ye a n d a le ss a ff e c te d c o n tr o la te ra l e ye E l-R a fe ie t a l., 2 0 1 1 P O A G — N T G 1 3 ₍₇ P O A G , 6 N T G ) 1 0 6 4 .7 ± 1 1 .5 6 2 .8 ± 1 3 .6 4 6 /5 4 3 0 /7 0 N S E l-R a fe ie t a l., 2 0 1 3 P O A G — N T G 5 7 (3 9 P O A G , 1 8 N T G ) 2 7 6 1 .9 ± 8 .6 5 8 .5 ± 1 0 .1 4 4 /5 6 3 7 /6 3 N S E n g e lh o rn e t a l., 2 0 1 1 P O A G 5 0 5 0 5 2 .2 ± 1 2 .6 (M ) 6 0 .0 ± 1 6 .9 (F ) 5 4 .0 ± 1 4 .2 (M ) 6 1 .4 ± 1 5 .1 (F ) 3 6 /4 6 4 4 /5 6 N S F re zz o tt ie t a l., 2 0 1 4 P O A G 1 3 1 2 5 1 .7 ± 6 .6 4 7 .3 ± 5 .1 7 7 /2 3 3 3 /6 4 A ll p a tie n ts h a d b ila te ra la d va n c e d g la u c o m a to u s vi su a lfie ld d a m a g e a c c o rd in g w ith th e H o d a p p /B a sc o m P a lm e r c la ss ific a tio n (m e a n M D w o rs e e ye = − 2 3 .2 d B ) F re zz o tt ie t a l., 2 0 1 6 P O A G 5 7 2 9 6 2 .1 ± 6 9 .3 5 8 ± 1 0 6 7 /2 3 5 2 /4 8 P O A G p a tie n ts w e re c la ss ifie d a c c o rd in g to th e H o d a p p /B a sc o m P a lm e r c la ss ific a tio n . 1 4 p a tie n ts h a d e a rly (S ta g e 1 ), 1 3 m o d e ra te (S ta g e 2 ), a n d 3 0 se ve re (S ta g e 3 ) d is e a se G a ra c ie t a l., 2 0 0 9 P O A G 1 6 1 0 6 3 6 1 5 6 /4 4 6 0 /4 0 T h e g la u c o m a to u s e ye s w e re st ra tifie d a c c o rd in g to se ve rit y o f vi su a lfie ld d e fe c ts in to si x g ro u p s b y u si n g th e H o d a p p -P a rr is h sy st e m (C o n ti n u e d )

T A B L E 1 | C o n tin u e d A u th o r, y e a r G ty p e N p a ti e n ts A g e (y e a rs ) M e a n ± S D S e x M /F (% ) C li n ic a l c h a ra c te ri s ti c s G H G H G H G e re n te e t a l., 2 0 1 5 P O A G 1 7 8 6 1 .8 ± 1 0 .9 5 6 .4 ± 1 3 .9 4 1 /5 9 6 3 /3 7 T h e p a tie n ts w e re a ss ig n e d to th re e su b g ro u p s: ( T h a m e t a l., 2 0 1 4 ) in iti a l g la u c o m a , (2 ) a sy m m e tr ic a lg la u c o m a a n d (3 ) se ve re g la u c o m a , a c c o rd in g to th e V F d e fe c t p a tt e rn in b o th e ye s. G io rg io e t a l., 2 0 1 8 P O A G — N T G 3 4 (1 7 P O A G , 1 7 N T G ) 2 9 5 8 .6 ± 1 3 .4 (P O A G ) 5 8 .9 ± 1 3 .7 (N T G ) 5 7 .9 ± 9 .9 7 6 /2 4 (N T G ) 5 3 /4 7 (P O A G ) 5 2 /4 8 G la u c o m a p a tie n ts w e re c la ss ifie d w ith H o d a p p /B a sc o m P a lm e r g la u c o m a se ve rit y S ta g in g . M ild /m o d e ra te /s e ve re = 1 0 /2 /5 in b o th P O A G a n d N T G . H e rn o w o e t a l., 2 0 1 1 P O A G 8 1 2 7 2 6 7 8 8 /1 2 7 5 /2 5 P a rt ic ip a n t in c lu si o n c rit e ria w e re th e fo llo w in g : (1 ) a g la u c o m a to u s V F d e fe c t o f a t le a st 1 0 ◦in d ia m e te r in a t le a st o n e q u a d ra n t, a ff e c tin g b o th e ye s; (2 ) V F d e fe c ts h a d to in c lu d e th e p a ra c e n tr a lr e g io n s in b o th e ye s; (3 ) th e d e fe c ts h a d to h a ve b e e n p re se n t fo r a t le a st 3 ye a rs H u a n g e t a l., 2 0 1 5 P A C G 2 1 2 1 5 2 ± 1 3 .8 6 0 .6 ± 4 .6 3 8 /6 2 4 3 /5 7 N S Ji a n g e t a l., 2 0 1 7 P O A G 1 3 1 3 3 2 .4 ± 6 .2 3 0 .4 ± 4 .8 7 7 /2 3 7 7 /2 3 O n ly e a rly a n d m id -s ta g e w e re in c lu d e d (s ta g e 1 , 2 a n d 3 o f th e G la u c o m a S ta g in g S ys te m 2 ) K a u sh ik e t a l., 2 0 1 4 P O A G 9 9 6 9 6 8 4 4 /5 6 3 3 /6 7 G la u c o m a p a tie n ts w ith b in o c u la r, sy m m e tr ic a ls u p e rio r, o r in fe rio r vi su a l h e m ifie ld d e fe c ts w e re se le c te d . T h e d iff e re n c e b e tw e e n th e u n a ff e c te d a n d a ff e c te d h e m ifie ld se n si tiv ity (in d e c ib e ls ) h a d to b e m o re th a n 3 :1 . L e st a k e t a l., 2 0 1 4 P O A G — N T G 1 6 ₍₈ P O A G , 8 N T G ) 8 R a n g e 4 0 –7 3 (P O A G ) 4 0 –7 0 (N T G ) 2 3 -6 5 6 3 /2 7 2 5 /7 5 N S L ie t a l., 2 0 1 2 P O A G 3 0 3 0 5 0 N S 8 0 /2 0 8 0 /2 0 A c c o rd in g to B e c ke r vi su a lfie ld st a g e s P O A G p a tie n ts w e re d iv id e d in to 9 e a rly st a g e a n d 2 1 a d va n c e d -l a te st a g e . L ie t a l., 2 0 1 4 P O A G 2 1 2 2 4 6 .4 ± 1 6 .4 4 5 .6 ± 1 1 .9 4 8 /5 2 5 0 /5 0 N S L ie t a l., 2 0 1 7 P A C G 2 5 2 5 5 2 5 2 4 0 /6 0 4 0 /6 0 P A C G e ye s m e a n IO P = 3 1 m m H g . A ll p a tie n ts u n d e rw e n t g la u c o m a su rg e ry . 1 9 /2 5 u n d e rw e n t M R I a ft e r su rg e ry L u e t a l., 2 0 1 3 P O A G 1 5 1 5 4 8 ± 2 0 4 8 ± 1 9 9 3 /7 9 3 /7 N S M ic h e ls o n e t a l., 2 0 1 3 P O A G -N T G 2 6 (1 3 P O A G , 1 3 N T G ) 7 5 7 .4 ± 1 2 .7 (P O A G ) 5 9 .5 ± 1 3 .1 (N T G ) 5 4 .6 ± 1 2 .1 4 6 /5 4 (P O A G ) 3 8 /6 2 (N T G ) 4 3 /5 7 G la u c o m a se ve rit y w e re a ss e ss e d w ith H R T M u ra ie t a l., 2 0 1 5 P O A G 3 2 1 9 5 9 .5 ± 1 3 .7 5 6 .5 ± 1 4 5 3 /4 7 6 3 /3 7 A ve ra g e M D − 7 .1 7 d B in th e rig h t e ye a n d − 8 .2 6 d B in th e le ft e ye . M u rp h y e t a l., 2 0 1 6 P O A G 2 6 (1 3 e a rly − 1 3 a d va n c e d ) 9 6 2 .4 ± 2 .1 (e a rly ) 6 3 .6 ± 2 .3 (a d va n c e d ) 6 1 .3 ± 3 .1 5 4 /4 6 (e a rly ) 3 9 /6 1 (a d va n c e d ) 3 3 /6 7 N S N u c c ie t a l., 2 0 1 2 P O A G 2 4 1 2 6 0 N S 7 0 /3 0 N S N S O m o d a ka e t a l., 2 0 1 4 P O A G 1 9 0 6 6 .1 ± 9 .0 N A 6 8 /3 2 N A 1 6 e ye s w e re P O A G a n d 2 2 w e re N T G Q in g e t a l., 2 0 1 0 P O A G 6 0 4 9 .5 N A 3 3 /6 7 N A A sy m m e tr ic vi su a lfie ld d a m a g e a n d sp a re d c e n tr a lv is io n . (C o n ti n u e d )

T A B L E 1 | C o n tin u e d A u th o r, y e a r G ty p e N p a ti e n ts A g e (y e a rs ) M e a n ± S D S e x M /F (% ) C li n ic a l c h a ra c te ri s ti c s G H G H G H S c h o e m a n n e t a l., 2 0 1 4 P O A G 3 9 2 2 6 3 .9 ± 9 .3 6 3 .3 ± 1 1 .9 3 3 /6 7 4 1 /5 9 N S S id e k e t a l., 2 0 1 4 P O A G 6 0 (3 0 m ild , 3 0 se ve re ) 3 0 6 8 .4 ± 8 .9 (m ild ) 6 5 .6 ± 9 .0 (s e ve re ) 6 3 .5 ± 8 .4 3 7 /6 7 (m ild ) 7 3 /2 7 (s e ve re ) 4 0 /6 0 T h e c a te g o ris a tio n in to m ild a n d se ve re g la u c o m a w a s d o n e u si n g th e H o d a p p –P a rr is h –A n d e rs o n (H P A ) c la ss ific a tio n . S o n g e t a l., 2 0 1 2 P A C G 3 0 1 6 6 1 ± 8 L st im u la tio n 6 1 ± 8 (R st im u la tio n ) 5 7 ± 8 3 7 /6 3 3 8 /6 2 T h e p a tie n ts w e re a ss ig n e d to th e e a rly V F d e fe c t g ro u p (p a ra c e n tr a ls c o to m a , n a sa ll a d d e r) o r th e a d va n c e d V F d e fe c t g ro u p (q u a d ra n ta n o p ia , c e n tr a lv is u a l fie ld a n d te m p o ra li sl a n d ). S o n g e t a l., 2 0 1 4 P O A G 3 9 4 1 3 4 .8 ± 9 .9 3 4 .8 ± 9 .7 8 2 /1 8 8 1 /1 9 N S Te llo u c k e t a l., 2 0 1 6 P O A G 5 0 5 0 6 1 .9 ± 6 .9 6 1 .9 ± 7 .0 4 0 /6 0 4 0 /6 0 S e ve rit y o f g la u c o m a w a s d e fin e d o n H o d a p p -P a rr is h -A n d e rs o n c la ss ific a tio n W a n g e t a l., 2 0 1 3 P A C G 2 3 2 0 5 4 5 0 3 9 /6 1 3 5 /6 5 S e ve rit y o f g la u c o m a w a s d e fin e d o n H o d a p p -P a rr is h -A n d e rs o n c la ss ific a tio n W a n g e t a l., 2 0 1 6 P O A G 2 5 2 5 4 4 .6 ± 1 3 .0 3 6 .8 ± 1 1 .6 4 4 /5 6 5 2 /4 8 N S W a n g e t a l., 2 0 1 6 a P O A G 2 5 2 5 4 4 .6 ± 1 3 .0 3 6 .8 ± 1 1 .6 4 4 /5 6 5 2 /4 8 N S W a n g e t a l., 2 0 1 6 b P O A G 2 5 2 5 4 4 .6 ± 1 3 .0 3 6 .8 ± 1 1 .6 4 4 /5 6 5 2 /4 8 N S W ill ia m s e t a l., 2 0 1 3 P O A G 1 5 1 5 6 6 .1 ± 1 1 .2 6 5 .6 ± 1 1 .3 6 7 /3 3 6 7 /3 3 N S Y u e t a l., 2 0 1 3 P O A G 3 6 4 0 4 6 .5 4 6 .5 7 5 /2 5 7 4 /2 6 Tw o su b g ro u p s (a m ild a n d se ve re g ro u p ) b a se d o n H o d a p p -P a rr is h -A n d e rs o n c la ss ific a tio n Y u e t a l., 2 0 1 4 P O A G 3 6 (1 9 + ₁7) 2 0 4 2 .6 ± 1 4 .5 (m ild ) 4 8 .1 ± 1 6 .6 (s e ve re ) 4 3 .3 ± 1 5 .1 5 7 /4 3 (m ild ) 7 1 /2 9 (s e ve re ) 5 5 /4 5 1 9 m ild a n d 1 7 se ve re P O A G p a tie n ts b a se d o n H o d a p p -P a rr is h -A n d e rs o n c la ss ific a tio n Y u e t a l., 2 0 1 5 P O A G 3 7 (2 0 + ₁7) 2 0 4 3 .6 ± 1 4 .5 (m ild ) 4 8 .1 ± 1 6 .6 (s e ve re ) 4 3 .3 ± 1 5 .1 5 9 /4 1 (m ild ) 7 1 /2 9 (s e ve re ) 5 5 /4 5 2 0 m ild a n d 1 7 se ve re P O A G p a tie n ts b a se d o n H o d a p p -P a rr is h -A n d e rs o n c la ss ific a tio n Z h a n g e t a l., 2 0 1 2 N T G 3 0 3 0 5 4 .8 ± 1 1 .9 5 3 .9 ± 1 1 .2 5 0 /5 0 5 3 /4 7 N S Z h a n g e t a l., 2 0 1 3 P O A G -P A C G 2 0 2 0 4 5 4 5 4 0 /6 0 4 0 /6 0 8 P O A G , 1 2 P A C G . D iff e re n t st a g e s (f ro m e a rly to a d va n c e d ) Z h a n g e t a l., 2 0 1 5 P O A G 2 3 2 9 4 7 ± 7 4 8 ± 7 6 1 /3 9 6 6 /3 6 9 e a rly -m o d e ra te g la u c o m a a n d 1 4 a d va n c e d g la u c o m a Z h a n g e t a l., 2 0 1 6 P O A G — N T G 1 8 (1 0 + 8) 1 8 3 3 .0 ± 5 .6 3 3 .0 ± 5 .6 7 8 /2 2 7 8 /2 2 1 0 P O A G , 8 N T G a ll e a rly st a g e Z h o u e t a l., 2 0 1 7 a P O A G 1 1 1 1 6 0 .0 ± 9 .2 5 5 .9 ± 7 .5 3 6 /6 4 6 4 /3 4 M ild to m o d e ra te P O A G Z h o u e t a l., 2 0 1 7 b P O A G 9 9 6 1 ± 1 1 5 8 ± 5 4 4 /5 6 6 7 /3 3 N S Z ik o u e t a l., 2 0 1 2 P O A G 1 8 1 8 5 7 .1 ± 1 1 .4 N S 7 8 /2 2 N S N S * D u n c a n e t a l. (2 0 0 7 a ) a n d D u n c a n e t a l. (2 0 0 7 b) s h a re th e s a m e pa ti e n ts , G , gl a u c om a ; H , h e a lth y; C D R , C u p/ di s c ra ti o; yr s , ye a rs ; N R , n ot re por te d; MD , Me a n D e vi a ti on ; R E, ri gh t e ye ; L E, le ft e ye ; R N F L , re ti n a ln e rv e fibe r la ye r; N S , n o t s pe c ifi e d; N A , n o t a ppl ic a bl e ; V F, vi s u a lfi e ld; H R T, H e ide lbe rg R e ti n a tom ogr a ph .

T A B L E 2 | O u tc o m e s o f st u d ie s w ith st ru c tu ra lb ra in a n a ly si s. A u th o r, y e a r B ra in a re a a n a ly z e d P a ra me te r a n a ly z e d R e s u lt s D T I B o la c c h ie t a l., 2 0 1 2 In tr a o rb ita lo p tic n e rv e a t tw o d iff e re n t le ve ls : p ro xi m a la n d d is ta lt o th e O N H F ra c tio n a la n is o tr o p y (F A ) a n d m e a n d iff u si vi ty (M D ) A t e a rly st a g e h ig h e r M D a t th e p ro xi m a ls ite w ith re sp e c t to th e d is ta ls ite . In c o n tr a st , a t se ve re st a g e s b o th th e p ro xi m a la n d th e d is ta lp o rt io n sh o w e d a lte re d M D . FA is a lte re d in b o th st a g e s b o th in th e p ro xi m a la n d d is ta lp a rt . B o u c a rd e t a l., 2 0 1 6 W h ite m a tt e r o f a ll b ra in FA a n d M D R e d u c e d FA in c lu st e rs in b ila te ra lo c c ip ita lp o le (c o m p ris in g O R a n d fo rc e p s m a jo r) , su p e rio r p a rie ta ll o b e , b o d y a n d sp le n iu m o f c o rp u s c a llo su m . C h e n Z . e t a l., 2 0 1 3 W h ite m a tt e r o f a ll b ra in FA a n d M D . C o rr e la tio n w ith c lin ic a lm e a su re m e n t B ila te ra lO T a n d O R sh o w e d d e c re a se d FA a n d in c re a se d M D . FA c o rr e la te s w ith C D R , R N F L th ic kn e ss a n d vi su a lf u n c tio n . E l-R a fe ie t a l., 2 0 1 1 O p tic ra d ia tio n A xi a l, ra d ia l, m e a n d iff u si vi tie s a n d FA G la u c o m a su b je c ts h a ve in c re a se d ra d ia ld iff u si vi ty a n d m e a n d iff u si vi ty si g n ific a n t vo xe ls w ith a m a in c o n c e n tr a tio n in th e p ro xi m a lp a rt o f th e rig h t o p tic ra d ia tio n E l-R a fe ie t a l., 2 0 1 3 A sp e c ifie d R O Io n th e se g m e n te d o p tic ra d ia tio n D iff e re n t d iff u si o n te n so r d e riv e d m e a su re s. T h e ir a b ili ty fo r d e te c tin g a n d d is c rim in a tin g d iff e re n t g la u c o m a e n tit ie s T h e d is c rim in a tio n a c c u ra c y b e tw e e n h e a lth y a n d g la u c o m a (P O A G a n d N T G ) su b je c ts w a s 9 4 .1 % , b e tw e e n h e a lth y a n d P O A G w a s 9 2 .4 % a n d it in c re a se d to 1 0 0 % b e tw e e n h e a lth y a n d N T G g ro u p s. D is c rim in a tio n b e tw e e n g la u c o m a e n tit ie s (P O A G a n d N T G ) h a d a n a c c u ra c y o f 9 8 .3 % . E n g e lh o rn e t a l., 2 0 1 1 O p tic ra d ia tio n V o lu m e o f th e o p tic ra d ia tio n a n d g ra d in g o f m ic ro a n g io p a th ic le si o n s (m ild , m o d e ra te a n d se ve re ) 4 4 % g la u c o m a p a tie n ts sh o w e d si g n ific a n t ra re fa c tio n o f th e o p tic ra d ia tio n : th e vo lu m e w a s re d u c e d to 6 7 ± 1 6 % c o m p a re d w ith c o n tr o ls . C e re b ra l m ic ro a n g io p a th y o f O R w a s h ig h e r a m o n g g la u c o m a p a tie n ts . F re zz o tt ie t a l., 2 0 1 4 W h o le b ra in w h ite m a tt e r FA , a xi a ld iff u si vi ty (A D ), ra d ia ld iff u si vi ty (R D ) A lte re d in te g rit y (d e c re a se d FA o r in c re a se d d iff u si vi tie s) a lo n g th e vi su a l p a th w a y (o p tic tr a c ts , c h ia sm , ra d ia tio n ) o f P O A G a n d a ls o in n o n vi su a lW M tr a c ts (s u p e rio r lo n g itu d in a lf a sc ic le , a n te rio r th a la m ic ra d ia tio n , c o rt ic o sp in a lt ra c t, m id d le c e re b e lla r p e d u n c le ). F re zz o tt ie t a l., 2 0 1 6 W h o le b ra in w h ite m a tt e r FA , A D , R D . D iff e re n c e s b e tw e e n h e a lth y a n d w h o le P O A G a n d b e tw e e n h e a lth y a n d e a rly st a g e P O A G . D e c re a se d FA a n d h ig h e r A D a lo n g th e vi su a lp a th w a y (o p tic tr a c ts , c h ia sm , ra d ia tio n ) o f P O A G a n d a ls o in n o n vi su a lW M tr a c ts (s u p e rio r lo n g itu d in a lf a sc ic le , su p ra m a rg in a lg yr u s a n d su p e rio r p a rie ta ll o b u le ). S im ila r re su lts in th e e a rly st a g e g la u c o m a . G a ra c ie t a l., 2 0 0 9 O p tic n e rv e a n d o p tic ra d ia tio n FA a n d M D . C o rr e la tio n w ith d is e a se se ve rit y P O A G N O a n d O R h a d si g n ific a n tly h ig h e r M D a n d si g n ific a n tly lo w e r FA . A n e g a tiv e c o rr e la tio n b e tw e e n m e a n FA fo r th e o p tic n e rv e s a n d g la u c o m a st a g e w a s o b se rv e d . G io rg io e t a l., 2 0 1 8 W h o le b ra in w h ite m a tt e r FA , A D , R D . D iff e re n c e s b e tw e e n h e a lth y, P O A G a n d N T G . D e c re a se d FA a n d h ig h e r A D a lo n g th e vi su a lp a th w a y (o p tic tr a c ts , c h ia sm , ra d ia tio n ) a n d a ls o in n o n vi su a lW M tr a c ts (s u p e rio r lo n g itu d in a lf a sc ic le , W M a d ja c e n t to p re c u n e u s, in fe rio r fr o n ta lg yr u s, su p e rio r p a rie ta ll o b e ) in b o th P O A G a n d N T G . D iff e re n c e s w e re fo u n d in th e n o n vi su a la re a s a b n o rm a lit ie s b e tw e e n P O A G a n d N T G . K a u sh ik e t a l., 2 0 1 4 O p tic ra d ia tio n R D , A D , M D , FA in O R . O R fib e rs w e re se p a ra te d in to tr a c ts su b se rv in g th e su p e rio r o f in fe rio r h e m ifie ld o f th e vi su a lfie ld . FA w a s lo w e r a n d M D w a s h ig h e r in P O A G O R c o m p a re d w ith c o n tr o ls . U n a ff e c te d O R tr a c ts sh o w e d c h a n g e s in R D c o m p a re d w ith c o n tr o ls L u e t a l., 2 0 1 3 O c c ip ita lw h ite m a tt e r FA O c c ip ita lw h ite m a tt e r in P O A G h a d lo w e r FA va lu e s. (C o n ti n u e d )

T A B L E 2 | C o n tin u e d A u th o r, y e a r B ra in a re a a n a ly z e d P a ra me te r a n a ly z e d R e s u lt s M ic h e ls o n e t a l., 2 0 1 3 O p tic ra d ia tio n FA , A D a n d R D o f th e o p tic ra d ia tio n s a n d th e ir c o rr e la tio n w ith g la u c o m a se ve rit y in d ic a to rs D T I-d e riv e d p a ra m e te rs o f th e a xo n a li n te g rit y (F A , A D ) a n d d e m ye lin a tio n (R D ) o f th e o p tic ra d ia tio n a re lin ke d to H R T-b a se d in d ic e s o f g la u c o m a se ve rit y. M u ra ie t a l., 2 0 1 5 O p tic ra d ia tio n FA o f o p tic ra d ia tio n . C o rr e la tio n w ith g lu c o se m e ta b o lis m in th e st ria te c o rt e x st u d ie d w ith P E T FA in o p tic ra d ia tio n s w a s lo w e r in p a tie n ts w ith g la u c o m a . T h e re w e re si g n ific a n t c o rr e la tio n s b e tw e e n FA o f th e o p tic ra d ia tio n a n d ip si la te ra ls tr ia ta lg lu c o se m e ta b o lis m . N u c c ie t a l., 2 0 1 2 O p tic n e rv e FA a n d M D . C o rr e la tio n w ith o p tic n e rv e st ru c tu re (G D x-V C C , H R T, O C T ) D T Ip a ra m e te rs o f th e a xo n a la rc h ite c tu re o f th e o p tic n e rv e sh o w g o o d c o rr e la tio n w ith m o rp h o lo g ic a lf e a tu re s o f th e o p tic n e rv e h e a d a n d R N F L d o c u m e n te d w ith G D x-V C C , H R T-III a n d O C T. O m o d a ka e t a l., 2 0 1 4 O p tic n e rv e FA a n d A D . C o rr e la tio n w ith o p tic n e rv e st ru c tu re (O C T ) a n d M D D T Ip a ra m e te rs c o rr e la te d w ith R N F L a n d M D a t V F. S c h o e m a n n e t a l., 2 0 1 4 O p tic ra d ia tio n FA . C o rr e la tio n w ith th e e xt e n t o f c e re b ra lw h ite m a tt e r le si o n s (W M L ). T h e re w a s a si g n ific a n t c o rr e la tio n b e tw e e n FA a n d W M L in P O A G re g a rd in g th e to ta l b ra in , th e p e riv e n tr ic u la r re g io n , a n d th e o p tic ra d ia tio n in b o th h e m is p h e re s. S id e k e t a l., 2 0 1 4 O p tic n e rv e a n d o p tic ra d ia tio n FA a n d M D a n d th e ir d is c rim in a n t p o w e r b e tw e e n m ild a n d se ve re g la u c o m a a n d c o rr e la tio n w ith R N F L . FA a n d M D in th e o p tic n e rv e a n d o p tic ra d ia tio n d e c re a se d a n d in c re a se d re sp e c tiv e ly a s th e d is e a se p ro g re ss e d . FA a t th e o p tic n e rv e h a d th e h ig h e st se n si tiv ity (8 7 % ) a n d sp e c ific ity (8 0 % ). FA va lu e s d is p la ye d th e st ro n g e st c o rr e la tio n w ith R N F L th ic kn e ss in th e o p tic n e rv e . Te llo u c k e t a l., 2 0 1 6 O p tic ra d ia tio n s FA , M D , R D , A D FA w a s lo w e r a n d R D h ig h e r th a n c o n tr o ls . C o rr e la tio n w ith fu n c tio n a la n d st ru c tu ra l d a m a g e . W a n g e t a l., 2 0 1 3 O p tic n e rv e FA , M D . C o rr e la tio n w ith R N F L m e a su re d w ith O C T FA w a s lo w e r a n d M D h ig h e r th a n c o n tr o ls . C o rr e la tio n w ith R N F L . Z h a n g e t a l., 2 0 1 2 O p tic n e rv e FA , M D . C o rr e la tio n w ith R N F L m e a su re d w ith O C T FA w a s lo w e r a n d M D h ig h e r th a n c o n tr o ls . C o rr e la tio n w ith R N F L . Z h o u e t a l., 2 0 1 7 a O p tic tr a c t a n d o p tic ra d ia tio n FA , R D , A D , M D . C o rr e la tio n w ith vi su a lfie ld lo ss a n d R N F L FA w a s lo w e r a lo n g th e o p tic tr a c ts a n d ra d ia tio n s in P O A G . FA c o rr e la te d w ith vi su a l fie ld lo ss b u t n o t w ith R N F L . Z ik o u e t a l., 2 0 1 2 W h o le b ra in w h ite m a tt e r FA a n d M D A si g n ific a n t d e c re a se o f FA w a s o b se rv e d in th e in fe rio r fr o n to -o c c ip ita lf a sc ic u lu s, th e lo n g itu d in a la n d in fe rio r fr o n ta lf a sc ic u li, th e p u ta m e n , th e c a u d a te n u c le u s, th e a n te rio r a n d p o st e rio r th a la m ic ra d ia tio n s, a n d th e a n te rio r a n d p o st e rio r lim b s o f th e in te rn a lc a p su le o f th e le ft h e m is p h e re . V B M B o u c a rd e t a l., 2 0 0 9 w h o le b ra in 2 1 m m d ia m e te r V O I a t th e p o st e rio r p o le : 1 p o st e rio r a n d 1 a n te rio r in b o th su p e rio r a n d in fe rio r b a n ks o f th e c a lc a rin e su lc u s in e a c h h e m is p h e re C h a n g e s in g ra y m a tt e r d e n si ty in th e a ll b ra in a n d V O I a n a ly si s. (1 ) b ila te ra lr e d u c tio n o f g ra y m a tt e r d e n si ty o n th e m e d ia la sp e c t o f th e o c c ip ita ll o b e , a t th e a n te rio r h a lf o f th e c a lc a rin e fis su re s. (2 ) g ra y m a tt e r d e n si ty is m o re re d u c e d in th e a n te rio r th a n in th e p o st e rio r re g io n . (C o n ti n u e d )

T A B L E 2 | C o n tin u e d A u th o r, y e a r B ra in a re a a n a ly z e d P a ra me te r a n a ly z e d R e s u lt s C h e n Z . e t a l., 2 0 1 3 W h o le b ra in D iff e re n c e s in g ra y m a tt e r vo lu m e (G M V ) P O A G sh o w e d a si g n ific a n tly d e c re a se d G M V in th e lin g u a lg yr u s, c a lc a rin e g yr u s, p o st c e n tr a lg yr u s, su p e rio r fr o n ta lg yr u s, in fe rio r fr o n ta lg yr u s, a n d ro la n d ic o p e rc u lu m o f b o th si d e s, a n d in th e R in fe rio r o c c ip ita lg yr u s, L p a ra c e n tr a ll o b u le , R su p ra m a rg in a lg yr u s, a n d R c u n e u s. T h e G M V w a s si g n ific a n tly la rg e r in P O A G in b o th si d e s o f th e m id d le te m p o ra lg yr u s, in fe rio r p a rie ta lg yr u s, a n g u la r g yr u s, a n d L su p e rio r p a rie ta lg yr u s, L p re c u n e u s, a n d L m id d le o c c ip ita lg yr u s. F re zz o tt ie t a l., 2 0 1 4 W h o le b ra in D iff e re n c e s in g ra y m a tt e r vo lu m e P O A G p a tie n ts sh o w e d b ra in a tr o p h y in b o th vi su a lc o rt e x a n d o th e r d is ta n t G M re g io n s (f ro n to p a rie ta lc o rt e x, h ip p o c a m p ia n d c e re b e lla r c o rt e x) . F re zz o tt ie t a l., 2 0 1 6 W h o le b ra in D iff e re n c e s in g ra y m a tt e r vo lu m e N o d iff e re n c e s c o n si d e rin g w h o le P O A G . L o w e r G M vo lu m e in o c c ip ita lc o rt e x a n d h ip p o c a m p u s o n ly in a d va n c e d P O A G . G io rg io e t a l., 2 0 1 8 W h o le b ra in D iff e re n c e s in g ra y m a tt e r vo lu m e b e tw e e n h e a lth y, P O A G a n d N T G . B o th g ro u p s sh o w e d re d u c e d G M V in vi su a lc o rt e x a n d b e yo n d it. C o m p a re d w ith N T G , P O A G h a d m o re a tr o p h ic vi su a lc o rt e x. H e rn o w o e t a l., 2 0 1 1 R O I: o p tic n e rv e , o p tic c h ia sm , o p tic tr a c ts , la te ra l g e n ic u la te n u c le i( L G N ) a n d th e o p tic ra d ia tio n s V o lu m e o f R O Is a n d c o rr e la tio n w ith V F se n si tiv ity C o m p a re d w ith th e c o n tr o ls , su b je c ts w ith g la u c o m a sh o w e d re d u c e d vo lu m e o f a ll st ru c tu re s a lo n g th e vi su a lp a th w a y, in c lu d in g th e o p tic n e rv e s, th e o p tic c h ia sm , th e o p tic tr a c ts , th e L G N , a n d th e o p tic ra d ia tio n s. N o si g n ific a n t c o rr e la tio n b e tw e e n th e vo lu m e o f vi su a lp a th w a y a n d M D o f V F. Ji a n g e t a l., 2 0 1 7 W h o le b ra in D iff e re n c e s in g ra y m a tt e r vo lu m e . C o rr e la tio n w ith R N F L T h e re g io n s o f th e b ra in w ith in c re a se d vo lu m e s c o m p a re d w ith th e c o n tr o lg ro u p w e re th e m id b ra in , L b ra in st e m , fr o n ta lg yr u s, c e re b e lla r ve rm is , L in fe rio r p a rie ta l lo b u le , fr o n ta ll o b e , c a u d a te n u c le u s, th a la m u s, p re c u n e u s, a n d B A 7 , 1 8 , a n d 4 6 . L ie t a l., 2 0 1 2 W h o le b ra in D iff e re n c e s in g ra y m a tt e r vo lu m e C o m p a re d w ith c o n tr o ls , b ra in re g io n s w ith G M d e n si ty c h a n g e s w e re n o t fo u n d in th e e a rly st a g e b u t o n ly in th e a d va n c e d -l a te st a g e o f P O A G p a tie n ts . G M d e n si ty re d u c tio n w a s m a in ly lo c a te d in th e b ila te ra lp rim a ry vi su a lc o rt e x (B A 1 7 a n d B A 1 8 ), b ila te ra lp a ra c e n tr a ll o b u le (B A 5 ), R p re c e n tr a lg yr u s (B A 6 ), R m id d le fr o n ta lg yr u s (B A 9 ), R in fe rio r te m p o ra lg yr u s (B A 2 0 ), R a n g u la r g yr u s (B A 3 9 ), L p ra e c u n e u s (B A 7 ), L m id d le te m p o ra lg yr u s (B A 2 1 ), a n d su p e rio r te m p o ra lg yr u s (B A 2 2 ). In c re a se d G M d e n si ty w a s fo u n d in B A 3 9 . In th e a d va n c e d -l a te st a g e o f P O A G , so m e re d u c e d G M d e n si ty a re a s w e re re la te d to b in o c u la r m e a n d e fe c t (M D ) a n d d is e a se d u ra tio n . W a n g e t a l., 2 0 1 6 W h o le b ra in a n d R O I( L G N , V 1 , V 2 , a m yg d a la , h ip p o c a m p u s) G ra y m a tt e r vo lu m e . C o rr e la tio n w ith c lin ic a l p a ra m e te rs . S ig n ific a n t vo lu m e sh rin ka g e s in th e L G N b ila te ra lly , R V 1 , L a m yg d a la a n d n o d iff e re n c e in V 2 a n d h ip p o c a m p u s. C o rr e la tio n w ith c lin ic a lv a ria b le s. W ill ia m s e t a l., 2 0 1 3 9 3 b ra in st ru c tu re s D iff e re n c e s in g ra y m a tt e r vo lu m e 5 d iff e re d re g io n s d iff e r si g n ific a n tly b e tw e e n P O A G a n d h e a lth y: a ll w e re la rg e r in th e g la u c o m a g ro u p a n d w e re a ll c o m p o n e n ts o f th e vi su a la ss o c ia tio n c o rt e x. To ta lb ra in vo lu m e w a s a ls o la rg e r in th e g la u c o m a g ro u p . Z h a n g e t a l., 2 0 1 5 W h o le b ra in D iff e re n c e s in g ra y m a tt e r vo lu m e C o m p a re d to c o n tr o ls , a re g io n w ith si g n ific a n t re d u c tio n o f G M V w a s d e te c te d in th e a n te rio r c a lc a rin e fis su re o f a d va n c e d P O A G p a tie n ts b u t n o t in e a rly -m o d e ra te P O A G . Z ik o u e t a l., 2 0 1 2 W h o le b ra in D iff e re n c e s in g ra y m a tt e r vo lu m e In P O A G th e re w e re a si g n ific a n t re d u c tio n in th e L vi su a lc o rt e x vo lu m e , th e L la te ra l g e n ic u la te n u c le u s, a n d th e in tr a c ra n ia lp a rt o f th e O N s a n d th e c h ia sm a . (C o n ti n u e d )

T A B L E 2 | C o n tin u e d A u th o r, y e a r B ra in a re a a n a ly z e d P a ra me te r a n a ly z e d R e s u lt s S B M B o la c c h ie t a l., 2 0 1 2 W h o le b ra in c o rt e x C o rt ic a lt h ic kn e ss o n fla t m a p L o c a lt h in n in g in th e vi su a lc o rt e x a re a s in P O A G : 1 c lu st e r in B A 1 9 L H (li n g u la ), 2 c lu st e r in B A 1 9 R H (f u si fo rm g yr u s a n d c u n e u s) . W a n g e t a l., 2 0 1 6 V 1 a n d V 2 C o rt ic a lt h ic kn e ss . C o rr e la tio n w ith c lin ic a lp a ra m e te rs . T h e rig h t V 1 th ic kn e ss w a s si g n ific a n tly re d u c e d in g la u c o m a . C o rr e la tio n w ith c lin ic a l va ria b le s. Y u e t a l., 2 0 1 3 W h o le b ra in c o rt e x C o rt ic a lt h ic kn e ss . C o rr e la tio n w ith c lin ic a lp a ra m e te rs . P O A G p a tie n ts sh o w e d b ila te ra lc o rt ic a lt h in n in g in th e a n te rio r h a lf o f th e vi su a l c o rt e x a ro u n d th e c a lc a rin e su lc i( c a lc a rin e c o rt e x) in c lu d in g th e rig h t B A 1 7 a n d le ft B A 1 7 a n d B A 1 8 . S o m e sm a lle r re g io n s lo c a te d in th e le ft m id d le te m p o ra lg yr u s (B A 3 7 ) a n d th e fu si fo rm g yr u s (B A 1 9 ) a ls o sh o w e d th in n in g re la tiv e to n o rm a l c o n tr o ls . T h e th ic kn e ss o f th e V C c o rr e la te d p o si tiv e ly w ith R N F L th ic kn e ss . S ig n ific a n t d iff e re n c e s b e tw e e n m ild a n d se ve re g ro u p s w e re o b se rv e d . Y u e t a l., 2 0 1 4 R O Is : V 5 /M T + , a n te rio r a n d p o st e rio r su b re g io n s o f V 1 a n d V 2 C o rt ic a lt h ic kn e ss a n d vo lu m e in n o rm a l, m ild (M P ) a n d se ve re (S P ) P O A G p a tie n ts . C o rr e la tio n w ith c lin ic a l p a ra m e te rs D e c re a se d c o rt ic a lt h ic kn e ss in V 5 /M T + a re a in th e M P g ro u p a n d in a ll o f th e vi su a l a re a s e xc e p t th e p o st e rio r su b re g io n o f V 1 in th e S P g ro u p . G ra y m a tt e r vo lu m e in th e p o st e rio r su b re g io n o f V 2 a n d m e a n c u rv a tu re in th e V 5 /M T + w e re si g n ific a n tly c h a n g e d in th e S P g ro u p . T h e c lin ic a lm e a su re m e n ts w e re p o si tiv e ly c o rr e la te d w ith th e c o rt ic a lt h ic kn e ss . Y u e t a l., 2 0 1 5 R O Is : V 1 , V 2 , ve n tr a lV 3 , V 4 a n d V 5 /M T + C o rt ic a lt h ic kn e ss in n o rm a l, m ild (M P ) a n d se ve re (S P ) P O A G p a tie n ts . C o rr e la tio n w ith c lin ic a lp a ra m e te rs D e c re a se d c o rt ic a lt h ic kn e ss w a s d e te c te d in th e b ila te ra lV 5 /M T + a re a s in th e M P g ro u p a n d th e L V 1 , b ila te ra lV 2 a n d V 5 /M T + a re a s in th e S P g ro u p . C o rt ic a lt h in n in g o f th e b ila te ra lV 2 a re a s w a s d e te c te d in th e S P g ro u p c o m p a re d w ith th e M P g ro u p . C o rt ic a lt h in n in g o f th e se vi su a la re a s w a s re la te d to th e o p h th a lm o lo g ic m e a su re m e n ts . B A , B ro dm a n n A re a ; L H , L e ft H e m is ph e re ; R H , R igh t H e m is ph e re ; V O I, V ol u m e of in te re s t; O R , opti c a l ra di a ti on ; O T, opti c tr a c ts ; C D R , c u p-di s c ra ti o; R N F L , re ti n a l n e rv e fibe r la ye r; W M, w h ite m a tte r; G M, gr a y m a tte r; G MV , gr a y m a tte r vo lu m e ; MD , m e a n de vi a ti o n ; MT + , m iddl e te m por a lv is u a la re a .

Dependence on glaucoma severity of changes in white matter tissue studied with DTI was demonstrated. Glaucoma severity showed a negative correlation with FA, and a positive correlation with MD and RD values of white matter tracts involved in the visual process (Garaci et al., 2009; Nucci et al., 2012; Zhang et al., 2012; Chen Z. et al., 2013; Michelson et al., 2013; Wang et al., 2013; Omodaka et al., 2014; Sidek et al., 2014; Tellouck et al., 2016; Zhou et al., 2017a). Correlation was found between DTI parameters and RNFL, mean deviation of visual field, cup-to-disc ratio.

Significant gray matter reduction within the primary visual cortex emerged from many studies using VBM (Hernowo et al., 2011; Li et al., 2012; Zikou et al., 2012; Chen W. W. et al., 2013; Williams et al., 2013; Frezzotti et al., 2014, 2016; Zhang et al., 2015; Wang et al., 2016; Jiang et al., 2017; Giorgio et al., 2018). Specifically, a significant reduction was found only in the anterior part of occipital pole (Boucard et al., 2007) strengthen the idea of retinotopic damage. Other studies showed clusters of gray matter reduction in glaucoma patients in areas other than occipital pole, including the lingual gyrus, calcarine gyrus, postcentral gyrus, superior frontal gyrus, inferior frontal gyrus, rolandic operculum, cerebellar cortex, and hippocampi (Li et al., 2012; Chen W. W. et al., 2013; Frezzotti et al., 2014).

The extent of gray matter atrophy was dependent on the level of glaucoma severity (Li et al., 2012; Zhang et al., 2015; Wang et al., 2016). Indeed, Frezzotti et al found lower gray matter volume only in advanced POAG (Frezzotti et al., 2016).

Moreover, gray matter was increased in some brain areas (middle temporal gyrus, inferior parietal gyrus, angular gyrus, midbrain, brainstem, frontal gyrus, cerebellar vermis, thalamus) of glaucomatous patients (Li et al., 2012; Chen W. W. et al., 2013; Williams et al., 2013; Jiang et al., 2017). All these brain regions involved were associated with visual functions.

Alterations in visual cortex has been demonstrated also with SBM. In particular, the five studies using SBM demonstrated a thinning in the visual cortex of POAG (Bolacchi et al., 2012; Yu et al., 2013, 2014, 2015; Wang et al., 2016). Reduced cortex thickness was not limited to primary visual cortex, but also involved association visual areas, such as lingula, fusiform gyrus, cuneus, middle temporal gyrus (Bolacchi et al., 2012; Yu et al., 2013, 2014, 2015). Positive correlation was found between thinning of visual cortex and clinical measurements (Yu et al., 2013, 2014, 2015; Wang et al., 2016). Correlation with glaucoma severity was also demonstrated by significant differences of visual cortex thickness between mild and severe glaucoma groups, with increased damage in late-stage glaucoma (Yu et al., 2013).

Outcomes of Functional and Metabolic

Analysis

Studies reporting functional and metabolic activity in glaucomatous patients are reported in Table 3.

Functional activity resulted greatly reduced within primary visual cortex after visual input from the glaucomatous eye in all studies using fMRI both in POAG (Duncan et al., 2007a; Qing et al., 2010; El-Rafei et al., 2013; Lestak et al., 2014; Borges et al., 2015; Gerente et al., 2015; Murphy et al., 2016; Zhang et al., 2016; Jiang et al., 2017; Zhou et al., 2017b), NTG (El-Rafei et al., 2013;

Lestak et al., 2014; Zhang et al., 2016) and PACG patients (Song et al., 2012).

Resting state fMRI (Rs-fMRI) is a tool for studying the human brain functional connectivity in resting state, without visual stimulation (Biswal et al., 2010). Voxel-wise degree centrality (DC) represents the number of connections for a given voxel and it, thus, quantifies the ability for information integration. The decreased connectivity was found in areas related to vision and also in other networks related to working memory and attention in POAG patients (Dai et al., 2013; Frezzotti et al., 2014, 2016; Chen et al., 2017; Giorgio et al., 2018). Decreased functional connectivity even without visual tasking was also observed in the bilateral visual cortices of PACG patients (Boucard et al., 2016).

Metabolic neuronal dysfunction was studied through quantification of certain biochemical compounds with proton MRS in two studies. The main brain metabolites studied by MRS included N-acetylaspartate (NAA), Choline (Cho), and Creatine (Cr). NAA is localized within neurons and a decreased in NAA concentration is a sign of neuronal loss. Choline is a marker of membrane integrity, it decreases when a damage of neurons occurred. Creatinine, implied in energy metabolism, should remain constant throughout the brain even in neurodegenerative disease. Its concentration is used to calculate metabolic ratio such as NAA:Cr and Cho:Cr. Results of the two studies using MRS were contradictory, Boucard et al (Boucard et al., 2007) found no significant differences in the brain metabolites between the patients and the control group. On the contrary,Zhang et al. (2013), found decreased brain metabolites which are marker for neuronal integrity in geniculo-calcarine and striate area of occipital pole.

DISCUSSION

Studies of glaucomatous degeneration in the brain were initially based on experiments conducted on monkey who were induced glaucoma. The studies identified degeneration at the lateral geniculate nucleus (LGN) and primary visual cortex (V1) in response to increased IOP and optic nerve damage (Yücel et al., 2000, 2001). These results were supported by the same results in post-mortem human studies that reported a significant neurodegeneration in optic nerve, LGN and visual cortex in a glaucoma patient (Gupta et al., 2006). The advent of non-invasive brain imaging techniques has led to an increase in studies investigating the involvement of the brain in glaucoma pathology. The detection of brain neurodegeneration in glaucomatous subjects could open new future frontiers. As an example, innovative brain imaging methods have been proposed in the early detection of the disease and in the evaluation of therapeutic efficacy of novel neuroprotective strategies (Brown et al., 2016). This systematic review is aimed at bringing together different results deriving from other research regarding brain involvement in patients with glaucoma.

Integration of Structural and Functional

Results

Studying brain changes in glaucoma patients both structurally, functionally, and metabolically provides for more information.

T A B L E 3 | O u tc o m e s o f st u d ie s w ith fu n c tio n a la n d m e ta b o lic b ra in a n a ly si s. A u th o r, y e a r B ra in a re a a n a ly z e d P a ra me te r a n a ly z e d R e s u lt s fM R I B o rg e s e t a l., 2 0 1 5 V 1 a n d V 2 a re a s in b o th h e m is p h e re B O L D re sp o n se w ith in th e L P Z a n d a m a tc h e d a re a c o rr e sp o n d in g to h e a lth y re tin a (c o n tr o lR O I) S tim u lu s: c e n tr a lfil e d (1 6 ◦) d yn a m ic c h e c ke rb o a rd w ith h ig h a n d lo w c o n tr a st m o n o c u la rly p re se n te d R e d u c tio n o f a c tiv a tio n in th e L P Z c o m p a re d to c o n tr o lR O I fo r st im u lu s in g la u c o m a to u s e ye (o n ly fo r m e d iu m a n d h ig h c o n tr a st st im u li) in b o th V 1 a n d V 2 . N o d iff e re n c e s in th e fe llo w e ye re sp o n se s. D u n c a n e t a l., 2 0 0 7 a V is u a la re a s (V 1 , V 2 , V 3 ) B O L D re sp o n se s a ft e r st im u li a re p re se n te d in th e p e rip h e ry . D iff e re n t st im u li, a ll w ith c o n tr a st -r e ve rs in g c h e c kb o a rd p a tt e rn : e xp a n d in g rin g s, ro ta tin g w e d g e s, m e rid ia n -m a p p in g st im u lu s, 1 6 ◦ is o p te r, fu ll-fie ld c o n tr a st -r e ve rs in g c h e c kb o a rd . C o rr e la tio n w ith O N a ss e ss m e n t R e d u c e d a c tiv ity in V 1 . P a tt e rn o f d e te rio ra tio n o f B O L D a c tiv ity re fle c te d p a tt e rn o f d e te rio ra tio n o f o p tic d is c (e va lu a te d w ith th re e te c h n iq u e s: O C T, H R T, G D x) . E l-R a fe ie t a l., 2 0 1 3 V is u a la re a s (V 1 , V 2 , V 3 ) B O L D re sp o n se s a ft e r st im u li a re p re se n te d in th e p e rip h e ry . D iff e re n t st im u li, a ll w ith c o n tr a st -r e ve rs in g c h e c kb o a rd p a tt e rn : e xp a n d in g rin g s, ro ta tin g w e d g e s, m e rid ia n -m a p p in g st im u lu s, 1 6 ◦ is o p te r, fu ll-fie ld c o n tr a st -r e ve rs in g c h e c kb o a rd . C o rr e la tio n w ith vi su a lfil e d d e fe c t T h e sp a tia lp a tt e rn o f a c tiv ity o b se rv e d in V 1 a g re e d w ith th e p a tt e rn o f vi su a lfie ld lo ss . G e re n te e t a l., 2 0 1 5 O c c ip ita lp o le a n d c a lc a rin e R O Is B O L D re sp o n se s to b in o c u la r st im u li (p o la r a n g le st im u lu s c o n si st in g o f a ro ta tin g w e d g e ). A ss o c ia tio n w ith st ru c tu ra la n d fu n c tio n a lo c u la r fin d in g s. S ig n ific a n t a ss o c ia tio n s b e tw e e n b in o c u la r V F se n si tiv iti e s a n d R N F L th ic kn e ss w ith fM R Ir e sp o n se s in th e o c c ip ita lp o le a n d th e c a lc a rin e R O Is . Ji a n g e t a l., 2 0 1 7 W h o le b ra in B O L D re sp o n se s to 8 H z b la c k a n d w h ite c h e c kb o a rd c o n tr a st st im u li H ig h e r b ra in a c tiv a tio n in P O A G w a s p rim a ril y lo c a te d in th e R su p ra m a rg in a lg yr u s, fr o n ta lg yr u s, su p e rio r fr o n ta lg yr u s, L in fe rio r p a rie ta l lo b u le , L c u n e u s, L m id c in g u la te a re a a n d fr o n ta ll o b e . O n ly th e L c u n e u s n e g a tiv e ly c o rr e la te d w ith R N F L . R in fe rio r p a rie ta ll o b u le , m id d le fr o n ta l g yr u s, m id d le o c c ip ita lg yr u s, a n d in fe rio r te m p o ra lg yr u s sh o w e d p o si tiv e c o rr e la tio n s w ith R N F L . L e st a k e t a l., 2 0 1 4 V is u a lc o rt e x B O L D re sp o n se s to st im u li: b la c k/w h ite (B W ) a n d ye llo w /b lu e (Y B ) c h e c ke rb o a rd p a tt e rn T h e e xt e n t o f a c tiv a tio n d id n o t d iff e r st a tis tic a lly b e tw e e n g la u c o m a to u s (b o th P O A G a n d N T G ) a n d c o n tr o ls . T h e d iff e re n c e in th e m a g n itu d e o f a c tiv a tio n d u rin g th e B W a n d Y B st im u la tio n is m a rk e d ly h ig h e r in th e P O A G . N o d iff e re n c e s b e tw e e n B W a n d Y B in N T G a n d c o n tr o ls . M u rp h y e t a l., 2 0 1 6 V is u a lc o rt e x a n d h ig h e r-o rd e r vi su a lb ra in B O L D re sp o n se s to 8 H z F lic ke rin g st im u li R e d u c e d vi su a lc o rt e x a c tiv ity . T h e p rim a ry vi su a lc o rt e x a ls o e xh ib ite d m o re se ve re fu n c tio n a ld e fic its th a n h ig h e r-o rd e r vi su a lb ra in a re a s. T h e p rim a ry V C w a s re d u c e d b e fo re vi su a lfie ld lo ss . Q in g e t a l., 2 0 1 0 V is u a lc o rt e x B O L D re sp o n se s to 8 H z h e m ifie ld c h e c kb o a rd c o n tr a st st im u li T h e B O L D fM R Is ig n a lc h a n g e in th e p rim a ry vi su a lc o rt e x c o rr e sp o n d in g to c e n tr a lv is u a li n p u t fr o m th e m o re se ve re ly a ff e c te d e ye w a s le ss th a n th a t o f th e fe llo w e ye . S o n g e t a l., 2 0 1 2 P rim a ry a n d S e c o n d a ry vi su a l c o rt e x B O L D re sp o n se s to 8 H z fu ll-sc re e n b la c k a n d w h ite fli p c h e c kb o a rd st im u li. T h e e xt e n t a n d in te n si ty o f vi su a lc o rt e x a c tiv a tio n w a s d e c re a se d . In P A C G p a tie n ts . Z h a n g e t a l., 2 0 1 6 D iff e re n t la ye rs o f th e L G N , su p e rio r c o lli c u lu s (S C ), e a rly vi su a lc o rt ic e s (V 1 , V 2 a n d M T ) R e sp o n se s to M st im u lu s (lo w sp a tia lf re q u e n c y a t 3 0 % lu m in a n c e c o n tr a st , a t 1 0 H z) a n d P st im u lu s (h ig h sp a tia lf re q u e n c y, is o lu m in a n t re d /g re e n sq u a re w a ve p a tt e rn , re ve rs in g c o n tr a st a t 0 .5 H z) E a rly g la u c o m a p a tie n ts sh o w e d m o re re d u c tio n o f re sp o n se to tr a n si e n t a c h ro m a tic st im u li th a n to su st a in e d c h ro m a tic st im u li in th e m a g n o c e llu la r la ye rs o f th e L G N , a s w e ll a s in th e su p e rfic ia ll a ye r o f th e S C . M a g n o c e llu la r re sp o n se s in th e L G N w e re a ls o si g n ific a n tly c o rr e la te d w ith th e d e g re e o f b e h a vi o ra ld e fic its to th e g la u c o m a to u s e ye . E a rly g la u c o m a p a tie n ts sh o w e d n o re d u c tio n o f fM R Ir e sp o n se in th e e a rly vi su a lc o rt e x. (C o n ti n u e d )

T A B L E 3 | C o n tin u e d A u th o r, y e a r B ra in a re a a n a ly z e d P a ra me te r a n a ly z e d R e s u lt s Z h o u e t a l., 2 0 1 7 b R e tin o to p ic a re a s (V 1 , V 2 , V 3 ) C o rt ic a lm a g n ific a tio n fa c to rs a n d B O L D % c h a n g e s a s a fu n c tio n o f e c c e n tr ic ity . 2 vi su a ls tim u li: a se rie s o f ro ta tin g w e d g e s a n d a se rie s o f e xp a n d in g o r c o n tr a c tin g rin g s. C o rr e la tio n a n a ly si s b e tw e e n B O L D % c h a n g e s a n d vi su a lfie ld sc o re s, a n d b e tw e e n B O L D % c h a n g e s a n d R N F L th ic kn e ss e s B O L D c h a n g e s o f P O A G w e re re d u c e d c o m p a re d to n o rm a l. fM R I re tin o to p ic m a p p in g re ve a le d e n la rg e d re p re se n ta tio n o f th e p a ra fo ve a in th e vi su a lc o rt e x o f P O A G . rs -fM R I C a ie t a l., 2 0 1 5 S p o n ta n e o u s b ra in fu n c tio n a l c o n n e c tiv ity w ith in th e w h o le b ra in V o xe l-w is e d e g re e c e n tr a lit y (D C ) = d ire c t c o n n e c tio n s fo r a g iv e n vo xe li n th e vo xe l-w is e c o n n e c to m e b e fo re a n d 3 m o n th s a ft e r su rg e ry . C o rr e la tio n o f D C w ith c lin ic a lv a lu e s P A C G p re -s u rg e ry : d e c re a se d D C in b ila te ra lV C , in c re a se d D C in le ft A C C a n d c a u d a te . P A C G p o st -s u rg e ry : in c re a se d D C in b ila te ra lV C a n d L p re c e n tr a lg yr u s c o m p a re d to p re -s u rg e ry . N e g a tiv e c o rr e la tio n b e tw e e n D C in V C a n d IO P p re -s u rg e ry . C h e n e t a l., 2 0 1 7 S p o n ta n e o u s re g io n a lb ra in a c tiv ity in th e vi su a lc o rt e x In tr in si c fu n c tio n a ls p o n ta n e o u s n e u ro n a la c tiv ity th o u g h t re g io n a l h o m o g e n e ity (R e H o ). C o rr e la tio n w ith c lin ic a lm e a su re m e n ts C o m p a re d w ith c o n tr o ls , P A C G sh o w e d h ig h e r R e H o va lu e in th e L fu si fo rm g yr u s (B A 3 7 ), L c e re b e llu m a n te rio r lo b e , R fr o n ta l-te m p o ra ls p a c e (B A 4 8 ), a n d R in su la (B A 4 8 ), a n d lo w e r R e H o va lu e in th e b ila te ra lm id d le o c c ip ita l g yr u s (B A 1 8 ), L c la u st ru m , a n d R p a ra c e n tr a ll o b u le lo b e (B A 4 ). S ig n ific a n t c o rr e la tio n w ith d u ra tio n d is e a se , R N F L , C D R . D a ie t a l., 2 0 1 3 R O Is d e fin e d w ith in B ro d m a n n a re a s re la te d to vi si o n (B A 1 7 , B A 1 8 , B A 1 9 , B A 7 ) F u n c tio n a lc o n n e c tiv ity (F C ) b e tw e e n th e R O Is a n d o th e r b ra in a re a s D e c re a se d F C in th e P O A G g ro u p b e tw e e n B A 1 7 a n d R in fe rio r te m p o ra l, L fu si fo rm , L m id d le o c c ip ita l, R su p e rio r o c c ip ita l, L p o st c e n tr a l, R p re c e n tr a l g yr i, a n d a n te rio r lo b e o f th e le ft c e re b e llu m . In c re a se d F C w a s fo u n d b e tw e e n B A 1 7 a n d th e L c e re b e llu m , R m id d le c e re b e lla r p e d u n c le , R m id d le fr o n ta lg yr u s, a n d e xt ra -n u c le a r g yr u s. P o si tiv e F C w a s d is a p p e a re d b e tw e e n h ig h e r vi su a lc o rt ic e s (B A 1 8 /1 9 ) w ith th e c e re b e lla r ve rm is , R m id d le te m p o ra l, a n d R su p e rio r te m p o ra lg yr i. N e g a tiv e F C d is a p p e a re d b e tw e e n B A 1 8 /1 9 a n d th e R in su la r g yr u s F re zz o tt ie t a l., 2 0 1 4 S p o n ta n e o u s b ra in fu n c tio n a l c o n n e c tiv ity w ith in th e w h o le b ra in F u n c tio n a lc o n n e c tiv ity (F C ) a c ro ss 8 d e fin e d re st in g st a te n e tw o rk s (R S N s) : vi su a l, a u d ito ry , se n so rim o to r, d e fa u lt m o d e , w o rk in g m e m o ry (r ig h t a n d le ft ), d o rs a la tt e n tio n a n d e xe c u tiv e n e tw o rk s. D e c re a se d F C in vi su a l, w o rk in g m e m o ry a n d d o rs a la tt e n tio n n e tw o rk s a n d in c re a se d F C in vi su a la n d e xe c u tiv e n e tw o rk s. F re zz o tt ie t a l., 2 0 1 6 S p o n ta n e o u s b ra in fu n c tio n a l c o n n e c tiv ity w ith in th e w h o le b ra in F u n c tio n a lc o n n e c tiv ity (F C ) a c ro ss 1 3 d e fin e d re st in g st a te n e tw o rk s (R S N s) : vi su a l( V N ), a u d ito ry , se n so rim o to r, d e fa u lt m o d e (D M N , a n te rio r a n d p o st e rio r) , w o rk in g m e m o ry (W M N , rig h t a n d le ft ), fr o n to -m e d ia la n d o rb ito fr o n ta l, e xe c u tiv e c o n tr o l, sa lie n c e , su b c o rt ic a l( S c N ), te m p o ra lp o le n e tw o rk s P O A G p a tie n ts h a d lo w e r F C in th e V N a n d in th e W M N , h ig h e r F C in th e D M N a n d in th e S c N . T h e se a b n o rm a lit ie s w e re a lre a d y p re se n t in th e su b g ro u p o f p a tie n ts w ith st a g e 1 . G io rg io e t a l., 2 0 1 8 S p o n ta n e o u s b ra in fu n c tio n a l c o n n e c tiv ity w ith in th e w h o le b ra in F u n c tio n a lc o n n e c tiv ity (F C ) a c ro ss 1 2 d e fin e d re st in g st a te n e tw o rk s (R S N s) : d e fa u lt m o d e , fr o n ta le xe c u tiv e c o n tr o l( E C N , m e d ia l, a n d m e d io -l a te ra l), rig h t a n d le ft fr o n to p a rie ta lw o rk in g m e m o ry , d o rs a la tt e n tio n , a u d ito ry /l a n g u a g e ve n tr a la tt e n tio n (V A N ), vi su a l( V N , p rim a ry , a n d se c o n d a ry ), m e d ia lt e m p o ra l( lim b ic ) a n d c e re b e lla r n e tw o rk s F C w a s a lte re d in N T G a t sh o rt -r a n g e le ve l[ vi su a ln e tw o rk (V N ), ve n tr a l a tt e n tio n n e tw o rk ] a n d in P O A G a t lo n g -r a n g e le ve l( b e tw e e n se c o n d a ry V N a n d lim b ic n e tw o rk ). F C o f P O A G w a s h ig h e r th a n N T G in b o th V N a n d e xe c u tiv e n e tw o rk . H u a n g e t a l., 2 0 1 5 S p o n ta n e o u s b ra in fu n c tio n a l c o n n e c tiv ity w ith in th e w h o le b ra in A m p lit u d e o f lo w -f re q u e n c y flu c tu a tio n (A L F F ), a n in d e x to d e te c t sp o n ta n e o u s n e u ro n a la c tiv ity C o m p a re d w ith h e a lth y, P A C G p a tie n ts h a d si g n ific a n tly lo w e r A L F F a re a s in th e le ft p re c e n tr a lg yr u s, b ila te ra lm id d le fr o n ta lg yr u s, b ila te ra ls u p e rio r fr o n ta lg yr u s, rig h t p re c u n e u s, a n d rig h t a n g u la r g yr u s, a n d h ig h e r A L F F a re a in th e rig h t p re c e n tr a lg yr u s. T h e re w e re si g n ific a n t n e g a tiv e c o rr e la tio n s b e tw e e n th e m e a n A L F F si g n a lv a lu e o f th e m id d le fr o n ta lg yr u s a n d th e c o n tr a la te ra lm e a n R N F L th ic kn e ss . (C o n ti n u e d )

T A B L E 3 | C o n tin u e d A u th o r, y e a r B ra in a re a a n a ly z e d P a ra me te r a n a ly z e d R e s u lt s L ie t a l., 2 0 1 4 S p o n ta n e o u s b ra in fu n c tio n a l c o n n e c tiv ity w ith in th e w h o le b ra in A L F F. C o rr e la tio n b e tw e e n A L F F a n d th e d is e a se st a g e C o m p a re d w ith c o n tr o ls , P O A G p a tie n ts sh o w e d si g n ific a n tly d e c re a se d A L F F in th e vi su a lc o rt ic e s, p o st e rio r re g io n s o f th e d e fa u lt-m o d e n e tw o rk (D M N ), a n d m o to r a n d se n so ry c o rt ic e s. A L F F va lu e s w e re in c re a se d in th e p re fr o n ta lc o rt e x, L su p e rio r te m p o ra lg yr u s (S T G ), R m id d le c in g u la te c o rt e x (M C C ), a n d L in fe rio r p a rie ta ll o b u le (IP L ). S e ve rit y d is e a se st a g e c o rr e la te d w ith A L F F o f so m e a re a s (L c u n e u s, b ila te ra lM T G a n d R p re fr o n ta lc o rt e x) . L ie t a l., 2 0 1 7 In tr in si c fu n c tio n a lc o n n e c tiv ity (iF C ) in th e c e n te rs o f th e V 1 S e e d -b a se d iF C a n a ly si s b e fo re a n d 3 m o n th s a ft e r th e su rg e ry . C o rr e la tio n b e tw e e n iF C a n d c lin ic a lv a ria b le s (d is e a se d u ra tio n , IO P, R N F LT , C D R , V A ) P re -P A C G : c o m p a re d to h e a lth y, d e c re a se d iF C b e tw e e n L V 1 a n d R V 2 (c o ve rin g th e c u n e u s, c a lc a rin e a n d lin g u a lg yr u s) a n d in c re a se d iF C b e tw e e n L V 1 a n d L te m p o ra l-p a rie ta l, L a n d R fr o n ta lo p e rc u la -i n su la -b a sa l g a n g lia re g io n , a n d R in fe rio r p a rie ta ll o b u le . P o s t-P A C G : in c re a se d iF C b e tw e e n th e L V 1 a n d b ila te ra lV 2 , a n d b e tw e e n th e L V 1 a n d L o r R p o st c e n tr a lg yr u s; d e c re a se d iF C b e tw e e n th e L V 1 a n d th e d o rs a l-a tt e n tio n a n d fr o n to p a rie ta lc o n tr o ln e tw o rk s. C o rr e la tio n b e tw e e n iF C a n d V A S o n g e t a l., 2 0 1 4 S p o n ta n e o u s re g io n a lb ra in a c tiv ity in th e vi su a lc o rt e x In tr in si c fu n c tio n a ls p o n ta n e o u s n e u ro n a la c tiv ity th o u g h t re g io n a l h o m o g e n e ity (R e H o ). C o rr e la tio n w ith c lin ic a lp a ra m e te rs C o m p a re d to c o n tr o ls , P O A G sh o w e d in c re a se d R e H o in th e R d o rs a l a n te rio r c in g u la te d c o rt e x, th e b ila te ra lm e d ia lf ro n ta l g yr u s a n d th e R c e re b e lla r a n te rio r lo b e , a n d d e c re a se d R e H o in th e b ila te ra lc a lc a rin e , p re c u n e u s g ry u s, p re /p o st c e n tr a lg yr u s, L in fe rio r p a rie ta l lo b u le a n d L c e re b e llu m p o st e rio r lo b e . C h a n g e s in sp o n ta n e o u s a c tiv ity a re a ss o c ia te d w ith c lin ic a lp a ra m e te rs . W a n g e t a l., 2 0 1 6 a F u n c tio n a lc o m m u n ic a tio n o f a n a to m ic a lly se p a ra te d st ru c tu re s. N e tw o rk a n a ly si s a t b o th g lo b a la n d lo c a ll e ve ls N o si g n ific a n t d iff e re n c e s o f th e g lo b a ln e tw o rk m e a su re s w e re fo u n d b e tw e e n th e tw o g ro u p s. H o w e ve r, th e lo c a lm e a su re s w e re ra d ic a lly re o rg a n iz e d in g la u c o m a p a tie n ts . W a n g e t a l., 2 0 1 6 b F u n c tio n a lc o n n e c tiv ity A lte ra tio n s o f fu n c tio n a lc o n n e c tiv ity (F C ) a n d c o n n e c tio n s w ith in a n d b e tw e e n th e su b n e tw o rk s o f th e vi su a ln e tw o rk a n d th e d e fa u lt m o d e n e tw o rk (D M N ) in g la u c o m a F C a n a ly si s sh o w e d th a t th e F C in th e o c c ip ita lp o le o f th e vi su a ln e tw o rk w a s d e c re a se d in P O A G p a tie n ts w h ile n o a lte ra tio n s w e re fo u n d in th e F C o f th e D M N in p a tie n ts . M R S B o u c a rd e t a l., 2 0 0 7 O c c ip ita lp o le in b o th h e m is p h e re C o n c e n tr a tio n s o f th e 0 m e ta b o lit e s N -a c e ty la sp a rt a te (N A A ), C re a tin e (C r) a n d C h o lin e (C h o ) N o si g n ific a n t d iff e re n c e s fo r a n y m e ta b o lit e s c o n c e n tr a tio n b e tw e e n g la u c o m a , a g e -r e la te d m a c u la r d e g e n e ra tio n a n d h e a lth y g ro u p s. Z h a n g e t a l., 2 0 1 3 G e n ic u lo -c a lc a rin e a n d th e st ria te a re a o f o c c ip ita ll o b e R a tio o f N -a c e ty la sp a rt a te (N A A )/C re a tin e (C r) , C h o lin e (C h o )/C r, g lu ta m in e a n d g lu ta m a te (G lx )/C r S ig n ific a n t d e c re a se s in N A A /C r a n d C h o /C r b u t n o d iff e re n c e in G lx /C r w a s fo u n d in g la u c o m a c o m p a re d to h e a lth y su b je c ts in b o th th e G C T a n d th e st ria te a re a . B O L D , bl o o d o xy g e n a ti o n le ve l-de pe n de n t; L P Z, le s ion pr oj e c ti o n zon e ; R O I, re gi on of in te re s t; V C , vi s u a lc or te x; A C C , a n te ri or c in gu la te c or te x; L , le ft; R , ri gh t; O N , opti c n e rv e .