| Revised: 11 April 2018 | Accepted: 20 April 2018

DOI: 10.1002/brb3.1010

ORIGINAL RESEARCH

Altered white matter connectivity associated with visual
hallucinations following occipital stroke
Sara A. Rafique1

| John R. Richards2 | Jennifer K. E. Steeves1

1
Department of Psychology, Centre for
Vision Research, York University, Toronto,
ON, Canada
2

Department of Emergency
Medicine, University of California, Davis,
Medical Center, Sacramento, California
Correspondence
Jennifer Steeves, 1032 Sherman Health
Science Research Centre, York University,
4700 Keele St., Toronto, ON M3J 1P3,
Canada.
Email :[email-masked]
Funding information
Natural Sciences and Engineering Research
Council of Canada, Grant/Award Number:
327588; Canada Foundation for Innovation,
Grant/Award Number: 12807

Abstract
Introduction: Visual hallucinations that arise following vision loss stem from aberrant
functional activity in visual cortices and an imbalance of activity across associated
cortical and subcortical networks subsequent to visual pathway damage. We sought
to determine if structural changes in white matter connectivity play a role in cases of
chronic visual hallucinations associated with visual cortical damage.
Methods: We performed diffusion tensor imaging (DTI) and probabilistic fiber tractography to assess white matter connectivity in a patient suffering from continuous
and disruptive phosphene (simple) visual hallucinations for more than 2 years following right occipital stroke. We compared these data to that of healthy age-matched
controls.
Results: Probabilistic tractography to reconstruct white matter tracts suggests regeneration of terminal fibers of the ipsilesional optic radiations in the patient.
However, arrangement of the converse reconstruction of these tracts, which were
seeded from the ipsilesional visual cortex to the intrahemispheric lateral geniculate
body, remained disrupted. We further observed compromised structural characteristics, and changes in diffusion (measured using diffusion tensor indices) of white matter tracts in the patient connecting the visual cortex with frontal and temporal
regions, and also in interhemispheric connectivity between visual cortices.
Conclusions: Cortical remapping and the disruption of communication between visual cortices and remote regions are consistent with our previous functional magnetic
resonance imaging (fMRI) data showing imbalanced functional activity of the same
regions in this patient (Rafique et al, 2016, Neurology, 87, 1493–1500). Long-term
adaptive and disruptive changes in white matter connectivity may account for the
rare nature of cases presenting with chronic and continuous visual hallucinations.
KEYWORDS

diffusion tensor imaging, magnetic resonance imaging, stroke, vision loss, visual
hallucinations, white matter

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.
Brain and Behavior. 2018;8:e01010.
https://doi.org/10.1002/brb3.1010

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1 | I NTRO D U C TI O N

RAFIQUE et al.

suppress the hallucinations with rTMS would in part, if not wholly,
be due to white matter connectivity changes. There are presently no

Visual hallucinations can occur as a secondary consequence of vision

cases in the literature that have investigated white matter in cases of

loss in individuals who are otherwise cognitively healthy. The type of

visual hallucinations following visual pathway damage.

hallucinatory image is related to the site of damage along the visual pathway, and/or the visual processing function of the implicated region(s).
Lesions of the optic radiations, calcarine, and early visual cortices can

2 | M E TH O DS

result in simple (phosphene) hallucinations, whereas involvement of
higher visual processing areas is associated with complex visual halluci-

The study was approved by York University’s Office of Research

nations (ffytche, 2008; Vaphiades, Celesia, & Brigell, 1996).

Ethics. All individuals gave informed written consent.

Previous functional magnetic resonance imaging (fMRI) studies
have shown visual hallucinations following visual pathway damage are
associated with disorganized functional activity in visual cortices across

2.1 | Patient and control participants

both hemispheres, and in interconnected cortical and subcortical net-

In brief, we evaluated a 31-year-old female experiencing persistent

works (ffytche et al., 1998; Rafique, Richards, & Steeves, 2016). We

and disruptive phosphene visual hallucinations within an incom-

sought to determine if structural changes in white matter connectivity

plete congruous left homonymous hemianopia following right suba-

are also present in cases of chronic visual hallucinations following visual

cute occipital stroke. At the time of initial investigation, occipital

pathway damage. Diffusion tensor imaging (DTI) and probabilistic fiber

ischemia (Figure 1a) and calcarine artery vasospasm were observed.

tractography enable noninvasive investigation of white matter struc-

Electroencephalogram (EEG) recordings were normal, ruling out an

ture. DTI quantifies the diffusion of water in white matter tracts, which

epileptic origin for the visual hallucinations. We assessed the patient

is influenced by underlying microstructure and orientation of axonal

2.5 years following stroke and onset of phosphene hallucinations, at

fibers, and provides information about their integrity. Water diffusion

which time the calcarine artery vasospasm and ischemia had resolved.

can be characterized by diffusion tensor indices: fractional anisotropy

The phosphene hallucinations consisted of moving and vibrating

(FA; directionality of diffusion parallel to fiber tracts), mean diffusivity

white/gray images resembling shattered glass, small-medium mostly

(MD; directionally averaged measure of diffusion), axial diffusivity (AD;

circular lights, and occasional lightning bolts and irregular zigzag lines.

measure of diffusion parallel to axonal fibers), and radial diffusivity (RD;

The patient history is described in more detail in our previous study

measure of diffusion perpendicular to axonal fibers). Fiber tracking al-

(Rafique et al., 2016).

gorithms use directions of greatest diffusion to estimate white matter
fiber orientation (Ciccarelli, Catani, Johansen-Berg, Clark, & Thompson,

Seven

age-matched

female

control

participants

(mean

age = 29 years) with no history of neurological disorders, and nor-

2008). Probabilistic fiber tractography employs Bayesian modeling to

mal or corrected-to-normal vision (>0.2 logMAR) were recruited.

infer these fiber directions and generate three-dimensional depictions

All participants were right-handed with no known contraindications

of white matter tracts (Behrens et al., 2003).
We investigated a patient experiencing chronic and continuous

to MRI. All participants had taken part in a previous fMRI study
(Rafique et al., 2016).

phosphene visual hallucinations following occipital stroke. In a previous study, the patient underwent fMRI and therapeutic treatment
with repetitive transcranial magnetic stimulation (rTMS) to the lesion
site to provide relief from hallucinations that were interfering with

2.2 | Magnetic resonance imaging acquisition
Imaging was acquired with a 3-Tesla Siemens Magnetom® Tim

quality of life. fMRI showed aberrant functional activity in visual corti-

Trio magnetic resonance scanner and a Siemens 32 channel high-

ces, and an imbalance of activity across frontal, parietal, temporal, and

resolution brain array coil (Siemens, Erlanger, Germany). Whole-

cerebellar regions prior to rTMS treatment (Rafique et al., 2016). In this

brain diffusion-weighted scanning, T1-weighted, and T2-weighted

study, we investigated whether the previously documented aberrant

turbo spin echo fluid-attenuated inversion recovery (FLAIR) imaging

functional activity and persistent nature of hallucinations in the pa-

sequences were obtained. Full details on MRI acquisition are pro-

tient (Rafique et al., 2016) were a reflection of compromised structural

vided in Supporting Information.

characteristics of white matter connectivity. We used DTI and probabilistic tractography to examine white matter connectivity between
cortical regions implicated in our previous fMRI study. Moreover, in

2.3 | Data analyses

our previous fMRI study, we observed some restoration of functional

All DTI analyses were performed using FSL’s DTI processing pipeline

activity in the patient following treatment with rTMS. However, this

(FMRIB, Oxford, UK; www.fmrib.ox.ac.uk/fsl).

redistribution of functional activity in the patient did not completely
match that of controls; and despite a significant reduction in intensity
of visual hallucination with rTMS treatment, the hallucinations per-

2.3.1 | Image processing and normalization

sisted, albeit to a lesser extent (Rafique et al., 2016). We further ex-

Diffusion images underwent preprocessing. T1-weighted and dif-

pected that this incomplete functional restoration and failure to fully

fusion images were registered to standard MNI space (MNI152

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RAFIQUE et al.

F I G U R E 1 MR images for the patient. (a) T2-weighted image shows right occipital ischemia at the time of stroke. (b) Diffusion tensor
image of a color-coded FA map for the patient. Reduced anisotropy is observed at the lesion site (yellow box), with disruption in diffusivity at
the right (R) inferior longitudinal fasciculus (ILF)/inferior fronto-occipital fasciculus (IFOF), which merge with the optic radiations (OR). Red
represents fibers crossing left to right, green represents fibers in the posterior-anterior direction, and blue represents fibers in the inferior-
superior direction. Average MNI coordinates of lesion site: x = 15, y = −68, z = 5. FA: fractional anisotropy
1 × 1 × 1 mm). Full details on image processing and normalization to

intrahemispheric tracts seeded from the visual cortex (including pri-

standard space are provided in Supporting Information.

mary and association cortices, i.e., Brodmann areas 17, 18, 19), to
an end point in subregions of frontal lobe gyri (superior, middle, and

2.3.2 | Diffusion tensor indices

inferior), temporal lobe gyri (superior and middle temporo-occipital),
parietal lobules (superior and inferior), and precentral and postcentral

The diffusion tensor indices FA, MD, AD, and RD were extracted from

gyri, independently. In addition, we reconstructed the optic radiations

eleven major white matter tracts of John Hopkins University (JHU)

using a seed at the lateral geniculate body ending at the primary visual

White-Matter Tractography Atlas (Wakana et al., 2007) for each par-

cortex. A converse reconstruction of these intrahemispheric tracts was

ticipant using Tract-Based Spatial Statistics (TBSS; Smith et al., 2006).

performed using a seed at the primary visual cortex ending at the lat-

Diffusion tensor indices were extracted from the following bilateral

eral geniculate body as these are shown to differ from feedforward

tracts: anterior thalamic radiations, corticospinal tracts, cingulum

connections (Shipp, 2007; Sillito, Cudeiro, & Jones, 2006). Tracts were

(cingulate gyrus and hippocampus), inferior fronto-occipital fasciculi,

reconstructed for all participants and both hemispheres. We further

inferior longitudinal fasciculi, superior longitudinal fasciculi, tempo-

investigated interhemispheric visual cortex connectivity by generat-

ral aspects of superior longitudinal fasciculi, and uncinate fasciculi.

ing tracts between visual cortices in both directions, that is, tracts

Diffusion tensor indices were also extracted from the forceps major

seeded from the right visual cortex ending in the left visual cortex,

and minor. Full details on obtaining diffusion tensor indices from white

and vice versa. Reference to seed and end points does not imply tract

matter tracts are provided in Supporting Information. The extracted

directionality, but strictly refers to the generation of tracts from every

diffusion tensor indices underwent statistical analyses to compare the

point in the seed to only enter and terminate at the target end point.

patient with controls using the modified independent one-tailed t test

Probabilistic tractography was determined in standard MNI space.

for single case studies (Crawford & Garthwaite, 2002). We report sig-

Tracts were visually inspected for changes in size and orientation com-

nificant differences in diffusion tensor indices (Table 1) at p < 0.05, and

pared with the contralateral hemisphere, and comparing the patient

trending significance at p < 0.1.

with controls. Complete details on reconstructing probabilistic fiber
tractography are provided in Supporting Information.

2.3.3 | Probabilistic fiber tractography
Our main interests were tracts connected with the visual cortex (primary and association cortices), consistent with the location of the
patient’s lesion site. Tracts of interest were generated to cortical re-

3 | R E S U LT S
3.1 | Diffusion tensor indices

gions of interest based on our previous fMRI findings, which showed

A color-coded FA map for the patient indicating the lesion site is

functional differences in blood oxygen level-dependent (BOLD) sig-

shown in Figure 1b. Table 1 contains values for diffusion tensor

nal between the patient (prior to rTMS, consistent with visual system

indices obtained from the major white matter tracts and demon-

status at time of DTI acquisition) and controls (Rafique et al., 2016).

strates significant differences in diffusivity between the patient and

Probabilistic tractography was therefore employed to reconstruct

controls.

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TA B L E 1

RAFIQUE et al.

Diffusion tensor indices for major white matter tracts
MD (×10 −3)

FA

White matter
tracts

Controls

R ATR

0.508 ± 0.020

0.501

0.692 ± 0.017

L ATR

0.513 ± 0.014

0.484

0.695 ± 0.020

Patient

Controls

AD (×10 −3)
Patient

RD (×10 −3)

Controls

Patient

Controls

Patient

0.693

1.102 ± 0.020

0.689

1.108 ± 0.035

1.099

0.487 ± 0.020

0.490

1.073

0.489 ± 0.016

0.497

R cCG

0.574 ± 0.035

0.625

0.671 ± 0.029

0.676

1.136 ± 0.055

1.221

0.438 ± 0.035

0.403

L cCG

0.607 ± 0.031

0.628

0.689 ± 0.026

0.688

1.221 ± 0.063

1.247

0.424 ± 0.029

0.409

R cH

0.588 ± 0.063

0.551

0.558 ± 0.058

0.637

0.928 ± 0.079

1.049

0.373 ± 0.061

0.432

L cH

0.588 ± 0.052

0.546

0.594 ± 0.051

0.593

1.014 ± 0.073

0.971

0.384 ± 0.054

0.404

R CT

0.626 ± 0.014

0.608

0.664 ± 0.018

0.670

1.197 ± 0.030

1.179

0.397 ± 0.018

0.415

L CT

0.633 ± 0.012

0.612

0.663 ± 0.022

0.673

1.202 ± 0.047

1.195

0.387 ± 0.009

0.412

FMa

0.685 ± 0.022

0.675

0.718 ± 0.019

0.726

1.423 ± 0.025

1.410

0.366 ± 0.027

0.383

FMi

0.570 ± 0.024

0.564

0.718 ± 0.019

0.729

1.249 ± 0.023

1.261

0.452 ± 0.025

0.463

R IFOF

0.562 ± 0.030

0.530

0.726 ± 0.019

0.751

1.236 ± 0.020

1.240

0.471 ± 0.032

0.506

L IFOF

0.561 ± 0.022

0.548

0.750 ± 0.017

0.735

1.280 ± 0.018

1.240

0.486 ± 0.023

0.482

R ILF

0.562 ± 0.028

0.517

0.724 ± 0.017

0.737

1.229 ± 0.023

1.240

0.471 ± 0.027

0.509

L ILF

0.549 ± 0.020

0.555

0.748 ± 0.019

0.727

1.265 ± 0.023

1.240

0.490 ± 0.023

0.471

R SLF

0.535 ± 0.019

0.497

0.686 ± 0.020

0.689

1.118 ± 0.027

1.080

0.468 ± 0.018

0.494

L SLF

0.516 ± 0.013

0.490

0.716 ± 0.017

0.714

1.146 ± 0.017

1.108

0.501 ± 0.020

0.518

R tSLF

0.586 ± 0.025

0.539

0.672 ± 0.021

0.683

1.149 ± 0.031

1.116

0.433 ± 0.026

0.467

L tSLF

0.557 ± 0.017

0.532

0.716 ± 0.017

0.719

1.193 ± 0.016

1.159

0.478 ± 0.021

0.499

R UF

0.518 ± 0.036

0.498

0.736 ± 0.027

0.734

1.206 ± 0.044

1.165

0.502 ± 0.037

0.519

L UF

0.514 ± 0.029

0.487

0.736 ± 0.018

0.730

1.192 ± 0.029

1.172

0.507 ± 0.027

0.508

Notes. AD: axial diffusivity; ATR: anterior thalamic radiation; cCG: cingulum (cingulate gyrus); cH: cingulum (hippocampus); CT: corticospinal tract; FA,
fractional anisotropy; FMa: forceps major; FMi: forceps minor; IFOF: inferior fronto-occipital fasciculus; ILF: inferior longitudinal fasciculus; L: left; MD:
mean diffusivity; R: right; RD: radial diffusivity; SLF: superior longitudinal fasciculus; tSLF: temporal aspect of superior longitudinal fasciculus; UF: uncinate fasciculus.
The columns list (from left to right) the major white matter tracts and their associated diffusion tensor indices for controls and the patient. Data are
presented as mean (±SD) control and single patient values.
Arrows indicate significant increase/decrease in patient’s diffusion tensor index relative to controls (black arrows represent p < 0.1; red arrows represent p < 0.05).

3.2 | Probabilistic fiber tractography

Reconstruction of the optic radiations in the patient shows a
marked displacement of ipsilesional optic radiations relative to the

Reconstruction of intrahemispheric tracts seeded from the visual

contralesional hemisphere and controls. The terminal fibers of the

cortex to the inferior frontal gyrus showed an increase in tracts for

patient’s ipsilesional optic radiations are seen to deviate anterior to

the patient within the ipsilesional visual cortex compared with the

the lesion site (Figure 4).

contralesional hemisphere and controls (Figure 2a). Similar to that,

Altered interhemispheric communication between visual

for intrahemispheric tracts seeded from the ipsilesional visual cortex

cortices is observed in the patient. Tracts seeded from the

to the precentral gyrus, the patient showed increased tracts close to

ipsilesional visual cortex fail to terminate in the contralesional

the precentral gyrus relative to the contralesional hemisphere and

visual cortex, and instead discontinue at the midline. However,

controls (Figure 2b).

the converse is spared as tracts seeded from the contralesional

Probabilistic tractography for the patient further showed in-

visual cortex continue past the midline and terminate in the ip-

complete intrahemispheric tracts seeded from the ipsilesional visual

silesional visual cortex (Figure 5). In comparison, control partic-

cortex to superior temporal and middle temporo-occipital gyri, and

ipants demonstrated overlapping interhemispheric connections

the lateral geniculate body, compared with the contralesional hemi-

(Figure 5).

sphere and controls (Figure 3a–c, respectively). This is observed

Given that directionality cannot be inferred from probabilistic

from the absence of intrahemispheric tracts within the ipsilesional

tractography, it is important to note that tracts seeded from the lat-

visual cortex in the patient; instead, the tracts originate further an-

eral geniculate body to the visual cortex are intermingled with and

teriorly, closer to anterior temporo-occipital regions.

cannot be differentiated from the converse reconstruction of these

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RAFIQUE et al.

F I G U R E 2 Probabilistic fiber
tractography for intrahemispheric tracts
seeded from the visual cortex to (a)
inferior frontal gyrus (white mask), and
(b) precentral gyrus (lime green mask).
Only one control example is presented
here, all other controls are presented in
Supporting Information Figures S1–S2,
respectively. See Figure 5 for an example
of the visual cortex mask (red mask). L:
left (contralesional in the patient); R: right
(ipsilesional in the patient)
tracts (i.e., seeded from the visual cortex to the lateral geniculate

4 | D I S CU S S I O N

body) using this method. The same applies to interhemispheric visual
cortex tracts.

Diffusion imaging highlights changes in diffusion indices of major

For ease of comparison of probabilistic fiber tractography

white matter tracts associated with the patient’s lesion site com-

between the patient and controls, we only present data of one

pared with controls. These differences are consistent with regions

control example here. The results of probabilistic tractography

previously implicated in visual hallucinations. Moreover, probabilis-

for all other controls are presented in Supporting Information

tic fiber tractography demonstrates changes in white matter tracts

Figures S1–S7. Despite interindividual variation in tracts, the pa-

between the visual cortex and remote regions in the patient that are

tient consistently showed these differences compared with all

consistent with previously observed alterations in functional activa-

control participants.

tion between the patient and controls.

No differences were observed between the patient and controls for intrahemispheric tracts seeded from the visual cortex to superior and middle frontal gyri, and postcentral gyrus.
Probabilistic tractography did not reveal tracts from the visual

4.1 | White matter changes with occipital
stroke and associated vision loss

cortex to the middle temporal gyrus or parietal lobules in the pa-

In the patient, we observed incomplete intrahemispheric tracts

tient or controls.

from the ipsilesional visual cortex to superior temporal and middle

F I G U R E 3 Probabilistic fiber tractography for intrahemispheric tracts seeded from the visual cortex to (a) superior temporal gyrus
(yellow mask), (b) middle temporo-occipital gyrus (peach mask), and (c) lateral geniculate body (pink mask). Only one control example is
presented here, all other controls are presented in Supporting Information Figures S3–S5. See Figure 5 for an example of the visual cortex
mask (red mask). L: left (contralesional in the patient); R: right (ipsilesional in the patient)

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RAFIQUE et al.

primary regions contributing to the perception of visual hallucinations (Rafique et al., 2016).
Changes in FA and/or AD of the superior (including temporal aspects) and inferior longitudinal fasciculi in the patient (Table 1) are
therefore not surprising given the disruption to diffusivity at the stroke
site (Figure 1), and consequent changes in tractography between regions concerned with these fasciculi (Figures 2–3). Altered FA suggests
changes to white matter microstructure (Jones, Simmons, Williams, &
Horsfield, 1999) indicative of change in aspects of connectivity (Jones,
Knösche, & Turner, 2013). AD measures are considered variable in
white matter changes and pathology; however, a decrease is observed
in axonal injury/damage (Song et al., 2002). Despite involvement of
intrahemispheric ipsilesional tracts in the patient (Figures 2a and 3b–
c) implicating the ipsilesional inferior fronto-occipital fasciculus, the
F I G U R E 4 Probabilistic fiber tractography of the optic
radiations. Tracts were seeded from the lateral geniculate body to
the visual cortex (red mask). Only one control example is presented
here, all other controls are presented in Supporting Information
Figure S6. See Figure 3c for an example of the lateral geniculate
body mask (pink mask). L: left (contralesional in the patient); R: right
(ipsilesional in the patient)

contralesional inferior fronto-occipital fasciculus showed significantly
lower AD (Table 1). A possible explanation for contralesional inferior
fronto-occipital fasciculus involvement may be from sharing of axons
implicated with the lesion site.
Alterations in interhemispheric white matter connectivity between visual cortices in the patient (Figure 5) offer further explanation to the disorganized and imbalanced functional activity in visual
processing regions previously observed across both hemispheres,

temporo-o ccipital gyri (Figure 3a–b, respectively). This finding

for example, greater functional activity in the contralesional hemi-

is consistent with observed differences in functional activation

sphere (Rafique et al., 2016).

within these regions between the patient and controls during a
basic visual task (Rafique et al., 2016). Although there was only
an increase in intrahemispheric tracts from the ipsilesional visual
cortex to the inferior frontal gyrus (Figure 2a), the patient has
shown significantly greater functional activation in bilateral in-

4.2 | Compensatory white matter changes with
occipital stroke and associated vision loss
The marked displacement of the ipsilesional optic radiations in the

ferior frontal gyri compared with controls (Rafique et al., 2016).

patient (Figure 4) suggests recovery of function with new connec-

These regions are connected via major white matter tracts, the

tions via recruitment of peri-infarct regions that adapt to new roles

superior longitudinal and inferior fronto-o ccipital fasciculi. The

after stroke (Carmichael, 2003; Cramer, 2008). Damage to the

superior longitudinal fasciculus connects frontal, parietal, tempo-

optic radiation pathway is consistent with the presence of hemia-

ral, and occipital lobes (Catani, Howard, Pajevic, & Jones, 2002),

nopia visual field loss in the patient (Rafique et al., 2016). However,

while the inferior fronto-o ccipital fasciculus connects the frontal

we do not see this recovery in the converse reconstruction of

lobe with posterior aspects of parietal, temporal, and occipital

these tracts (seeded from the visual cortex to the lateral geniculate

lobes (Martino, Brogna, Robles, Vergani, & Duffau, 2010). The in-

body) in the patient (Figure 3c). It is quite notable that, the loca-

ferior fronto-o ccipital fasciculus further passes through the lateral

tion of terminal fibers of the ipsilesional optic radiations is consist-

geniculate body and claustrum (Kier, Staib, Davis, & Bronen, 2004).

ent with the location of disorganized functional activity anterior

Not only did the patient show incomplete tracts from the ipsile-

to the patient’s lesion at the lingual gyrus (Rafique et al., 2016).

sional visual cortex to the intrahemispheric lateral geniculate body

In this patient, it appears that input from the retina to ipsilesional

(Figure 3c), our previous fMRI findings implicate the ipsilesional

visual cortex via reorganization of optic radiations produces sus-

claustrum in the genesis of visual hallucinations in this patient

tained sensory responses in new structural circuits in peri-infarct

(Rafique et al., 2016). The inferior longitudinal fasciculus connects

regions; and this aberrant neuronal firing produces the perception

anterior temporal and posterior occipito-temporal regions of the

of phosphene hallucinations in the area of hemianopic visual field

occipital lobe, including visual association areas, fusiform, and

loss. Indeed, in vivo cortical recordings of mice show an effect of

parahippocampal gyri (Catani, Jones, & Donato, 2003; Wakana,

prolonged depolarization at remapped peri-infarct regions and in

Jiang, Nagae-Poetscher, Van Zijl, & Mori, 2004). Given that the le-

regions with greater connectivity poststroke (Brown, Aminoltejari,

sion site involved right visual association areas (Figure 1; Rafique

Erb, Winship, & Murphy, 2009). A DTI study in an infant with peri-

et al., 2016), we expect the right inferior longitudinal fasciculus to

natal temporo-parieto-occipital stroke shows the same pattern of

be compromised (Figure 1; Table 1). The visual association areas

regeneration of ipsilesional optic radiations (Seghier et al., 2005)

(e.g., lingual gyrus and cuneus) showed the most obvious altera-

as our patient. In both cases, the location of terminal fibers of

tions in functional activity in our patient and were considered the

the regenerated optic radiations is consistent with the location of

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F I G U R E 5 Probabilistic fiber tractography of interhemispheric connections between visual cortices. In the patient, tracts seeded
from the ipsilesional (R) hemisphere (light green tracts) do not cross the midline to terminate in the contralesional (L) hemisphere, while
contralesional to ipsilesional (dark green tracts) interhemispheric tracts do. In controls, tracts seeded from the right visual cortex (dark blue
tracts) do cross the midline to connect with the left visual cortex, and vice versa (blue tracts), resulting in overlapping interhemispheric
connections (light blue and pink tracts). Only one control example is presented here, all other controls are presented in Supporting
Information Figure S7. L: left (contralesional in the patient); R: right (ipsilesional in the patient)

disorganized ipsilesional functional activity. Moreover, ipsilesional

tracts. Early lesions studies of the occipital lobe in animals show

functional activation in the infant was localized anterior to the le-

retinotopic reorganization and changes of neuronal response prop-

sion at the lingual gyrus in the same manner as our patient. No

erties in the ipsilesional hemisphere, and aberrant distribution of

follow-up was reported in the infant past 20 months of age; there-

callosal connections in both ipsi-and contralesional hemispheres

fore, we cannot ascertain whether visual hallucinations manifested

(Payne & Lomber, 2001; Restrepo, Manger, Spenger, & Innocenti,

in the infant.

2003). Changes in contralesional tracts (Figure 2) may occur to com-

Lower FA and increased RD were observed in the contrale-

pensate for changes in ipsilesional tracts, or from pruning that oc-

sional corticospinal tract of the patient (Table 1). An increase in RD

curs from loss of interhemispheric communication following stroke

suggests white matter pathology (Song et al., 2002) in this motor

(Grefkes et al., 2008). Increased ipsilesional tracts in the patient

pathway. Although motor deficits were not a consequence of

(Figure 2a) suggest recruitment of redundant/association neurons.

stroke in our patient, corticospinal tract plasticity following early

Global overconnectivity is observed in patients with hemianopia

vision loss is thought to arise from overcoming difficulty with eye-

following occipital stroke, with greater node strength in ipsilesional

hand coordination from loss of vision (Yu et al., 2007). Many cor-

temporal and orbitofrontal areas as well as the contralesional visual

ticospinal neurons originate in the precentral gyrus (Dum & Strick,

association cortex (Guo, Jin, Feng, & Tong, 2014).

1991), and accordingly, we observed an increase in tracts from the
ipsilesional visual cortex to the intrahemispheric precentral gyrus
(Figure 2b). These combined findings may compensate for the
need for increased left eye-hand coordination following left hom-

4.3 | White matter changes associated with
persistent visual hallucinations

onymous hemianopia visual field loss in the patient (Rafique et al.,

Reduced FA of the contralesional anterior thalamic radiation in the

2016). Consistent with these structural white matter changes,

patient (Table 1), which connects the anterior and dorsomedial tha-

subtraction analysis of fMRI responses during a basic visual task

lamic nuclei with the prefrontal cortex (Wakana et al., 2004), sug-

between the patient and controls has shown greater patient ac-

gests changes to white matter microstructure and connectivity of

tivation in the ipsilesional (right) precentral gyrus, while controls

this tract (Jones et al., 1999, 2013). Thalamic degeneration is pre-

showed greater activation in the left precentral gyrus (Rafique

viously implicated in visual hallucinations (Manford & Andermann,

et al., 2016).

1998), consistent with its involvement in this patient.

Changes in white matter tracts in the patient at both ipsi-and

The inferior longitudinal and inferior fronto-occipital fasciculi are

contralesional hemispheres stem from altered intra-and interhemi-

involved in visual perception (ffytche, 2008) and visual processing

spheric communication, for example, major forceps, or commissural

(Fox, Iaria, & Barton, 2008). As in our patient, visual hallucinations

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RAFIQUE et al.

have been linked to lower FA in the inferior longitudinal fasciculus

show clear disturbance to white matter tracts in regions that are

in individuals with schizophrenia (Ashtari et al., 2007), and demen-

far from the cyst (e.g., Figure 2a). Our tractography findings in the

tia with Lewy bodies (Kantarci et al., 2010), suggesting an associ-

patient may also be influenced by diffusion properties of the le-

ation of visual hallucinations with temporo-
occipital projections.

sion, for example, diffusion values within the lesion may be out-

Furthermore, frontal lesions can produce visual hallucinations in the

side of probabilistic tractography thresholds. A greater number of

temporal and occipital lobes thought to arise through the spread

streamlines (tracts) can occur in probabilistic tractography in cases

of increased activity from one area to another (Schneider, Crosby,

of Wallerian degeneration, where intact pathways with higher

Bagchi, & Calhoun, 1961). Consistent with this notion, direct elec-

anisotropy will show a greater number of streamlines than the

trical stimulation of the inferior frontal gyrus evokes visual halluci-

damaged pathways (Jones, 2010). However, the probabilistic trac-

nations of faces considered to originate from activity propagated

tography approaches used in this study (multifiber and a priori re-

in the prefrontal cortex along white matter pathways to face pro-

gions of interest) are shown to track reliably (Behrens, Berg, Jbabdi,

cessing regions (Vignal, Chauvel, & Halgren, 2000), for example, via

Rushworth, & Woolrich, 2007; Dyrby et al., 2007), are fairly accu-

the inferior longitudinal fasciculus. In addition to frontal stimulation,

rate in cases of crossing fibers, and can track through areas of low

stimulation of the temporal lobe (Lee, Hong, Seo, Tae, & Hong, 2000;

FA (Jones, 2010) such as degeneration of microstructure following

Penfield & Perot, 1963) and visual cortices (Lee et al., 2000) also

stroke and in artefacts (Behrens et al., 2003; Jones, Travis, Eden,

evokes visual hallucinations. This suggests that it is not simply an in-

Pierpaoli, & Basser, 2005). As we are unable to acquire longitudinal

crease and/or disorganization of activity in visual associated cortices

data, we can only speculate as to the nature of the tracts with re-

that produce visual hallucinations (ffytche et al., 1998; Rafique et al.,

spect to regeneration. Further, changes in diffusion tensor indices

2016), but rather the additional involvement of these white matter

in our patient cannot simply be interpreted as compromised micro-

tracts (and accordingly specific networks) that differentiates these

structure of white matter, for example, specific to axonal changes

patients from those with similar disorders who do not experience

or neurodegeneration. Interpretation of diffusion indices is uncer-

visual hallucinations.

tain when other factors such as glial cells or crossing fibers of similar density may contribute to water diffusion (Jbabdi, Behrens, &

4.4 | Limitations
Given the single case study approach of the present research, we

Smith, 2010). We can be more certain that axonal loss has occurred
from known Wallerian degeneration in stroke, and accordingly the
degeneration of neurons.

appreciate that the data may be insufficient to generalize spe-

Although we are cognizant that this is a single case study and

cific plasticity effects following occipital stroke associated with

acknowledge that this case report using DTI is speculative, we

chronic visual hallucinations. In addition, due to the number of

have attempted to constrain the methods to the best of our abil-

independent t tests, and the less conservative threshold of trend-

ity by comparing to an age-matched control group, as well as intra-

ing results (p < 0.1), some differences in diffusion tensor indices

individual tracts, and previous fMRI data to strengthen the validity

between the patient and controls (Table 1) may reflect statisti-

of the current findings.

cal noise. Further diffusion imaging studies in patients with visual
pathway damage who perceive visual hallucinations and those
who do not are necessary in order to isolate factors predispos-

5 | CO N C LU S I O N

ing individuals to visual hallucinations. To our knowledge, other
than the case of perinatal stroke (Seghier et al., 2005), there are

In short, our results point toward interruption of specific white

no other studies reported in the literature investigating white

matter tracts (networks) and cortical remapping as the root of

matter structure in visual pathway damage with or without visual

disorganized functional activity in the patient that leads to the

hallucinations. Knowledge of white matter structure is pivotal in

continued perception of visual hallucinations. Cortical reorganiza-

elucidating underlying mechanisms of brain function associated

tion may offer explanation for the chronic and persistent nature

with chronic and disruptive visual hallucinations in these patients.

of the hallucinations in this patient, differentiating this case from

Evaluation of white matter connectivity in other leading causes of

the more common reports of acute visual hallucinations (Manford

vision loss associated with visual hallucinations (e.g., age-r elated

& Andermann, 1998; Vaphiades et al., 1996). Diffusion imaging

macular degeneration) is also needed to confirm or refute our hy-

and fiber tractography combined with fMRI in future studies will

potheses implicating specific structural networks and remapping

provide a more accurate visualization of plasticity following visual

with visual hallucinations.

pathway damage associated with visual hallucinations in order to

The patient presents with a benign subarachnoid cyst at the
occipital pole. The cyst impinges on deeper occipital and cerebel-

ascertain treatment modalities directed at improving functional
outcome.

lar structures, and its location is sufficiently far removed that we
would not expect it to directly affect the reconstruction of white
matter tracts in this study. Therefore, the cyst would not account
for the atypical anatomy of these tracts. Our results continue to

AC K N OW L E D G M E N T S
We would like to thank all participants for their contribution.

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RAFIQUE et al.

C O N FL I C T O F I N T E R E S T S
None declared.

ORCID
Sara A. Rafique

http://orcid.org/0000-0003-3636-4001

Jennifer K. E. Steeves

http://orcid.org/0000-0002-7487-4646

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S U P P O R T I N G I N FO R M AT I O N
Additional supporting information may be found online in the
Supporting Information section at the end of the article.

How to cite this article: Rafique SA, Richards JR, Steeves
JKE. Altered white matter connectivity associated with visual
hallucinations following occipital stroke. Brain Behav.
2018;8:e01010. https://doi.org/10.1002/brb3.1010