RESEARCH ARTICLE

Reversible Functional ConnectivityDisturbances during Transient Global

Amnesia

Michael Peer, MSc,1,2 Mor Nitzan, MSc,2,3 Ilan Goldberg, MD, PhD,1,2

Judith Katz,1 J. Moshe Gomori, MD,4 Tamir Ben-Hur, MD, PhD,1,2 and

Shahar Arzy, MD, PhD1,2

Objective: Transient global amnesia (TGA), an abrupt occurrence of severe anterograde episodic amnesia accompanied byrepetitive questioning, has been known for more than 50 years. Despite extensive research, there is no clear evidence forthe underlying pathophysiological basis of TGA. Moreover, there is no neuroimaging method to evaluate TGA in real time.Methods: Here we used resting-state functional magnetic resonance imaging recorded in 12 patients during the acutephase of TGA together with connectivity and cluster analyses to detect changes in the episodic memory network in TGA.Results: Our results show a significant reduction in functional connectivity of the episodic memory network duringTGA, which is more pronounced in the hyperacute phase than in the postacute phase. This disturbance is bilateral,and reversible after recovery. Although the hippocampus and its connections are significantly impaired, other partsof the episodic memory network are also impaired. Similar results were obtained for the analysis of the episodicmemory network whether it was defined in a data-driven or literature-based manner.Interpretation: These results suggest that TGA is related to a functional disturbance in the episodic memory net-work, and supply a neuroimaging correlate of TGA during the acute phase.

ANN NEUROL 2014;75:634–643

Transient global amnesia (TGA) is among the most

enigmatic phenomena in neurology. TGA is defined

as “a syndrome characterized by the rapid onset of

antero- and retrograde amnesia, accompanied by tempo-

ral disorientation and iterative questioning that lasts up

to 24 hours.”1 During the attack, patients are alert and

communicative, and personal identity is preserved.2 Neu-

ropsychologically, TGA is characterized by severe antero-

grade amnesia for episodic memory, but not semantic,

procedural, or recognition memory.1,3,4 Retrograde

amnesia is characterized by a temporal gradient, as older

memories are more easily retrieved than newer ones, over

a span that might reach several decades.2,3 TGA is char-

acterized by a short hyperacute phase (usually 1–8 hours)

in which memory is significantly impaired, disorientation

is very severe, and iterative questioning is a hallmark, fol-

lowed by a postacute phase of gradual recovery of orien-

tation and memory, which mostly lasts up to 24

hours.5,6 Despite hundreds of published cases, and exten-

sive neurological, neuropsychological, and neuroimaging

studies, the etiology of TGA remains unclear. Moreover,

TGA diagnosis during the acute phase is based solely on

clinical evaluation. Previous neuroimaging studies using

positron emission tomography (PET) in TGA patients

reported abnormalities in the hippocampus, amygdala,

lentiform nucleus, and prefrontal cortex,7–9 but also in

various other regions,1,6 making these studies difficult to

interpret.6 Two single-case studies using task-related func-

tional magnetic resonance imaging (fMRI) identified

reversible reduced activity in a network of temporolimbic

brain regions.10,11 In recent years, more and more studies

based on diffusion-weighted imaging (DWI) MRI

View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.24137

Received Oct 7, 2013, and in revised form Mar 6, 2014. Accepted for publication Mar 7, 2014.

Address correspondence to Dr Arzy, Neuropsychiatry Lab, Department of Neurology, Faculty of Medicine, Hadassah Hebrew University Medical School,

Jerusalem, Israel. E-mail: shahar.arzy@ekmd.huji.ac.il

From the 1Department of Neurology, Hadassah Hebrew University Medical School, Jerusalem, Israel; 2Faculty of Medicine, Hadassah Hebrew University

Medical School, Jerusalem, Israel; 3Racah Institute of Physics, Hebrew University of Jerusalem, Jerusalem, Israel; and 4Department of Radiology,

Hadassah Hebrew University Medical Center, Jerusalem, Israel.

634 VC 2014 American Neurological Association

protocols have pointed to hippocampal lesions, confined

to the CA1 part of the hippocampus, that correlate with

TGA.12–15 Such lesions were detected in 70% of TGA

patients, yet they were found bilaterally in only 12% of

patients, although bilateral lesions are assumed to be

needed to cause memory impairment as severe as in

TGA.13,16 Interestingly, lesions mostly develop over 24

to 48 hours after TGA onset, while patients are clinically

intact (but not during the acute memory impairment),

and disappear several weeks later.13,14

Based on the significant clinical manifestation of

TGA, we hypothesized that TGA should be detected at

least functionally during the attack, and more promi-

nently in the hyperacute phase. Moreover, we hypothe-

sized that this disturbance might affect not only the

hippocampus but also other parts of the episodic memory

network bilaterally. To test these hypotheses, we scanned

patients with TGA on their arrival to the emergency

room, using structural MRI and resting-state functional

MRI (RSfMRI). RSfMRI has proven to be a useful

method in the investigation of lesional and nonlesional

clinical neurological disorders.17–19 RSfMRI was per-

formed in patients in the hyperacute or postacute phase

of the disorder and after recovery, and in age-matched

healthy control subjects. Episodic memory networks were

defined in 2 ways: by identification of a subnetwork that

is highly functionally connected to the hippocampus in

separate control groups (“data-driven”), and based on a

meta-analysis of episodic memory studies (“literature-

based”). In addition, voxel-based morphometry (VBM)

was used to detect structural changes.

Patients and Methods

PatientsTwelve patients (age 5 62.7 6 7.4 years; 5 male) who presented

with TGA in the hyperacute or postacute phase were included in

the study (Table 1). All patients met the standard clinical criteria

for diagnosis of TGA2,6: anterograde amnesia witnessed by an

observer with resolution of symptoms within 24 hours, cognitive

impairment limited to amnesia with no clouding of conscious-

ness or loss of personal identity, and no focal neurological or epi-

leptic signs or a recent history of head trauma or seizures.

Physical neurological examination, computed tomography scan

of the brain, and electroencephalogram results were within nor-

mal limits. Neuropsychological evaluation did not reveal any

other deficits. None of the patients had a history of psychiatric

or neurological illness, except for 2 patients who had previous

episodes of TGA (see Table 1). All patients underwent RSfMRI

scan less than 14 hours after the amnestic onset. Five patients

were scanned during the hyperacute phase, and another 7 were

in the postacute phase at scan time (they no longer exhibited

temporal disorientation or repetitive questioning, but still dis-

played memory deficits).5 Five of the patients (4 hyperacute, 1

postacute) have kindly agreed to undergo a second RSfMRI scan

2 to 9 months after the TGA episode (postrecovery group). In

addition, 17 age-matched healthy volunteers (age 5 62.1 6 6.9

years; 8 male) were scanned as a control group. Volunteers had

no personal history of neurologic or psychiatric disorders, and

had normal structural MRI results. All participants gave written

informed consent, and the study was approved by the ethical

committee of the Hadassah Hebrew University Medical Center.

MRI Acquisition ProceduresPatients and healthy control subjects were scanned at the same

site using a Trio 3T system with a 32-channel head coil (Sie-

mens Medical Solutions, Erlangen, Germany) using the same

imaging sequence. Blood oxygen level–dependent (BOLD)

fMRI was performed using a whole brain, gradient-echo echo

planar imaging (EPI) sequence of 160 volumes (repetition

time/echo time 5 2,000/30 milliseconds; flip angle 5 900�; field

of view 5 192 3 192mm; matrix 5 64 3 64; 33 axial slices;

slice thickness/gap 5 4/0mm; voxel size 5 3 3 3 3 4mm). All

subjects were instructed to stay awake, keep their eyes open,

and remain still. In addition, high-resolution (1 3 1 3 1mm)

T1-weighted anatomical images were acquired to aid spatial

normalization to standard atlas space. All patients and healthy

control subjects were also scanned using a DWI protocol to

ensure the lack of past or current ischemic episodes, and in

search of potential hippocampal lesions.

fMRI PreprocessingPreprocessing was conducted using SPM8 (www.fil.ion.ucl.ac.

uk/spm), DPARSF,20 and MATLAB (MathWorks, Natick, MA)

software. The first 5 volumes were discarded to ensure magnet-

ization equilibrium. All functional time-series were slice-time–

corrected, and motion-corrected to the mean functional image

using a trilinear interpolation with 6 degrees of freedom, core-

gistered with the anatomical image, normalized to standard ana-

tomical space (Montreal Neurological Institute EPI template,

resampling to 3mm cubic voxels), and spatially smoothed

(4mm full-width half-maximum [FWHM], isotropic). Addi-

tional preprocessing steps included the removal of linear trends

to correct for signal drift and filtering with a 0.01 to 0.15Hz

band-pass filter to reduce non-neuronal contributions to BOLD

fluctuations. In line with recent concerns regarding the effect of

subjects’ motion on functional connectivity characteristics,21–23

we performed multiple regression of 24 motion parameters24: 6

rigid-body head motion parameter values—x, y, and z transla-

tions and rotations—their value at the previous time point, and

the 12 corresponding squared values. In addition, motion

“spikes” were also included as regressors (identified by framew-

ise displacement of 0.5mm), in addition to global mean, white

matter, and cerebrospinal fluid signals.25 The percent of motion

spikes was matched between experimental groups by addition

of arbitrary spike regressors at random time points.

Extraction of Regionwise Resting-State TimeSeriesTo measure functional connectivity we first defined a whole

brain network using the Automatic Anatomical Labeling (AAL)

Peer et al: Functional Connectivity in TGA

May 2014 635

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ANNALS of Neurology

636 Volume 75, No. 5

atlas, which defines 45 brain regions in each cerebral hemi-

sphere.26 To ensure that voxels in each region were indeed a

part of the cerebral cortex, we used the new-segment algorithm

of SPM8, which identifies different tissue types on the T1 ana-

tomical image of each subject, and used the resulting gray mat-

ter image to create a mask of the gray matter (gray matter

segmentation intensity> 0.01). We used this mask to ensure

that only gray matter voxels were used for averaging each

region. To avoid using voxels that are affected by signal drop-

out,27 we fitted a Gaussian model to the voxel intensity graph

across the image and used a threshold of a 5 0.01 to create a

mask including only high-intensity voxels and excluding voxels

with low functional signal. Fitting was performed on images

before the smoothing, filtering, and covariates regression steps,

which change the image intensity (average goodness of fit

[adjusted R2] 2 0.8). Regions containing <10 voxels after

masking were removed from further analyses. The BOLD signal

was averaged across each region resulting in a time series of the

average activity within each region. To construct a whole brain

functional connectivity network we computed the Pearson cor-

relation coefficient between each pair of functional regions in

the atlas, resulting in a 90 3 90 functional connectivity matrix.

Fisher r-to-z transform was applied on the correlation values to

improve normality in statistical tests.

Identification of the Episodic Memory NetworkNetworks of brain regions involved in episodic memory were

identified using 2 different strategies:

1. Data-driven: In view of the central role of the hippo-

campus in episodic memory,28 we used the hippo-

campi as seeds and identified regions that showed

significant functional correlation with the hippocampi

(Fig 1A). To this aim, we randomly chose 8 control

subjects and measured the functional connectivity

between their left and right hippocampi and each of

the remaining AAL brain areas (178 connections

overall). On each of these connectivity values, a Stu-

dent t test (false discovery rate–corrected) was per-

formed across subjects to identify significant

correlation values. The 8 control subjects were

excluded from further analyses to avoid bias resulting

from their use in network definition. This process

was repeated 10 times (repeated random cross-valida-

tion) and averaged to obtain the final results. The

data-driven network includes areas that appeared

more than once in the different runs.

2. Literature-based: We used a meta-analysis of 24 func-

tional imaging studies29 to outline cerebral structures

involved in episodic memory. The authors used the

effect–location method to identify a “core” network

of regions involved in episodic memory processing

(see Fig 1B). This network was partially similar

(65%) to the data-driven network (see Fig 1).

We used the resulting networks to create functional con-

nectivity submatrices from the whole brain connectivity matrix

(31 3 31 and 17 3 17 matrices, respectively). The correlation

values were averaged across each submatrix to obtain a single

value for each subject, representing overall connectivity between

regions of the episodic memory network. Linear regression

across all subjects was performed with each subject’s average

absolute movement score (across the 6 motion parameters) as a

coregressor, to further remove the contribution of subjects’

motion to the functional connectivity values (rotation scores

were converted from degrees to millimeters by calculating dis-

placement on the surface of a sphere of radius 50mm21).

Mann–Whitney U tests (1-tailed) were performed on the con-

nectivity values across the experimental groups (hyperacute,

postacute, postrecovery, healthy control subjects) to identify sig-

nificant connectivity disturbances (comparison of test–retest in

the same patients was conducted using a Wilcoxon signed rank

test). Hemispheric laterality effect was computed using a 2-way

analysis of variance using experimental group and hemisphere

as factors. Networks were visualized using BrainNet Viewer

(www.nitrc.org/projects/bnv).

For further control, the analysis was also run on 2 other

brain networks, defined using the data-driven procedure: lan-

guage network (seed in the left angular gyrus) and motor net-

work (seeds in the precentral gyri). In addition, a subset of

regions comprising the amygdala, medial prefrontal, and ante-

rior and posterior cingulate cortex were used as a “stress-

related” network,30–33 to control for potential emotional effects.

To test for effects of other parameters on the data, Pearson cor-

relation was computed between functional connectivity values

and patient age, sex, TGA duration, time orientation score,

level of retrograde amnesia, TGA duration, time of MRI scan

from onset and end of TGA, and a multiple regression using

all of these parameters.

Clustering AnalysisTo identify subcomponents within the episodic memory net-

work and their inter-relations during TGA, regions within each

network were clustered using a hierarchical clustering algorithm

implemented in the MATLAB Statistics Toolbox (MathWorks).

The data were clustered using the Euclidean distance metric

with a complete linkage algorithm (furthest distance). Separate

clusters were identified according to 70% of maximal linkage.

The average connectivity within each cluster was computed by

averaging correlation values of each pair of regions within the

cluster, and intercluster connectivity was calculated as the aver-

age of all correlation values between pairs in different clusters.

Differences between groups were computed using Mann–Whit-

ney U tests.

Anatomical VBM AnalysisT1 images were spatially normalized and segmented into differ-

ent tissues using SPM8 (www.fil.ion.ucl.ac.uk/spm). Gray mat-

ter images were smoothed using a Gaussian kernel

(FWHM 5 8mm). The gray matter density of each patient was

compared in a voxel-based manner with the gray matter density

Peer et al: Functional Connectivity in TGA

May 2014 637

in the healthy control subjects group, using a random effects

analysis.34 In addition, gray matter intensity of TGA patients

was compared with their postrecovery scans using paired sample

t tests (p< 0.05, familywise error–corrected). This analysis was

applied on masks of: (1) whole brain, (2) data-driven episodic

memory network, (3) literature-based episodic memory

FIGURE 1: Episodic memory networks are identified according to (A) significant functional connectivity to the hippocampus inhealthy control subjects (data-driven) and (B) a meta-analysis of 24 functional imaging studies of episodic memory (literature-based). The centers of the identified regions in both hemispheres are presented on the Montreal Neurological Institute (MNI)template, along with the significant connections between them. Region sizes correspond to the average connectivity to therest of the network. Color coding corresponds to clustering analysis (frontocingulate: purple; medial temporal: turquoise; deepstructures: yellow; medial occipital: blue; inferior temporal: red; triangular frontal: orange). The Table (right) details the regionsincluded in each network. Sixty-five percent of the regions in the literature-based method also appear in the data-driven net-work. AAL 5 Automatic Anatomical Labeling; L 5 left; R 5 right; TGA 5 transient global amnesia.

ANNALS of Neurology

638 Volume 75, No. 5

network, and (4) hippocampal–parahippocampal regions only

(using a mask derived from the AAL atlas26).

Results

Functional Connectivity is Disturbed BilaterallyDuring TGA, in the Hyperacute Phase MoreThan in the Postacute PhaseFunctional connectivity within the episodic memory net-

work was computed for each participant by averaging all

connectivity values between regions in the network. These

connectivity values were compared among the 4 different

experimental groups (hyperacute, postacute, postrecovery,

healthy control subjects). In the data-driven network, sig-

nificant differences were found between hyperacute TGA

patients and healthy control subjects and between posta-

cute TGA patients and healthy control subjects

(p 5 0.003, 0.04, respectively; Fig 2). Similar results were

also found in the literature-based network: statistical anal-

yses showed a significant difference between patients in

the hyperacute phase and healthy control subjects

(p 5 0.006) and a difference between postacute TGA

patients and healthy control subjects, which was close to

significance (p 5 0.07). Pairwise comparison of initial

scans versus postrecovery scans for the 5 patients who

agreed to undergo such scans (4 patients in the hyper-

acute phase and 1 in the postacute phase) showed a

decrease in connectivity values during TGA, which was

significant in the literature-based network (p 5 0.03) and

close to significance in the data-driven network

(p 5 0.07). Postrecovery scans were not significantly dif-

ferent from scans of healthy control subjects (p> 0.3).

This disturbance was found in both hemispheres and sta-

tistical analysis did not reveal any difference between right

and left hemispheres (all p values, >0.2). These connec-

tivity differences were specific to the episodic memory

network, as no significant differences were found between

groups in other functional networks (motor, language,

p 5 0.33, 0.16, respectively), and in a network comprised

of stress-related regions (p 5 0.31).30–33

Distribution of Functional ConnectivityDisturbance of the Episodic Memory Networkin TGATo further investigate the connectivity disturbance in

TGA and its specificity to hippocampal connections, we

used a hierarchical clustering analysis of the healthy con-

trol subjects, which divides the episodic memory network

into clustered subnetworks based on their connectivity

FIGURE 2: Network connectivity. Average connectivity in the episodic memory network is shown for each experimental group.Analysis was performed separately in the (A) data-driven and the (B) literature-based networks. Note the similarity of resultsbetween the 2 networks. This effect was not apparent in (C) the language network, (D) the motor network, or (E) in stress-related regions. The post-recovery group includes patients from the hyper- and postacute groups, who were scanned severalmonths after recovery from transient global amnesia (TGA).

Peer et al: Functional Connectivity in TGA

May 2014 639

pattern, in a data-driven fashion. The clustering assign-

ments were similar across the 4 experimental groups in

the data-driven and literature-based networks, revealing 5

major clusters: orbitofrontal cingulate, medial temporal,

deep structures, inferior temporal, and occipital (Fig 3A;

in the literature-based network an additional cluster of

inferior frontal triangular gyri was found, which is anti-

correlated to the rest of the network).

Comparison of intercluster connectivity in control

subjects and in TGA patients (hyper- and postacute com-

bined) revealed significant connectivity disturbances

between the medial temporal cluster and other clusters,

but also between parts of the network that do not involve

the hippocampus (see Fig 3B). In addition to intercluster

connectivity disturbances, significant disturbances were

also apparent within the medial temporal, frontocingulate,

medial occipital, inferior temporal, and deep-structures

clusters (all p values <0.05). These findings point to a

functional connectivity disturbance in TGA that affects

large parts of the episodic memory network.

Correlation of Functional Connectivity toClinical Parameters and Subject MotionFunctional connectivity in the episodic memory network

was found to be positively correlated with scan time

from end of the hyperacute phase in postacute patients

(Fig 4; r 5 0.72, 0.70 in the data-driven and literature-

based networks respectively; p< 0.05) but not in hyper-

acute patients. This result demonstrates the recovery to

normal connectivity values during the postacute phase.

FIGURE 3: Hierarchical clustering of the episodic memory network. (A) Connectivity and subnetwork clusters in the data-driven(left) and literature-based (right) episodic memory networks. Each row/column represents a specific brain region. Strength offunctional connectivity between the corresponding regions is represented by color code. Hierarchical clustering revealed 6main clusters: frontocingulate (FC, purple), medial-temporal (MTL, turquoise), deep structures (DS, yellow), medial-occipital(MO, blue), inferiortemporal (IT, red) and inferior-frontal triangular (TR, orange). (B) Intra- and intercluster connectivity of TGA(transient global amnesia) patients (hyper- and postacute phases) and healthy control subjects in the data-driven (left) andliterature-based (right) episodic memory networks. Line width represents connectivity strength between clusters, and clustersize represents intracluster connectivity. Inter- and intracluster connectivity values that significantly differ between control sub-jects and TGA patients are marked by solid lines, and values that do not significantly differ are marked by dashed lines. Notethat functional disturbances are apparent in large parts of the episodic memory network. inf 5 inferior; L 5 left; med 5 medial;mid 5 middle; post 5 posterior; R 5 right; sup 5 superior.

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640 Volume 75, No. 5

No significant correlation was found between functional

connectivity and patient age, sex, severity of time disori-

entation, TGA duration, or length of retrograde amnesia.

Motion levels in the hyper- and postacute groups

were greater than in healthy control subjects (mean abso-

lute motion: 0.22mm, 0.29mm, and 0.19mm, respec-

tively), but were not significantly correlated with

functional connectivity results across all subjects

(r 5 20.14, 20.24 for the data-driven and literature-

based networks, respectively).

Structural FindingsOf the 12 TGA patients investigated in this study, only

1 patient (scanned 5 hours after TGA onset) showed a

hippocampal lesion in the DWI, which disappeared in

her postrecovery scan 3 months later. This finding is in

accordance with previous studies,13 which describe such

lesions in up to 80% of TGA patients, appearing usually

24 to 48 hours after TGA onset (note that all patients

were scanned <14 hours after TGA onset). No other

DWI lesions were detected in any of the patients.

VBM analysis applied on 4 related networks (whole

brain, data-driven episodic memory, literature-based epi-

sodic memory, hippocampus/parahippocampus) did not

show any significant difference between hyperacute, post-

acute, and postrecovery patients and healthy control sub-

jects, ruling out previous structural abnormality and/or a

long-lasting post-TGA structural effect.

Discussion

Functional examination of the episodic memory network

during TGA revealed several novel findings: there is a

significant reduction in functional connectivity within

the episodic memory network during TGA; the reduc-

tion is more pronounced in the hyperacute than in the

postacute phase; the disturbance gradually disappears

during the postacute phase and is fully reversible after

recovery; the disturbance is apparent in both cerebral

hemispheres; the disturbance is specific to the episodic

memory network; and although the hippocampus and its

connections are significantly impaired, other parts of the

episodic memory network are also impaired. Results were

consistent using 2 different constructions of the episodic

memory network (data-driven and literature-based).

As predicted, a functional connectivity disturbance

was found during the hyperacute phase of TGA, in

which correct identification of the disorder is of clinical

importance. This is in contrast with previously identified

TGA biomarkers such as hippocampal CA1 lesions,

which usually appear only 24 to 48 hours after the

attack, when the disorder had already resolved.13 The

disturbance gradually diminished during the postacute

phase, in accordance with the clinical picture. It com-

pletely resolved several weeks after the episode, compati-

ble with the usual disappearance time of hippocampal

DWI lesions.13,14 In addition, we did not find any con-

sistent gray matter density changes between scans; thus,

there is no evidence for any long-term consequences of

TGA that persist after the episode completely resolves.

Connectivity changes were found bilaterally, in

accordance with the clinical manifestation of severe amne-

sia,16 and previous neuroimaging studies in TGA.10,11,35,36

However, hippocampal DWI lesions in TGA are frequently

lateralized (83% of lesional patients13). We speculate that

although TGA is based on a bilateral disturbance, DWI

shows the disturbance only partially, as is also reflected in

30% of patients without pathological findings.13

In our analysis we found functional connectivity dis-

turbances not only in the hippocampi (as the DWI sug-

gests) but also in other regions of the episodic memory

network during TGA. This is in accordance with PET and

FIGURE 4: Correlation of functional connectivity to time ofscan in the postacute phase. Each point represents averageconnectivity in 1 postacute transient global amnesia (TGA)patient, in the (A) data-driven and (B) literature-based epi-sodic memory networks. The average connectivity values forhealthy control subjects are marked by X (6standard errorof the mean). Note the gradual recovery of functional con-nectivity to the level of healthy control subjects.

Peer et al: Functional Connectivity in TGA

May 2014 641

task-related fMRI studies of TGA patients who demon-

strated abnormalities in a network of regions including

mostly temporolimbic but also frontal regions.7–11 The

hippocampal DWI lesions might thus represent a dysfunc-

tion of a prominent node in a large-scale network underly-

ing mnemonic processes, in accordance with recent

proposals that episodic memory retrieval is a general pro-

cess in which the hippocampus has a prominent role, yet

is also dependent on further sensory and emotional infor-

mation processing regions.37,38 The discordance between

the focal DWI hippocampal lesions and the widespread

RSfMRI connectivity disturbances might thus represent a

disruption of the episodic memory network which is man-

ifested only partially in DWI imaging. Alternatively, focal

changes in the hippocampi might lead to large-scale altera-

tions of the episodic memory network. However, DWI

lesions are found mostly unilaterally, and unilateral dam-

age mostly leads to minor amnesic deficits,16 unlike TGA.

Although our results cannot clearly identify the exact path-

ophysiological mechanism underlying TGA, they do hint

at a large-scale process that encompasses the episodic-

memory network bilaterally.

Our study included 12 patients with TGA, encom-

passing all patients who presented at our institute with

acute TGA during 20 months and who met inclusion

criteria and were MRI-compatible. In addition to the rar-

ity of TGA (incidence approximately 5 of 100,000 per

year),6 the short duration of TGA episodes prevents

patients from seeking medical advice and admission to

the hospital in due time. Despite the relatively small

number of patients, our results were significant and com-

patible with the clinical phenomenology of TGA. Results

in the hyperacute phase were shown to be homogeneous

between patients and those for patients in the postacute

phase were variable and correlated with the time elapsed

from the end of the hyperacute phase to the time the

fMRI scan was performed. Group comparisons of posta-

cute patients with other groups might vary accordingly.

The parcellation in this study, used to identify the

large-scale brain network, was based on the commonly

used AAL brain atlas.26 Atlas-based methods might result

in certain overlaps between anatomical regions, due to

intersubject variability, which might contaminate some

regions with a certain amount of signal from neighboring

regions. To avoid such contamination, we used clustering

analysis for further interpretation of the results. This

limitation does not affect the validity of our main find-

ing of significant connectivity differences between the

different experimental groups.

Another limitation of this study is that patients, as

opposed to control subjects, were scanned in the midst of

a distressing medical situation. Several studies have tested

the effect of stress on functional connectivity.30–33 These

studies consistently found an increase in functional con-

nectivity between the amygdala, medial prefrontal, and

anterior and posterior cingulate cortex. Examination of

this “stress network” in our study groups did not show

any significant difference. Although we cannot rule out an

effect related to other elements of the medical situation,

this analysis and findings suggest that stress cannot

account for the reduction in functional connectivity of the

episodic memory network as was found in our study.

Difference in motion between experimental groups

might influence functional connectivity results. However,

the findings that: (1) patients in the postacute phase

moved more than patients in the hyperacute phase, (2)

there was no significant correlation between motion and

connectivity, and (3) our analyses included rigorous cor-

rections for motion, suggest that a motion difference

between experimental groups cannot explain our results.

In conclusion, using RSfMRI, this study demon-

strated a bilateral, reversible, functional connectivity dis-

turbance in the episodic memory network during TGA.

This disturbance might further serve as a neuroimaging

correlate to TGA. Further research is needed to distinguish

these findings from functional disturbances in other mem-

ory disorders, and possibly enable a deeper understanding

of the functional changes underlying amnesic processes.

Acknowledgment

This study was supported by the German–Israeli Founda-

tion for Scientific Research and Development (2280/

2011), the Marie Curie Intra-European Fellowship

within the framework of the EU-FP7 program (PIEF-

GA-2012-328124), the Ministry of Science and Technol-

ogy, Israel (3-10789), and the Swiss Federal Institute of

Technology–Hebrew University Brain Collaboration to

S.A, an Azrieli Fellowship from the Azrieli Foundation

(M.N.), and an Eshkol Fellowship (M.P.).

We thank our patients for their kind agreement to partic-

ipate in the study, S. Fisch and the staff of the MRI unit

and Neurology department of Hadassah Hebrew University

Medical Center for their help in patient management, and

U. Hertz and S. Aboud for their help in data analysis.

Potential Conflicts of Interest

T.B.-H.: advisory fees, Regenera Pharma, BrainWatch.

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