CASE REPORT

published: 25 February 2022

doi: 10.3389/fnhum.2022.778347

Differential Diagnosis of Akinetic

Mutism and Disorder of
Consciousness Using Diffusion
Tensor Tractography: A Case Report
Dong Hyun Byun and Sung Ho Jang*

Department of Physical Medicine and Rehabilitation, College of Medicine, Yeungnam University, Daegu, South Korea

This paper presents a case in whom a differential diagnosis of akinetic mutism

with a disorder of consciousness was made using diffusion tensor tractography
(DTT). A 69-year-old female patient was diagnosed with subarachnoid hemorrhage,
intraventricular hemorrhage, and intracerebral hemorrhage produced by the
subarachnoid hemorrhage. She exhibited impaired consciousness with a Coma
Recovery Scale-Revised score of 13 until 1 month after onset. Her impaired
consciousness recovered slowly to a normal state according to the Coma Recovery
Edited by:
Scale-Revised (23 points: full score) at 7 weeks after onset. On the other hand, she
Ken-Ichiro Tsutsui, exhibited the typical clinical features of akinetic mutism (no spontaneous movement
Tohoku University, Japan
[akinesia] or speech [mutism]). On the DTT performed at 1-month, the upper, and
Reviewed by:
lower dorsal ascending reticular activating systems, which are related to a disorder of
Edgar G. Ordóñez-Rubiano,
Hospital Infantil Universitario de San consciousness, showed an almost normal state. In contrast, the prefronto-caudate
José, Colombia and prefronto-thalamic tracts, which are related to akinetic mutism, showed severe
Hisse Arnts,
Amsterdam University Medical
injuries. These DTT results suggested that the patient’s main clinical features were not
Center, Netherlands a disorder of consciousness but akinetic mutism. Therefore, DTT for the ascending
*Correspondence: reticular activating system, and the prefronto-caudate and prefronto-thalamic tracts
Sung Ho Jang
could provide additional evidence for a differential diagnosis of DOC and AM at the early
[email protected]
stages of stroke.
Specialty section: Keywords: diffusion tensor tractography (DTT), akinetic mutism, disorder of consciousness (DOC),
This article was submitted to prefronto-caudate tract, prefronto-thalamic tract
Brain Imaging and Stimulation,
a section of the journal
Frontiers in Human Neuroscience
INTRODUCTION
Received: 16 September 2021
Accepted: 21 January 2022 A differential diagnosis of akinetic mutism (AM) and disorder of consciousness (DOC) can be
Published: 25 February 2022
clinically difficult at the early stages of a brain injury. AM is a rare neurological disorder of
Citation: impaired initiation and motivation for behavior (Arnts et al., 2020). The representative clinical
Byun DH and Jang SH (2022) features of AM are a lack of voluntary movement (akinesia) and absence of speech (mutism),
Differential Diagnosis of Akinetic
but eye-opening and spontaneous or environmentally induced visual tracking are maintained
Mutism and Disorder of
Consciousness Using Diffusion Tensor
(Arnts et al., 2020). Bilateral disruption of the fronto-subcortical circuit has been suggested as an
Tractography: A Case Report. important pathophysiological mechanism of AM (Mega and Cohenour, 1997; Nagaratnam et al.,
Front. Hum. Neurosci. 16:778347. 2004; Marin and Wilkosz, 2005; Jang and Kwon, 2017). In particular, an injury to the cortico-
doi: 10.3389/fnhum.2022.778347 striatal-pallidal-thalamic circuit is considered the most plausible pathophysiological mechanism

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Byun and Jang Diagnosis of AM and DOC

(Mega and Cohenour, 1997; Nagaratnam et al., 2004; Marin execute movements and speak according to the clinician’s order
and Wilkosz, 2005; Jang and Kwon, 2017). However, precise with some preservation of awareness. The patient’s daughter
reconstruction of the fronto-subcortical circuit in a live human provided signed, informed consent, and the institutional review
brain has been impossible. The introduction of diffusion tensor board approved the study protocol.
tractography (DTT), which is derived from diffusion tensor The diffusion tensor imaging data were acquired 1 month
imaging, enables the estimation and visualization of some neural after onset using a 1.5 T Philips Gyroscan Intera (Philips, Ltd.,
tracts of the fronto-subcortical circuit, including the prefronto- Best, Netherlands) with a six-channel head coil and single-
caudate and prefronto-thalamic (mediodorsal nucleus) tracts shot echo-planar imaging. For each of the 32 non-collinear
(Behrens et al., 2007; Leh et al., 2007; Jang and Yeo, 2014; diffusion-sensitizing gradients, contiguous slices parallel to the
Jang and Kwon, 2017). As a result, several DTT-based studies anterior commissure–posterior commissure line were acquired.
have reported that AM is related to injuries of the above two The imaging parameters were as follows: acquisition matrix
neural tracts, particularly the prefronto-caudate tract (Jang and = 96 × 96, reconstructed to matrix = 192 × 192 matrix,
Kwon, 2017; Jang et al., 2017a,b, 2018). On the other hand, DTT field of view = 240 mm × 240 mm, TR = 10,398 ms, TE =
also allows a reconstruction of the ascending reticular activating 72 ms, parallel imaging reduction factor (SENSE factor) = 2,
system (ARAS), which is an important neural network for EPI factor = 59, b = 1,000 s/mm2 , NEX = 1, and slice
controlling consciousness (Jang et al., 2019a,b). Thus, this study thickness = 2.5 mm. The diffusion-weighted imaging data were
hypothesized that reconstruction of the neural tracts related analyzed using tools within the Oxford Center for Functional
to AM and DOC using DTT could be useful in a differential Magnetic Resonance Imaging of the Brain (FMRIB) Software
diagnosis of AM and DOC. Library (FSL; www.fmrib.ox.ac.uk/fsl). Affine multi-scale two-
This case study describes a case of AM, which was confirmed dimensional registration was used to correct the head motion
from DOC by the clinical features and DTT. effects and image distortion due to eddy currents. Fiber tracking
was performed using a probabilistic tractography method based
on a multifiber model and was applied using the tractography
CASE DESCRIPTION routines implemented in FMRIB Diffusion software (5,000
streamline samples, 0.5 mm step lengths, curvature thresholds
A 69-year-old female patient was diagnosed with subarachnoid = 0.2; corresponding to a minimum angle of 80◦ ). All regions
hemorrhage caused by an aneurysm rupture in the anterior of interest (ROIs) were applied manually based on the previous
communicating artery and intraventricular hemorrhage, and studies and atlas (Daube, 1986; Morel et al., 1997; Afifi and
intracerebral hemorrhage in both basal forebrains produced Bergman, 2005; Johansen-Berg et al., 2005; Kringelbach, 2005;
by a subarachnoid hemorrhage (Fisher grade 4) (Fisher et al., Petrides, 2005; Brodmann and Gary, 2006; Leh et al., 2007;
1980). She underwent coiling and extraventricular drainage Morel, 2007; Klein et al., 2010; Yeo et al., 2013; Jang and Yeo,
through the right prefrontal lobe on the day of onset and 2014; Jang et al., 2014; Mendoza and Eblen-Zajjur, 2019). Two
ventriculoperitoneal shunt for hydrocephalus 5 days after portions of the ARAS were reconstructed by selecting the fibers
onset at the neurosurgery department of a general hospital. passing through the following regions of interest (ROIs): lower
Approximately 1 month after onset, she was transferred to dorsal ARAS (seed ROI, the pontine reticular formation [RF],
the rehabilitation department of a University hospital. The target ROI, thalamic intralaminar nucleus [ILN] at the level of
patient exhibited impaired consciousness (obedient to simple the inter-commissural plane between the anterior and posterior
commands, such as eye closing, eye tracking to visual stimuli, commissures), and the upper ARAS (neural connectivity of the
and head turning to the side of auditory stimuli), with a ILN to the cerebral cortex) (Daube, 1986; Morel et al., 1997;
Coma Recovery Scale-Revised (full score: 23; a higher score Afifi and Bergman, 2005; Morel, 2007; Yeo et al., 2013; Jang
indicates higher consciousness) score of 13 (auditory function, 3 et al., 2014). Based on 5,000 samples generated from the seed
[reproducible movement to command]; visual function, 4 [object voxel, the results for contact were visualized at a minimum
localization: reaching]; motor function, 2 [flexion withdrawal]; threshold of two for the lower dorsal ARAS and 10 for the neural
verbal function, 1 [oral reflexive movement]; communication, 1 connectivity of the ILN (upper ARAS). For the connectivity of
[non-functional: intentional]; and arousal, and 2 [eye opening the caudate nucleus (CN) to the prefrontal cortex (PFC), the
without stimulation] (Giacino et al., 2004). seed region of interest (ROI) was placed on the caudate nucleus,
Brain magnetic resonance images taken 1 month after which was isolated by the adjacent structures (medial boundary:
onset revealed leukomalactic lesions in both basal forebrains the lateral ventricle, lateral boundary: the anterior limb of the
(Figure 1A). Her impaired consciousness recovered slowly to internal capsule) (Leh et al., 2007; Yeo et al., 2013; Mendoza
a normal state as Coma Recovery Scale-Revised (23 points) and Eblen-Zajjur, 2019). To reconstruct the prefronto-thalamic
(auditory function, 4 [consistent movement to commend]; visual tracts (Johansen-Berg et al., 2005; Kringelbach, 2005; Petrides,
function, 5 [object recognition]; motor function, 6 [functional 2005; Brodmann and Gary, 2006; Klein et al., 2010; Jang and Yeo,
object use]; verbal function, 3 [intelligible verbalization]; 2014), a seed ROI was placed on the known anatomical location
communication, 3 [oriented]; and arousal, and 3 [attention) at of the mediodorsal nucleus of the thalamus on the coronal image
7 weeks after onset (Giacino et al., 2004). However, she showed (Johansen-Berg et al., 2005; Klein et al., 2010; Jang and Yeo,
no spontaneous movement or speech and remained in a lying 2014). Each target ROI was as follows: (1) dorsolateral PFC as
position all day with no spontaneous activity. However, she could Brodmann areas (BAs) 8, 9, and 46 on the coronal image; (2)

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Byun and Jang Diagnosis of AM and DOC

FIGURE 1 | (A) Brain CT images at onset reveal subarachnoid hemorrhage, intraventricular hemorrhage, and intracerebral hemorrhage in both basal forebrains.
(B) T2-weighted brain MR images at 1 month after onset show leulomalactic lesions in both forebrains. (C) The upper ascending reticular activating system (ARAS)
shows almost normal configurations in both hemispheres except for decreased neural connectivities to both basal forebrains (yellow arrows) compared with those of a
(Continued)

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Byun and Jang Diagnosis of AM and DOC

FIGURE 1 | normal control subject (50-year-old female). (D) The lower dorsal ARAS reveals almost normal configurations in both hemispheres compared with those
of a normal control subject (62-year-old female). (E) The neural connectivity of the caudate nucleus to the prefrontal cortex decreased in both hemispheres (violet
arrows) compared to those of a normal control subject (50-year-old female) (sky-blue arrows: artifact due to ventriculoperitoneal shunt, which was performed through
the right parietal approach). (F) All prefronto-thalamic tracts are not reconstructed (orange arrows) except for the right ventrolateral and left dorsolateral tracts, which
show severe thinning (green arrows) compared to those of a normal control subject (60-year-old female).

ventrolateral PFC as BAs 44, 45, and 47 on the coronal image; and prefronto-thalamic tracts because a reconstruction method for
(3) orbitofrontal cortex as BAs 47, 11, and 13 on the axial image the whole fronto-subcortical circuit has not been developed.
(Kringelbach, 2005; Petrides, 2005; Brodmann and Gary, 2006; Second, the results of DTT can be false positives or negatives
Klein et al., 2010; Jang and Yeo, 2014). The prefronto-thalamic due to crossing fibers and partial volume effects (Yamada et al.,
tracts were determined by selecting the fibers passing through the 2009). Third, follow up DTTs from the acute stage could provide
seed and each target ROI. better evidences. However, we could not scan the diffusion tensor
The upper and lower dorsal ARAS showed almost normal imaging at the acute stage because she was transferred from
configurations in both hemispheres except for decreased neural other hospital.
connectivities to both basal forebrains (Figures 1B,C). The In conclusion, a differential diagnosis of AK with DOC was
neural connectivity of the CN to the prefrontal cortex was made in this patient using the clinical features and DTT findings.
decreased in both hemispheres (Figure 1D). None of the The results suggest that DTT for the ARAS, prefronto-caudate
prefronto-thalamic tracts were reconstructed except for the right tract, and prefronto-thalamic tract could be additional evidence
ventrolateral and left dorsolateral tracts, which showed severe for a differential diagnosis of DOC and AM at the early stages
thinning (Figures 1E,F). of a stroke. On the other hand, further studies will be needed
to apply these DTT methods for other brain pathologies, such
DISCUSSION as hypoxic-ischemic brain injury, traumatic brain injury, and
global ischemia.
This patient showed a DOC until she was admitted to the
rehabilitation department 1 month after onset. She also revealed
the typical clinical features of AM (complete absence of DATA AVAILABILITY STATEMENT
spontaneous behavior [akinesia] and speech [mutism]) when her
consciousness had recovered to a normal state 7 weeks after The raw data supporting the conclusions of this article will be
onset (Marin and Wilkosz, 2005). As a result, her main clinical made available by the authors, without undue reservation.
features were not DOC but AM. In detail, it appeared that she
had combined clinical features of AM (main) and DOC (minor)
between 1 month and 7 weeks after onset because she could ETHICS STATEMENT
not execute movements and speak according to the clinician’s
The studies involving human participants were reviewed
order. Subsequently, at 7 weeks when her consciousness had
and approved by Yeungnam University Hospital. The
recovered to a normal state, she presented typical clinical features
patients/participants provided their written informed consent to
of AM (akinesia and mutism) without clinical features of DOC
participate in this study. Written informed consent was obtained
because she could execute movements and speak according to the
from the individual(s) for the publication of any potentially
clinician’s order. In addition, on 1-month DTT, the prefronto-
identifiable images or data included in this article.
caudate and prefronto-thalamic tracts showed severe injuries
whereas the ARAS revealed mild injuries. Thus, when she was
transferred to our hospital at 1 month after onset, we could AUTHOR CONTRIBUTIONS
assume that her main clinical features were not DOC but AM
based on 1-month DTT findings. DB: study concept, design, and critical revision of manuscript
Severe injury of the fronto-subcortical circuit (particularly, for intellectual content. SJ: study concept and design, manuscript
the prefronto-caudate, and prefronto-thalamic tracts) has been development, writing, funding, and critical revision of
suggested as the pathophysiological mechanism of AM (Mega manuscript for intellectual content. All authors contributed
and Cohenour, 1997; Nagaratnam et al., 2004; Jang and Kwon, to the article and approved the submitted version.
2017; Jang et al., 2017a,b, 2018). The upper and lower dorsal
ARAS showed an almost normal state in this patient, whereas
the prefronto-caudate and prefronto-thalamic tracts revealed FUNDING
severe injuries. These DTT results appeared to coincide with
the patient’s main clinical features of AM. This study had This work was supported by the National Research Foundation
some limitations. First, the whole fronto-subcortical circuit of Korea (NRF) grant funded by the Korean Government (MSIP)
could not be reconstructed except for the prefronto-caudate and (No. 2021R1A2B5B01001386).

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Byun and Jang Diagnosis of AM and DOC

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Conflict of Interest: The authors declare that the research was conducted in the
Jang, S. H., and Kwon, H. G. (2017). Akinetic mutism in a patient with mild
absence of any commercial or financial relationships that could be construed as a
traumatic brain injury: a diffusion tensor tractography study. Brain Inj. 31,
potential conflict of interest.
1159–1163. doi: 10.1080/02699052.2017.1288265
Jang, S. H., Lim, H. W., and Yeo, S. S. (2014). The neural connectivity
Publisher’s Note: All claims expressed in this article are solely those of the authors
of the intralaminar thalamic nuclei in the human brain: a
diffusion tensor tractography study. Neurosci. Lett. 579, 140–144. and do not necessarily represent those of their affiliated organizations, or those of
doi: 10.1016/j.neulet.2014.07.024 the publisher, the editors and the reviewers. Any product that may be evaluated in
Jang, S. H., Park, J. S., Shin, D. G., Kim, S. H., and Kim, M. S. this article, or claim that may be made by its manufacturer, is not guaranteed or
(2019b). Relationship between consciousness and injury of ascending endorsed by the publisher.
reticular activating system in patients with hypoxic ischaemic brain injury.
J. Neurol. Neurosurg. Psychiatry. 90, 493–494. doi: 10.1136/jnnp-2018- Copyright © 2022 Byun and Jang. This is an open-access article distributed under the
318366 terms of the Creative Commons Attribution License (CC BY). The use, distribution
Jang, S. H., and Yeo, S. S. (2014). Thalamocortical connections between the or reproduction in other forums is permitted, provided the original author(s) and
mediodorsal nucleus of the thalamus and prefrontal cortex in the human the copyright owner(s) are credited and that the original publication in this journal
brain: a diffusion tensor tractographic study. Yonsei Med. J. 55, 709–714. is cited, in accordance with accepted academic practice. No use, distribution or
doi: 10.3349/ymj.2014.55.3.709 reproduction is permitted which does not comply with these terms.

Frontiers in Human Neuroscience | www.frontiersin.org 5 February 2022 | Volume 16 | Article 778347