Consciousness is controlled by activation of the ascending reticular activating system
(ARAS). The ARAS consists mainly of the lower and upper parts between the thalamus
and cerebral cortex (Edlow et al., 2012; Yeo et al., 2013; Jang et al., 2014). Because
the ARAS is composed of several neuronal circuits connecting the brainstem to the
cortex. These neuronal connections begin from the reticular formation (RF) of the
brainstem and the intralaminar nucleus of thalamus to the cerebral cortex (Gosseroes
et al., 2011). In addition, the ARAS system also includes several brainstem nuclei
(such as dorsal raphe, locus coeruleus, pedunculopontine nucleus, median raphe and
parabrachial nucleus), non-specific thalamic nuclei, hypothalamus, and basal forebrain
(Fuller et al., 2011).
Development of diffusion tensor tractography (DTT), which is derived from diffusion
tensor imaging (DTI), has enabled three-dimensional reconstruction and estimation
of the ARAS of the live human brain (Yeo et al., 2013; Jang et al., 2014). Many studies
using DTT have demonstrated injury of the ARAS in various brain pathologies including
subarachnoid hemorrhage, cerebral infarction, traumatic brain injury, intracerebral
hemorrhage, and hypoxic ischemic brain injury (Jang et al., 2015a, b; Jang and Kim,
2015; Jang and Lee, 2015a; Jang and Seo, 2015), while only a few studies have reported
on the recovery of an injured ARAS in patients with brain injury (Jang et al., 2015c,
2016; Jang and Lee, 2015b).
In this study, we report on a stroke patient who showed recovery of a multiply injured
ARAS using DTT.
A 57-year-old male patient with a spontaneous intraventricular hemorrhage (IVH) and
left basal ganglia hemorrhage (ICH) underwent bilateral frontal extraventricular drainage
(EVD) for IVH (
Figure 1A
). One month from symptom onset, he was transferred to the department of rehabilitation.
He exhibited impaired alertness, with a Glasgow Coma Scale (GCS) score of 9 (eye opening:
4, best verbal response: 1, and best motor response: 4) and a Coma Recovery Scale-Revised
(CRS-R) score of 5 (auditory function: 0, visual function: 0, motor function: 3, verbal
function: 0, communication: 0, and arousal: 2) (Teasdale and Jennett, 1974; Giacino
et al., 2004). He showed quadriplegia of motor function (shoulder abductor: 0/0, elbow
flexor: 0/0, finger extensor: 0/0, hip flexor: 0/0, knee extensor: 0/0 and ankle dorsiflexor:
0/0). Brain MR images taken 1 month after onset showed multiple leukomalactic lesions
in both frontal lobes, left subcortical white matter and basal ganglia (
Figure 1A
). He underwent comprehensive rehabilitative therapy, which included neurotropic drugs
(pramipexole 3 mg, ropinirole 3 mg, amantadine 300 mg and levodopa 750 mg), physical
therapy, occupational therapy until 7 months after symptom onset. At 7 months after
onset, his GCS score had recovered to 15 (eye opening: 4, best verbal response: 5,
and best motor response: 6) with a GRS-R score of 22 (auditory function: 4, visual
function: 5, motor function: 6, verbal function: 3, communication: 1, arousal: 3).
He presented some recovery of the left hemiplegia after 7 months (shoulder abductor:
0/4–, elbow flexor: 0/4–, finger extensor: 0/3, hip flexor: 0/3, knee extensor: 0/3
and ankle dorsiflexor: 0/2+). However, we could not perform Mini-Mental State Exam
(MMSE) evaluation at 1 and 7 months due to poor awareness and cognition. The patient's
wife provided signed, informed consent and our institutional review board approved
the study protocol.
Figure 1
Brain magnetic resonance images (MRI) and diffusion tensor tractography (DTT) of a
57-year-old male patient with multiply injured ascending reticular activating systems
(ARAS).
(A) Brain MR images at 1 and 7 months after onset show multiple leukomalactic lesions
in bilateral frontal lobes and left subcortical white matter and basal ganglia. The
right lower dorsal (B) and bilateral ventral (C) ARAS were narrowed on 1-month DTT
images, and they had become thicker on 7-month DTT images (green arrows). The neural
connectivity of the ARAS to the right prefrontal cortex and basal forebrain was decreased
on 1-month DTT images, and it was increased on 7-month DTT images (D, green arrows).
R: Right; A: anterior.
DTI data were acquired twice (1 and 7 months after onset) using a 6-channel head coil
on a 1.5 T Philips Gyroscan Intera (Philips, Best, The Netherlands) with single-shot
echo-planar imaging. For each of the 32 non-collinear diffusion sensitizing gradients.
Imaging parameters were as follows: acquisition matrix = 96 × 96; reconstructed matrix
= 192 × 192; field of view = 240 × 240 mm2; repetition time = 10,726 ms; echo time
= 76 ms; b = 1,000 s/mm2; number of excitations = 1; and a slice thickness of 2.5
mm with no gap. Analysis of diffusion-weighted imaging data was performed using the
Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software
Library (FSL; www.fmrib.ox.ac.uk/fsl). Fiber tracking was performed using a probabilistic
tractography method based on a multifiber model, and applied in the current study
utilizing tractography routines implemented in FMRIB Diffusion (Behrens et al., 2007).
For the lower dorsal ARAS, the seed region of interest (ROI) was given at the RF of
the pons and the target ROI was given at the thalamic intralaminar nucleus (ILN) (Yeo
et al., 2013). For the lower ventral ARAS, the seed ROI was given at the pontine RF
and the target ROI was given at the hypothalamus (Jang and Kwon, 2015). Finally, for
the neural connectivity of the upper ARAS, the seed ROI was given at the ILN (Jang
et al., 2014). Out of 5,000 samples generated from the seed voxel, results for contact
were visualized at a threshold for the lower (dorsal and ventral) ARAS of a minimum
of 2, for upper neural connectivity of 15 streamlined through each voxel for analysis.
On 1-month DTT images, narrowing was observed in the right lower dorsal ARAS and bilateral
lower ventral ARAS, the neural connectivity between the thalamic of ILN and the cerebral
cortex was decreased in bilateral prefrontal cortices and basal forebrains (Figure
1B
,
C
). By contrast, on 7-month DTT images, the three narrowed neural tracts of the lower
dorsal and ventral ARAS were thickened, and the neural connectivity of the upper ARAS
to the right prefrontal cortex and basal forebrain was increased (Figure 1B
,
C
).
In this study, three portions of the ARAS (the lower dorsal and ventral ARAS, and
upper ARAS) were evaluated in a stroke patient using DTT. Multiple injuries of the
ARAS were observed on 1-month DTT images as follows: the right lower dorsal and bilateral
lower ventral ARAS were narrowed, and the neural connectivity of the upper ARAS from
the thalamic ILN to bilateral prefrontal cortices and basal forebrains was decreased.
These findings appear to suggest injury of the lower dorsal and ventral ARAS and the
upper ARAS. Previous studies have reported on injury of lower ARAS in patients with
stroke using DTT (Jang et al., 2015a, b; Jang and Seo, 2015). A few studies have demonstrated
the injury of lower ARAS due to transtentorial herniation and Kernohan's notch phenonmenon
following ICH, respectively (Jang et al., 2015b; Jang and Seo, 2015). In a recent
study reporting on an injury of the lower ARAS by IVH (Jang et al., 2015a), it appeared
that injury of the upper ARAS was due to bilateral EVD and intracerebral hemorrhage.
On 7-month DTT images, we found evidence indicating the recovery of the injured ARAS,
which showed thickening of the narrowed lower dorsal and ventral ARAS and increased
neural connectivity of the upper ARAS to the right forebrain and basal forebrain.
These findings indicate recovery of lower dorsal and ventral ARAS and upper ARAS.
At 7 months after onset, the patient showed marked recovery of consciousness to a
nearly normal state (GCS: 9->15, CRS-R: 5->22) compared to 1 month after onset. Our
results on the neural connectivity of the upper ARAS indicate that the recovery of
the upper ARAS connnectivity to the impotant areas (the prefrontal cortex and basal
forebrain) only in one hemisphere might be sufficient for good consciousness in only
one hemisphere and might be enough to achieve a nearly intact consciousness (Laureys
et al., 2000; Schiff, 2008, 2010; Jang and Lee, 2015b).
In conclusion, recovery of a multiply injured ARAS with the recovery of consciousness
was demonstrated in a stroke patient. Our results indicate that evaluation of the
ARAS using DTT would be necessary in elucidating the state of the ARAS, particularly
in stroke patients with multiple pathologies who undergo neuroinvasive neurosurgical
procedures. However, because it is a case report, further studies including larger
numbers of cases with multiple and various brain pathologies are warranted.
This work was supported by the National Research Foundation (NRF) of Korea Grant funded
by the Korean Government (MSIP), No. 2015R1A2A2A01004073.