Key-words:
Brain hemorrhage - diffusion tensor imaging - diffusion tensor tractography - fiber
tracking - unconsciousness - white matter injury
Introduction
Diffusion tensor imaging (DTI) and fiber tracking by diffusion tensor tractography
(DTT) are the modalities of noninvasive imaging of the white matter and used for the
reconstruction of the trajectory of the tracts. It is presently being primarily used
as a preoperative imaging tool that assists in planning surgical procedures to avoid
damage to the major tracts, especially in intrinsic brain tumors and epilepsy surgery.
Fiber tracking by tractography is a recent application which is gaining interest in
the study of white matter injury (WMI). DTT can be used to analyze the course, integrity,
anatomical connectivity, or possible disruption of the white matter fibers. It has
been so far used in traumatic diffuse axonal brain injury, cerebral ischemia, and
neurodegenerative disorders. We present our preliminary experience where DTI and DTT
were used to analyze the reason for poor conscious level in patients with intracerebral
hemorrhage (ICH) and aneurysmal subarachnoid hemorrhage (SAH) and also review the
literature available. All the patients in our study had white matter changes detected
on the DTT which correlated with the altered consciousness. The authors believe that
DTT could have a crucial role in the coming years for explaining the white matter
injuries, which lead to cognitive dysfunction.
Materials and Methods
DTI and fiber tracking were done in four patients admitted at Fujita Health University
Banbuntane Hospital, Japan, with decreased conscious level and cognitive dysfunction
following cerebrovascular accident (3 patients with aneurysmal SAH and one patient
with bifrontal hemorrhage), and DTI changes in the frontal white matter were analyzed.
The Glasgow coma scale (GCS) and Mini-Mental State Examination were used to assess
the cognitive changes. 3 Tesla magnetic resonance imaging (MRI) was used for image
acquisition using the standard protocols' region of interest (ROI) for the fractional
anisotropy (FA) values, and fiber tracking was manually fixed over the bilateral frontal
white matter. MRI (Vantage Centurian; Canon, Ingenia 3T; Philips) and DTI specifications
used were Sequence = SE-EPI, TR = 8059, TE = 49, ets = 1.0 ms BW = 1302 Hz/pixel,
FOV = 23 cm × 23 cm, MTX = 208 × 208, slice thickness = 2.0 mm, Gap = 0, number of
slice = 82, MultiBand SPEEDER = 2, PE-SPEEDER = 3, B = 1000 (12 axis), Fatsat = ON,
ime = 2:09.
Case 1
A 45-year-old female presented with sudden-onset headache. Her GCS was E4V4M6 (14/15)
with no focal neurological deficit. On evaluation, the patient was found to have ruptured
anterior communicating artery aneurysm with Fisher's Grade 4 SAH and left frontal
ICH [[Figure 1]]a. The patient underwent emergency left pterional craniotomy and clipping of aneurysm
[[Figure 1]]b. She also underwent a decompressive craniectomy and ventriculoperitoneal (VP)
shunt in the postoperative period. Patient's GCS remained at E2VaM5. DTI and DTT were
done at 6 weeks in which the cingulum and the fornix on the left side could not be
delineated and left frontal connectivity was decreased [[Figure 2]]a,[[Figure 2]]b,[[Figure 2]]c,[[Figure 2]]d. The patient progressed gradually to GCS E4VAM5 and tailored neurorehabilitation
was initiated.
Figure 1: (a) Computed tomography brain showing Fisher's Grade 4 subarachnoid hemorrhage with
left frontal intracerebral hemorrhage from ruptured ACOM aneurysm. (b) Computed tomography
brain showing postcraniotomy changes and clip in situ
Figure 2: (a) Diffusion tensor tractography showing thinning of left cingulum (red arrow) and
disconnection in the left frontal fibers (yellow arrow). (b) Diffusion tensor tractography
demonstrating normal cingulum on right with shunt-related black artefact. (c) Magnetic
resonance imaging showing the white matter changes in the left frontal region. (d)
Diffusion tensor tractography showing fornix on the right. It was absent on the left
side
Case 2
A 55-year-old hypertensive male patient had a fall and sustained head injury. His
GCS was E1V1M5, pupils were equal and reacting, computed tomography (CT) brain revealed
bifrontal contusion with bifrontal thin acute subdural hematoma [[Figure 3]]a. The patient was treated with anticerebral edema measures, and he gradually showed
improvement in his GCS to E4V4M6 on day 7 after injury, but he continued to have confusion
and cognitive dysfunction. MRI showed resolving bleed with edema [[Figure 3]]b. Diffusion-weighted imaging (DWI) and tractography done after 1 week revealed
discontinuation and reduction of fibers in the bilateral frontal white matter tracts
along with reduced FA values and thinning of right cingulum [[Figure 4]]a and [[Figure 4]]b.
Figure 3: (a) Plain computed tomography brain showing bifrontal contusion (left>right). (b)
Magnetic resonance imaging T1 weighted showing white matter edema surrounding the
contusion
Figure 4: (a) Tractography showing thinning of right cingulum. (b) Diffusion tensor tractography
showing discontinuation in bilateral frontal tracts
Case 3
A 56-year-old male patient presented with sudden-onset altered sensorium. His GCS
was E3V3M5, and imaging revealed ruptured right middle cerebral artery (MCA) aneurysm
with Fisher's Grade 4 SAH. During the surgery, the aneurysm re-ruptured, and clipping,
external ventricular drainage, and a decompressive craniectomy were done at another
center. Postoperative imaging revealed right frontal ICH. He also underwent VP shunt
and cranioplasty 4 weeks later. The patient's postoperative GCS continued to remain
E4VTM5 after 1 year, and he was referred to our center for neurorehabilitation. CT
brain revealed right frontal damage and gliosis [[Figure 5]]a. MRI with DWI and DTT showed severe reduction in connectivity from the right frontal
lobe and reduced FA values in the right frontal white matter [[Figure 5]]b, [[Figure 6]]a and [[Figure 6]]b.
Figure 5: (a) Postoperative computed tomography after 1 year showing right frontal gliotic
change. (b) Magnetic resonance imaging T2 image showing extensive white matter damage
right frontal region
Figure 6: (a) Diffusion tensor tractography showing reduction and disruption of the right frontal
white matter tracts (yellow arrow). (b) Diffusion tensor tractography showing discontinuation
of the right frontal white matter tracts (yellow arrow)
Case 4
A 64-year-old male presented with Fisher's Grade 4 SAH due to ruptured basilar artery
tip aneurysm [[Figure 7]]a and [[Figure 7]]b. The patient's GCS was E4V4M6 with no motor deficit. Coiling and external ventricular
drainage were done. Postoperatively, his GCS remained the same. He continued to have
confusion and memory deficit. Postoperative MRI revealed a small right frontal bleed
at the external ventricular drain insertion site [[Figure 8]]a. MRI DWI and tractography done 4 weeks later showed reduced FA values in the right
frontal region and discontinuation in the frontal fiber tracts [[Figure 8]]b.
Figure 7: (a) Plain computed tomography brain showing subarachnoid hemorrhage and intraventricular
hemorrhage Fisher's Grade 4. (b) Plain computed tomography brain showing subarachnoid
hemorrhage and intraventricular hemorrhage Fisher's Grade 4
Figure 8: (a) Magnetic resonance imaging showing right frontal bleed. (b) Diffusion tensor
tractography showing disruption in the right basal forebrain tract (bold yellow arrow)
Results
The variations in FA values of the bilateral frontal white matter and the tractography
findings in the cases are summarized in [[Table 1]].[[1]] The normal reference value of FA in the frontal white matter in a healthy adult
was taken as above 0.35. We found WMI with significant frontal white matter damage
in the form of thinning and anatomical disruption of the tracts in all the cases,
and this correlated with the cognitive status of the studied patients. Our preliminary
study results have shown that DTI can possibly reveal the anatomical basis for the
cognitive dysfunction and unconsciousness following brain hemorrhage and can be used
as a critical analytical tool in explaining the disintegration of the neural circuits.
The results can in turn be useful for the prognostication of the clinical outcome.
Table 1: Summary of results with the fractional anisotropy values of frontal white matter
and diffusion tensor tractography finding
Discussion
Neural circuits in consciousness and memory Limbic system
The limbic system is a complex part of the nervous system consisting of both cortical
and subcortical structures and plays a crucial role in the conscious level of the
patient. Cognition, emotions, behavior, and memory are among its many functions. The
intricate structural anatomy includes the cingulum, hippocampal formation (dentate
gyrus, hippocampus, and subicular complex), amygdala, septal area, and the hypothalamus.
Papez circuit and mamillothalamic tract
Shah et al.[[1]] have very elegantly presented the fiber dissection technique of the limbic system
by the Klingler technique, which provided the anatomical visualization and basis for
the voxel placement and ROI study in the DTI [[Figure 9]]a and [[Figure 9]]b. Papez circuit begins with the hippocampus and reaches the mammillary body via
the fornix. The mamillothalamic tract (MTT) then continues to the anterior nucleus
of the thalamus, which in turn is projected to the hippocampus by the cingulum which
completes the circuit [[Figure 10]]. Structurally, the MTT is a solid white matter band of fibers running along and
parallel to the forniceal columns and anterior bodies.[[2]] It is a major direct communication pathway of the thalamus with the mammillary
bodies of the hypothalamus, and the damage to it causes severe memory impairment,
resulting in amnesia and cognitive dysfunction. The amnestic syndrome or impairment
of recent memory was originally described by Korsakoff in alcoholics. Similar presentations
have also been described in head trauma, cerebrovascular disorders, and hypoxic brain
injury. The MTT is therefore one more important site of damage in the complex memory
circuit of the hippocampal–limbic system.[[3]],[[4]]
Figure 9: (a and b) The anatomical dissection of Papez circuit and limbic system and its connections
by Kingler technique done by Shah et al. a-hippocampus, b-fimbria, c-crus of fornix,
d-body of the fornix, e-column of the fornix, f-mammillary body, g- mamillothalamic
tract, h-anterior nucleus of thalamus
Figure 10: Tractography of Papez circuit and mamillothalamic tract using 7 Tesla magnetic resonance
imaging.
Ascending reticular activating system
The ascending reticular activating system (ARAS) or the reticular activating system
is a complex reticulum of neurotransmitter-specific synapses and interconnections
with cell bodies in the tegmentum of brainstem, basal forebrain, and thalamus. Also
called as the extrathalamic modulatory system, it is a crucial structure serving as
the center for control of consciousness and arousal. Human consciousness can be simplified
as consisting of two main components – arousal and awareness. Arousal pathways originating
in the brainstem reticular network activate the awareness networks in the cortex via
synapses in the thalamus and the frontal cortex or may project directly to the basal
forebrain circuits [[Figure 11]]. The pathway consists of the ventral and dorsal tegmental tracts projecting from
the thalamic nuclei to the basal forebrain and the middle forebrain bundle [[Figure 12]]. Several studies have demonstrated tractography and DWI changes in ARAS in patients
with decreased conscious level.[[5]],[[6]],[[7]],[[8]],[[9]]
Figure 11: Neural circuits in consciousness
Figure 12: Tractographic reconstruction of the ascending reticular activating system by Ordonez-Rubiano
et a/.[9] (ROI: 1 midbrain, 2 thalamus, 3 hypothalamus)
Diffusion tensor imaging and diffusion tensor tractography for evaluation of white
matter injury
Diffusion MRI of the brain was first adopted for the evaluation of acute ischemic
stroke during the early 1990s. The advent of 3 Tesla MRI and advanced software for
DTI and fiber tractography has opened an entirely new noninvasive window on the white
matter connectivity of the human brain. Based on the principles of Brownian motion,
imaging molecular water diffusion confers the ability to probe the microstructural
properties of biologic tissues and diffusion ellipsoids are derived from three-dimensional
Eigen vectors.[[1]] Fiber tracking is derived from the diffusion ellipsoids in the voxels in the ROI.
Noise, patient movement, and distortion from imaging artifacts such as aneurysm clip
and coil can disrupt the imaging.
Current applications of diffusion tensor imaging and fiber tractography
DWI is primarily being used as a diagnostic tool in ischemia, infection, tumors, demyelinating
disease, and diffuse axonal brain injury. It is also a useful for the presurgical
mapping of white matter pathways for planning the operative approach to avoid injury
to the tracts. Fiber tracking in the recovery period and assessment of cognitive and
motor outcome following brain hemorrhage is an evolving application of DTI.
White matter injuries in subarachnoid hemorrhage
Cognitive dysfunction is the most common morbidity after SAH, and it could be a complete
loss of consciousness, Vegetative State (VS), Minimally Conscious State (MCS), amnestic
state, behavioral changes, or impaired memory. Early brain injury following SAH can
occur both in the white and gray matter region. Several studies have indicated that
undetected WMI could be the reason for cognitive decline in these patients. WMI could
be focal or global and may result from blood–brain barrier disruption, neuroinflammation,
or ischemic and oxidative stress.[[10]],[[11]]
Recent studies have shown disruptions in the MTT and Papez circuit following SAH.
Jang et al. retrospectively studied 16 patients with SAH and found 62.5% of them to
have injury of the MTT (decrease in FA values and reduction in volume of tract) in
at least one hemisphere, which correlated positively with the cognitive dysfunction.
They hypothesized that the injury could be at the point where the tract is closest
to the cistern.[[12]] Jang et al. in another paper have also reported injury of the precommissural fornix
in a patient with ruptured MCA aneurysm. They observed bilateral discontinuation of
the forniceal cruses and reduction in fiber volume and FA values on DTI.[[13]] Another study by Jang and Kim has reported reduction in the number of fibers and
injury of the lower portion of the ARAS in patients with SAH.[[7]] Further, there is another study by Jang and Seo that evaluated multiple injuries
in the dorsal and ventral ARAS in a patient with ruptured ACOM aneurysm who had intraventricular
hemorrhage, SAH, and frontal ICH who underwent clipping and continued to have depressed
conscious level (GCS 10). DTT done at 6 weeks revealed narrowing of the right ventral
lower ARAS and decreased neural connectivity from the thalamic interlaminar nuclei
to both prefrontal cortices and basal forebrains.[[14]] This paper highlights how multiple sites of injury must be considered in patients
with decreased consciousness following aneurysmal SAH. Ordóñez-Rubiano et al. demonstrated
damage to the tegmental tracts and middle forebrain bundle in a patient with decreased
consciousness and bilateral frontal contusion following trauma.[[9]]
Hong et al. have done fiber tracking and DTI for 11 patients with ACOM aneurysm rupture
who had sustained memory impairment and found decreased FA values and absent trajectory
of the cingulum and the fornix in 54.5% and 63.6%, respectively, and they attributed
it to perforator infarct or mechanical injury caused by the hemorrhage.[[15]] A case report by Jang and Yeo demonstrated damage to the Papez circuit with injury
in the fornix and thalamocingulate tract in a patient who had provoked confabulations
and memory impairment after ACOM rupture.[[16]]
White matter injury in frontal hemorrhage
With basifrontal contusions and frontal ICH, there is a definite mechanical compression
of the basal forebrain tracts by the hemorrhage or disruption of the connecting fibers.
Structural damage to the fiber tracts demonstrated as thinning, reduction in the volume,
or absence on tractography with corresponding reduction in the mean FA values in the
frontal white matter of the affected side correlated with the poor conscious level
and cognitive dysfunction in our patients. Results in our paper were consistent with
the literature published so far. A summary of the sites of WMI and the neurological
dysfunction caused by it is given in [[Table 2]].
Table 2: Summary of the sites of white matter injury and outcome
White matter fiber tracking: A novel tool to predict the outcome and prognosis
Can we predict the cognitive recovery of patients with DTI? The answer is possibly
yes. Although the application of DTI as a prognostic tool is still in the early phase,
very promising results are being reported worldwide. By detecting the exact site of
white matter disruption in the tractography, it may be possible to predict the recovery
in patients with impaired consciousness and cognitive dysfunction. Identification
of the WMI by fiber tracking could pave way for novel and targeting therapeutic mechanisms
to prevent and repair WMI in the future. For example, the early detection of ARAS
injury in SAH by DTI could play a crucial role in in early initiation of neurorehabilitative
measures.[[7]] A recent study by Tsung et al. in 22 patients with brain injury showed that the
DTI had a distinct advantage over the conventional CT in assessing the tract injury
and can be used in formulating the treatment and rehabilitation plan.[[17]] More studies will be needed to arrive at a protocol-based tractography in detecting
circuit and tract-specific WMI in the unconscious patient.
Conclusion
DTT is a powerful noninvasive anatomic imaging tool for the demonstration of gross
fiber architecture and white matter injuries. Early recognition of WMI by fiber tractography
can help in tailored pharmacologic and electrophysiologic (e.g., deep brain stimulation)
treatment and neurorehabilitation program. It can also help in prognosticating the
patient outcome. The limitation of our study is that only few cases were studied and
a larger study would be required to conclusively prove the efficiency and specificity
of DTI as a diagnostic and predictive tool. The authors plan to follow-up the cases
studied at 6 months and study the recovery of WMI. In conclusion, the tractography
technology and imaging software programs are rapidly evolving, and with the advent
of 7 Tesla MRI machines, we could be soon looking at DTI which could precisely localize
the microstructural injuries even in the smaller fibers of the white matter. WMI-targeted
therapeutics could well be the future to prevent and repair the brain injury.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms.
In the form the patient(s) has/have given his/her/their consent for his/her/their
images and other clinical information to be reported in the journal. The patients
understand that their names and initials will not be published and due efforts will
be made to conceal their identity, but anonymity cannot be guaranteed.
