http://neurology.thelancet.com Vol 6 August 2007 699
Structural and functional neuroimaging in mild-to-moderate
Zwany Metting, Lars A Rödiger, Jacques De Keyser, Joukje van der Naalt
Head injury is a major cause of disability and death in adults. Signifi cant developments in imaging techniques have
contributed to the knowledge of the pathophysiology of head injury. Although extensive research is available on
severe head injury, less is known about mild-to-moderate head injury despite the fact that most patients sustain this
type of injury. In this review, we focus on structural and functional imaging techniques in patients with mild-to-
moderate head injury. We discuss CT and MRI, including diff erent MRI sequences, single photon emission computed
tomography, perfusion-weighted MRI, perfusion CT, PET, magnetic resonance spectroscopy, functional MRI and
magnetic encephalography. We outline the advantages and limitations of these various techniques in the contexts of
the initial assessment and identifi cation of brain abnormalities and the prediction of outcome.
Head injury is a leading cause of disability and death in
adults, and most patients (85–95%) are classifi ed as
having mild-to-moderate head injury.1–5 Most of these
patients recover within weeks to months without specifi c
therapy. However, a subgroup continues to experience
disabling symptoms that interfere with their return to
work or resumption of social activities.6–10 The burden
of these symptoms is not only personal but also
socioeconomic, as they are most common in young
patients in their 20s and 30s with full occupational status.
It is of paramount importance to identify those patients
who are prone to develop cognitive disability to promote
In recent decades, major advances in the development
of imaging techniques have contributed to the knowledge
of the pathophysiology of head injury. The capabilities of
structural imaging have been expanded by various
techniques suitable for visualising haemodynamic and
metabolic changes in the brain. Concurrently, the
treatment of patients with trauma is increasingly guided
by the rapid assessment of primary damage and
prevention of further deterioration. Hence, selection of
the technique most valuable in guiding management
during the acute phase of injury is essential, as is the
assessment of the additional value of the technique in
In this article, we present an overview of the current
imaging techniques in terms of their ability to reveal
structural or functional brain abnormalities in patients
with head injury. We focus on patients with mild-to-
moderate head injury, defi ned by a Glasgow coma score
of more than 8, as most patients sustain this type of head
injury and, in contrast to severe head injury, scarce
information is available on this topic. As some extensive
reviews of imaging studies in children are already
available, this review focuses on studies of mild-to-
moderate head injury in adults.14–16 We discuss advantages
and limitations of various techniques with regard to
the initial assessment and identifi cation of brain
abnormalities and their role in the prediction of
In traumatic brain injury, the mechanism of damage can
be classifi ed as primary and secondary. In general,
structural imaging techniques are used to visualise
primary brain injury. Primary brain injury occurs at the
moment of impact, with diff use axonal injury being the
most important primary lesion.5,17–19 Diff use axonal injury
is a consistent fi nding in mild, moderate, and severe
traumatic head injury, although the severity increases
with that of the head injury.20–22 Primary brain injury also
comprises focal abnormalities, such as contusions and
haematomas, as a result of either direct external contact
forces or from the movement of the brain within the
skull.17,23 Secondary brain injury, on the other hand,
develops within hours after impact as a result of primary
injury and mainly consists of ischaemia;24–26 this is best
visualised using functional imaging. In the emergency
setting, clinical management is guided by the imaging of
structural abnormalities requiring acute interventions.
During follow-up, structural imaging techniques are
most commonly used to explain post-concussional
symptoms or to predict outcome. Structural imaging
techniques in patients include CT and MRI.
CT is one of the fi rst developed and most commonly
applied imaging techniques in the acute phase of head
injury and can be used to detect haemorrhage,
parenchymal injury, and skull fractures. CT is the most
relevant imaging procedure for the detection of lesions
eligible for surgical intervention, as it is rapidly and easily
done, even in agitated patients.17,27,28
For mild and moderate head injury, there is no
agreement about routine CT scanning. There is
substantial variation among institutions in the ordering
of CT for patients with mild head injury, ranging from
16% to 74%.29 When all patients with mild-to-moderate
head injury are scanned, the incidence of abnormal
fi ndings is about 15%, increasing to 50% when a CT scan
is done in only those patients with neurological
symptoms.30 However, absence of focal neurological
abnormalities on physical examination does not rule out
Lancet Neurol 2007; 6: 699–710
Department of Neurology
(Z Metting MD, J De Keyser MD,
J van der Naalt MD) and
Department of Radiology
(L A Rödiger MD), University
Medical Center Groningen,
Joukje van der Naalt, Department
of Neurology, University Medical
Center Groningen, Hanzeplein 1,
9700 RB Groningen, Netherlands
http://neurology.thelancet.com Vol 6 August 2007
CT abnormalities.31 Since the introduction of the UK
National Institute for Health and Clinical Excellence
guidelines32 for management of head injury, the use of
CT has substantially increased,33,34 and the reported
incidence of intracranial abnormalities is about 10%. A
low Glasgow coma scale, the presence of a skull fracture,
old age, and focal neurological signs are associated with a
higher incidence of abnormal CT fi ndings in patients
with mild head injury.35–37 The overall sensitivity of CT to
abnormalities in acute head trauma is 63–75%.38,39 In
patients with mild-to-moderate head injury, oedema or
lesions on CT are related to problems with resumption of
work.39 Also, the presence of subarachnoid blood on CT
is a signifi cant predictor of outcome.40 Contusions in
frontal and temporal lobes, when present on CT, result in
relevant defi cits in outcome caused by behavioural and
cognitive problems.41,42 Lesion size is inversely associated
with outcome.43 Furthermore, about 20% of patients
who sustain mild-to-moderate head injury without
abnormalities on the admission CT have problems with
resuming work,39 suggesting that the conventional CT
scan has limited ability in detecting structural and
T1, T2, FLAIR, and T2*-weighted gradient recalled echo
MRI is the technique of choice in the subacute phase of
head injury and during follow-up. The diffi culty of using
MRI to evaluate skull fractures, the limitations in
monitoring patients during MRI, and the susceptibility
to motion artefacts related to the relatively long exposure
time discourage the use of this technique in the acute
phase of head injury. Although in earlier studies MRI
was inferior to CT in the detection of parenchymal and
subarachnoid haemorrhages, MRI is now as reliable as
CT in detecting these haemorrhages in the acute phase
because of improvements in MRI techniques.17,44–46
Moreover, MRI is more sensitive than CT in detecting
diff use axonal injury
contusions,22,38,47 especially in the frontal and temporal
regions at the base of the skull. 39,46 MRI is also more
sensitive in detecting small subdural haematomas
(fi gure 1) and brainstem injury.48 A third of patients with
mild-to-moderate head injury have focal atrophy in the
frontal and temporal regions on MRI in the chronic
phase, which is predictive of outcome.39 In addition to
whole brain atrophy, the number, size, and depth of
lesions are also associated with the degree of
unconsciousness and outcome.39,49–51 Serial MRI scanning
showed a resolution of lesions as well as simultaneous
improvement on neuropsychological testing.46,52
In one of four patients good recovery is observed
despite the presence of lesions on MRI scanning.53
However, about 15% of patients with a normal MRI have
a suboptimal outcome and problems with resumption of
work.39 Because there are some inconsistencies about
lesions and outcome, consideration of whether the
appropriate imaging sequences have been selected is
For years, T1-weighted and T2-weighted spin-echo
and fl uid-attenuated inversion recovery (FLAIR)-weighted
sequences were the most commonly used MRI sequences
in head injury. T2-weighted spin-echo sequences seem to
be more sensitive in detecting contusions compared with
T1-weighted spin-echo sequences. The sensitivity of
Figure 1: Subacute subdural haematoma
A 33-year-old woman who was involved in a car accident. Her initial Glasgow
coma score was 11. Non-contrast CT on admission showed a doubtful
hyperdense ridge over the right frontal lobe (A). FLAIR-weighted MRI sequences
on day 15 after trauma revealed a subdural haematoma in this area (B). Her
clinical condition remained stable.
Figure 2: Diff use axonal injury on MRI during follow-up
Top: a 31-year-old man who was involved in a motor cycle accident. His initial Glasgow coma score was 13.
Non-contrast CT on admission showed no abnormalities (A). MRI was obtained 6 weeks after trauma. MRI
T2-weighted spin-echo sequences revealed no obvious abnormalities (B), whereas T2*-weighted gradient-recalled
echo (GRE) images showed a hypointense lesion in the corpus callosum suggestive of diff use axonal injury (C).
Bottom: a 23-year-old woman after a bicycle accident. Her initial Glasgow coma score was 12. Non-contrast CT on
admission showed one small haemorrhagic lesion in the right frontal lobe (D). MRI was obtained 7 weeks after trauma.
T2-weighted spin-echo sequences (E) revealed no lesions, whereas T2*-GRE-weighted sequences (F) revealed multiple
hypointense lesions in the frontal lobes extending into the corpus callosum, suggestive of diff use axonal injury.
http://neurology.thelancet.com Vol 6 August 2007 701
FLAIR-weighted sequences is the same as or better than
T2-weighted spin-echo sequences in the assessment of
traumatic lesions.54 In the acute stage, FLAIR-weighted
sequences are used for the detection of diff use axonal
injury, oedema, and haemorrhage whereas in the
subacute and chronic stages FLAIR-weighted sequences
are mainly used for the detection of gliosis.27 Although
about 80% of diff use axonal injury lesions were thought
to be non-haemorrhagic in nature, improved MRI
techniques indicate that the proportion of haemorrhagic
diff use axonal injury lesions is in fact much greater than
T2*-weighted gradient-recalled echo sequences enable
visualisation of haemosiderin deposits as a result of
haemorrhage, possibly due to diff use axonal injury.55,56
T2*-weighted gradient-recalled echo imaging is better
than T1-weighted and T2-weighted spin-echo sequences
in the detection of traumatic lesions (fi gure 2).56,57 In a
study of patients with head injury of varying severity, the
number of lesions on T2*-weighted gradient-recalled
echo sequences was positively correlated with outcome,
whereas on T2-weighted imaging it was not.56 In patients
with mild head injury, there is a relation between MRI
abnormalities detected within 72 h of injury and neuro-
psychological defi cits.58,59 However, there was no relation
between these imaging fi ndings and return to work or
postconcussive symptoms,58 although slower reaction
times were detected.60
Susceptibility-weighted imaging is the most recently
developed MRI technique and has high sensitivity
for haemosiderin.61 Although further research is needed,
the sensitivity of susceptibility-weighted imaging for
the detection of haemorrhagic lesions in patients
with traumatic head injury is probably higher than that
of T2*-weighted gradient-recalled echo sequences
(fi gure 3).62
In general, for the detection of post-traumatic
abnormalities within 1–3 months of injury, MRI is
preferred, on the condition that appropriate MRI imaging
sequences are used.63
Diff usion-weighted imaging
Diff usion-weighted imaging is another MRI modality
that is primarily used to detect vasogenic or cytotoxic
oedema. This technique is sensitive to the random
movement of water molecules and can distinguish
between lesions with increased and restricted diff usion
in patients with head injury. The apparent diff usion
coeffi cient can be calculated and used to quantify the
degree of restriction of water molecules caused by head
injury. Diff usion-weighted imaging is widely used in
cerebral ischaemic stroke, showing changes before the
onset of visible abnormalities seen on conventional
imaging.64,65 In a few studies comprising mild head injury,
diff usion abnormalities were seen within days of
injury.59,66 In severe head injury, diff usion-weighted
imaging can be used to identify diff use axonal injury as
hyperintense lesions that are not visible on T2-weighted
spin-echo, T2*-weighted gradient-recalled echo, or FLAIR
sequences. Most of these diff use axonal injury lesions
show decreased diff usion probably due to cytotoxic
oedema within days67 to weeks of injury.68,69 Although
cytotoxic oedema predominates in head injury, there is
high diff usion in the acute phase, probably due to
vasogenic oedema.66,67 Diff usion-weighted imaging is
less sensitive than T2*-weighted gradient-recalled-echo
images for detecting haemorrhagic diff use axonal injury
lesions.67 However, the volume of lesions depicted with
diff usion-weighted imaging shows a stronger correlation
with clinical outcome in patients with head injury than
FLAIR, T2-weighted spin-echo, or T2*-weighted gradient-
Diff usion tensor imaging
A relatively new MRI technique, diff usion tensor imaging
is an extension of diff usion-weighted imaging that allows
the reconstruction of white matter tracts in the CNS.71–73
The advantage of diff usion tensor imaging is that it can
be used to visualise axonal injury, the major pathological
substrate of traumatic brain injury. This technique
measures the degree and directionality of water diff usion.
Water diff usion in tissue is modifi ed by its structural
environment, and in white matter, diff usion is greatest
along fi bre tracts parallel to the myelin sheaths. With
diff usion tensor imaging, the mean diff usivity and
fractional anisotropy can be determined; both parameters
are measures of axonal integrity. Diff usion tensor
imaging allows the reconstruction of the diff usion
direction, generating colour maps that reveal the location
and orientation of major white matter fi bre tracts in the
In patients with mild head injury, diff usion tensor
imaging in the acute phase showed reduced fractional
anisotropy in the normal appearing white matter,
predominantly in the internal capsule and corpus
callosum, most likely as a consequence of diff use axonal
injury.76 This pattern was also seen days to years after
Figure 3: Susceptibility-weighted imaging (SWI)
Images of the second patient of fi gure 2 after a bicycle accident. T2*-weighted
gradient-recalled echo (A) revealed doubtful lesions in the temporal regions,
whereas these lesions were clearly visible on SWI (B).
http://neurology.thelancet.com Vol 6 August 2007
mild head injury.77 Of interest here is that the brains of
asymptomatic professional boxers revealed comparable
changes.78 The degree of these water diff usion
abnormalities is correlated with the acute Glasgow coma
score and the Rankin score at discharge.72 Moreover,
reduced fractional anisotropy in the splenium is related
to cognitive dysfunction more than 1 year after injury.79
Thus far, there have been inconsistent fi ndings about
diff usivity in head injury, probably related to diff ering
pathophysiological processes that are thought to evolve
over time.80 Restricted diff usivity was observed within the
splenium and in the periphery of focal lesions, without
any associated increase in T2-weighted signal intensity.72,81
In chronic head injury survivors, however, there was a
positive correlation between increased diff usivity in
widespread areas of the cerebral cortex and learning and
Diff usion tensor imaging provides a powerful non-
invasive tool to study complex brain tissue architecture.
With recent improvements in hardware, diff usion tensor
imaging acquisition and calculation times have been
reduced to allow complete brain coverage and
visualisation in colour maps of white matter tracts in a
clinically acceptable period. More experience in diff usion
tensor imaging is needed, both for research and clinical
In summary, structural imaging techniques, such as
conventional CT and MRI, depict primary traumatic brain
injury. The timing of imaging is important as information
provided by CT imaging is most appropriate early in the
course of injury and MRI methods are more helpful in
the recovery phase. However, conventional CT and MRI
have a limited negative predictive value, as the absence of
abnormalities is no guarantee of optimum outcome. The
fi rst results of MRI modalities based on diff usion
methods, such as diff usion-weighted imaging and
diff usion tensor imaging, in head injury are promising.
As diff usion-based methods indirectly rely on the energy
status of the cells, these techniques could provide
information on secondary injury. Further investigation is
needed, especially in patients with mild-to-moderate head
injury. Because conventional CT and MRI cannot show
functional cerebral changes and therefore secondary
brain injury, functional imaging techniques might be of
more value in predicting outcome.
Functional imaging techniques are used to measure
haemodynamic or metabolic changes in the brain, mainly
in the subacute phase of injury when secondary injury is
developing. Secondary brain damage mainly consists of
ischaemia and is present in more than 80% of fatal cases
of head injury.25 Even in monitored patients, ischaemic
damage occurs. In a series of patients with diff ering
severity of head injury, 92% had one or more ischaemic
insults lasting for at least 5 min, despite being monitored
in a well equipped intensive-care unit.5
Functional imaging studies include haemodynamic
imaging such as single photon emission computed
tomography (SPECT) and PET, although the latter
technique also provides information on the metabolic
status of the brain. Although xenon-CT was one of the
fi rst techniques used to examine perfusion in patients
with head injury, information is available mainly on severe
head injury and as such is not relevant to this review.
Imaging techniques such as perfusion MRI and perfusion
CT are described, in which haemodynamic imaging is
added to a modality originally used for structural imaging,
thereby expanding the possibilities for the visualisation of
brain abnormalities. Advanced MRI techniques such as
functional MRI and magnetic resonance spectroscopy
(MRS) provide information on the metabolic state of the
brain with the former combining the accuracy of MRI
with information on activation patterns of localised brain
functions and the latter providing information on the
metabolic state of the brain.
SPECT is a procedure that provides an indirect indicator
of brain metabolism by measuring cerebral blood fl ow.83
Several radiotracers are available, with 99mTc-
hexamethylpropyleneamine oxide (HMPAO) being the
most common.84 In 40–70% of patients with mild-to-
moderate head injury, abnormal SPECT fi ndings are
observed,60,83,85–88 especially within the fi rst 3 months of
injury.85 Most of these patients have areas of
hypoperfusion, predominantly located in their frontal
and temporal lobes, basal ganglia, and thalami.
Hypoperfusion seen on SPECT imaging correlates with
Figure 4: Single photon emission computed tomography
A 29-year-old woman with amnesia lasting 35 min. There is diminished
perfusion in bilateral occipital and left temporal lobes. Reproduced with
permission from Elsevier.89
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the duration of post-traumatic amnesia after mild head
injury (fi gure 4).89,90 Also, hypoperfusion on SPECT
imaging is shown to be correlated with loss of
consciousness and postconcussional syndrome.90 In
symptomatic patients with long-standing mild traumatic
head injury and unremarkable structural brain imaging,
reduced CBF is seen on SPECT imaging, concordant
with neuropsychological testing.91 A negative initial
SPECT study is a reliable predictor of a favourable clinical
outcome at 3 months after mild head injury.53,87
In general, HMPAO SPECT seems to be more sensitive
than CT or MRI in the detection of brain abnormalities
in patients with mild-to-moderate head injury, with a
larger area of involvement on SPECT than on CT.92,93
However, the greater number of articles describing the
use of SPECT than any other technique in mild traumatic
brain injury does not indicate that it is more sensitive,
because its application is still limited by its poor
resolution, radiation exposure, and diffi culty in obtaining
Perfusion-weighted imaging, in which haemodynamically
weighted MRI sequences are based on the passage
of a contrast agent through the brain, is sensitive to
microscopic tissue-level changes in cerebral blood
volume, and parameters like cerebral blood volume,
mean transit time, and cerebral blood fl ow can also be
obtained.96 Garnett and colleagues64,97 did a perfusion MRI
study in the subacute phase of head injury and found low
cerebral blood volume in regions of focal pathology in
patients with contusions and oedema visible on
conventional MRI. In addition, there was one group of
patients who had reduced cerebral blood volume in a
normal-appearing brain. These patients had a signifi cantly
worse clinical outcome
abnormalities on perfusion MRI. Furthermore, these
measurements were present on average 10 days after the
injury, implying that delayed changes in haemodynamic
parameters, and not just acute changes, may be involved
in determining clinical outcome.64,97
An important limitation of this technique is that
quantifi cation remains diffi cult, together with limited
application in the emergency setting. Furthermore, the
use of a contrast agent is needed, unless the more
recently developed spin-labelling technique is used.
than patients without
Perfusion CT data are obtained by monitoring the fi rst
pass of an iodinated contrast agent bolus through cerebral
vasculature. Investigators can then calculate parameter
maps of cerebral blood volume, mean transit time, and
cerebral blood fl ow (fi gure 5), and the use of regions of
interest allows quantifi cation of perfusion in the
brain.95,98–100 In recent years, the broad introduction of fast
multidetector CT systems and the development of
commercially available software for perfusion analysis
have facilitated the application of cerebral perfusion
imaging in the clinical setting.95
After fi rst being used in patients with stroke, this
technique is gradually being used in those with head
injury. Perfusion CT features specifi c patterns in the
acute phase related to outcome in patients with severe
head injury. Normal brain perfusion or hyperaemia is
seen in patients with favourable outcome and oligaemia
is seen in patients with unfavourable outcome. Perfusion
CT is more sensitive than conventional unenhanced CT
in the detection of cerebral contusions, featured as areas
with lowered cerebral blood fl ow and cerebral blood
volume and increased mean transit time.101 Also, in the
fi rst study of head injury in children and in patients with
mild-to-moderate head injury, there were comparable
abnormalities.102,103 Perfusion CT values of cerebral blood
volume were lower in the immediate vicinity of epidural
or subdural haematomas.101 Apart from advantages such
as low exposure time and 24 h availability in most
hospitals, use is limited by partial brain coverage and
radiation exposure.98,99 The promising potential of
perfusion CT in the detection of secondary ischaemic
changes in the acute phase of head injury is unproven in
mild-to-moderate head injury.
Several studies have investigated the use of PET for the
assessment of patients with head trauma. PET provides
tomographic images of quantitative parameters describing
various features of brain haemodynamics, including
cerebral blood fl ow, cerebral blood volume, oxygen
extraction fraction, and cerebral metabolic rate of
oxygen.84,95 The most frequently used PET tracer is fl uorine-
18 labelled fl uorodeoxyglucose (FDG) for the detection of
regional glucose consumption.
PET studies generally show cerebral dysfunction beyond
the structural abnormalities demonstrated by CT and
MRI.94,104–106 About a third of these anatomical lesions are
associated with more widespread metabolic abnormalities,
Figure 5: Perfusion CT
A 49-year-old man who was involved in a bicycle accident. His initial Glasgow coma score was 14. Non-contrast CT
at admission showed no abnormalities (A), whereas perfusion CT revealed hypoperfusion in the frontal and
occipital lobes (B).
http://neurology.thelancet.com Vol 6 August 2007
and as much as 42% of PET abnormalities were not
associated with any anatomical lesions.107 Epidural and
acute subdural haematomas cause extensive reduction in
metabolism in both the involved adjacent cortex and the
corresponding contralateral cortex. Diff use axonal injury
causes widespread hypometabolism, predominantly in
the parieto-occipital cortex.104,107 The period of metabolic
reduction typically persists for several weeks regardless of
In the acute phase of mild head injury a normal FDG-
PET but an abnormal frontoparietal cortical brain
perfusion was found using SPECT. This suggests that
oedema and vasospasm secondary to mild traumatic
brain injury cause decreased perfusion detected by
SPECT, but that it is not severe enough to impair glucose
uptake.109 In patients with mild-to-moderate head injury,
a good correlation between severity of injury as measured
by the Glasgow coma scale and the extent of whole brain
metabolism was demonstrated, especially in patients
with a score of 13 or lower.94,110
In the chronic phase after mild head injury, there are
inconsistencies in PET fi ndings varying from regional
hypometabolism to global hypermetabolism.105,111 Chen and
colleagues112 found no diff erence in cerebral FDG uptake
between patients with mild head injury and controls in the
resting state.112 In patients with mild-to-moderate head
injury with postconcussive symptoms there is a correlation
between complaints and the number of PET metabolic
abnormalities, although both hypo metabolism and
hypermetabolism were seen in the same regions across
diff erent patients with mild head injury.111 In patients with
mild head injury and postconcussive symptoms, a high
incidence of temporal lobe injury is visible on FDG-PET,113
with a good association between PET abnormalities and
neuropsychological assessment.94,105,114 Global and regional
metabolic rates improve as patients clinically recover from
Besides glucose metabolism, information from PET
imaging of cerebral blood fl ow in patients with head
injury is also obtained with oxygen-15 labelled H2O, CO,
and O2 tracers. Information on patients with mild or
moderate head injury is scarce. Coles and colleagues115
showed that a large ischaemic brain volume was
associated with a poor outcome as measured with the
Glasgow outcome score 6 months after injury. In
addition, a PET study of patients with moderate-to-severe
head injury revealed the use of altered functional
neuroanatomical networks when performing memory
tasks,116 whereas patients with mild head injury had a
small increase in cerebral blood fl ow in the right
prefrontal cortex, compared with that in healthy people,
during a memory task.112
Although quantitative data can be obtained with PET
and it off ers a better resolution than SPECT, the
application of this technique is limited by radiation
exposure and scarce availability due to high costs. It is
mainly used as a research tool in a non-emergency
MRS off ers a unique approach for assessing the metabolic
status of the brain in vivo. In particular, this technique
provides a non-invasive means for quantifying numerous
metabolites such as N-acetyl aspartate, creatine, choline,
and lactate.117 Of particular importance is N-acetyl
aspartate, because it is considered a marker of neuronal
injury or loss. N-acetyl aspartate is found to be decreased
in cerebral contusions118 and in the corpus callosum.119
N-acetyl aspartate concentrations in grey matter were
predictive of overall neuropsychological ability in patients
with moderate-to-severe head injury.120 Moreover, a
N-acetyl aspartate/choline ratio is related to injury
severity and outcome even when white matter appears
normal on MRI (fi gure 6).121,122 Son and colleagues123
showed that in patients with mild head injury the N-acetyl
aspartate/creatine ratio was low in areas of pericontusional
oedema. Moreover, the lactate/creatine ratios were high
Figure 6: Magnetic resonance spectroscopy
A 19-year-old female who was involved in a motor vehicle accident. Her initial
Glasgow coma score was 11. Early MRI (ie, 18 days after injury) showed no
abnormalities, whereas magnetic resonance spectroscopy showed a low
N-acetyl aspartate/creatine ratio and a high choline/creatine ratio compared
with a healthy person. At the late study (ie, 8·1 months after injury)
conventional MRI remained unremarkable with a further decrease in the
N-acetyl aspartate/creatine ratio compared with that in the early study.
Reproduced with permission from Oxford Journals.121
http://neurology.thelancet.com Vol 6 August 2007 705
in these areas, suggestive of ischaemic damage.123 Patients
with good recovery, as measured with the Glasgow
outcome score, have high N-acetyl aspartate/creatine
ratios.124 Despite these positive results, other researchers
have found no associations between metabolic ratios and
outcome at 6 months in individuals with mild head
Choline, a marker for cell membrane disruption and
infl ammation, was high in the normal-appearing frontal
white matter,121,122 grey matter,120,126 and parieto-occipital
white matter.126 Friedman and colleagues120 showed that
increased choline concentrations in grey matter were
not related to neuropsychological outcome at 6 months
postinjury,120 contrary to another MRS study that revealed
that a high choline concentration in both white and grey
matter at 3 months after injury was signifi cantly related
to poorer outcome.127
Although MRS provides a rapid way to assess in vivo
brain composition, the interpretation of results is
hindered by reliance upon ratios in various brain regions.
Furthermore, the technique has a poor resolution and
only partial brain coverage, and its use is limited in the
acute phase of head injury.
Functional MRI is a non-invasive technique in which
blood-oxygen changes serve as an endogenous contrast
agent. Most current functional MRI studies are based on
the blood-oxygen-level-dependent (BOLD) method, in
which the signal is derived from local changes in the
ratio of deoxygenated to oxygenated haemoglobin that
accompany neuronal events. Deoxyhaemoglobin and
oxyhaemoglobin diff er in their magnetic properties, so
the changes in their relative proportions results in a
temporary change in the magnetic resonance signal of
the target region relative to surrounding tissue.128
Functional MRI is a promising technique because it
combines the anatomical precision of MRI with
functional information. Activation of brain regions
involved in a particular language or cognitive task can
be mapped, thereby increasing our knowledge of
neuropsychological dysfunction. To date, standardised
imaging protocols for functional MRI have been
developed mainly for the assessment and visualisation of
brain regions involved in cognition and behaviour. In
severe head injury, functional MRI displays a more
regionally dispersed pattern of cerebral activation,
lateralised to the right hemisphere.129,130
In a study on head injuries of varying severity, there
were changes in brain activation, suggesting that altered
neural networks mediate cognitive control after head
injury, possibly as a result of diff use axonal injury.131 In
patients with pure diff use axonal injury, compensatory
activation of the prefrontal region was seen in comparison
to healthy controls.132
McAllister and colleagues133 used functional MRI in
patients with mild-to-moderate head injury to probe
working memory function (ie, the ability to retain
information and to manipulate it in reaction to newly
incoming material) within about 1 month of injury133
and in some cases 1 year later.134 Patients with head
injury diff ered from control individuals in the activation
pattern of working memory circuitry, with signifi cantly
higher activation on functional MRI during moderate
working memory load conditions, especially in the
parietal and prefrontal regions. Task performance did
not diff er between patients and controls, suggesting
that injury-related changes to modulating working
memory might underlie some of the memory
complaints after mild head injury.128,133,134 In a study of
concussed athletes with mild head injury, patients had
low activation in the right prefrontal cortex compared
with healthy controls on a memory task.135 However,
football players have larger amplitude and more
extensive activation patterns, predominantly in parietal,
lateral frontal, and cerebellar regions, after a motor
sequencing task in the absence of a decline in
Functional MRI is a promising diagnostic imaging
method for the assessment of cognitive, task-related
dysfunction in the chronic phase after head injury.
Functional MRI has the advantage over imaging
techniques such as PET and SPECT because multiple
sessions can be done on a single patient in a short period
of time. These features promote prospective studies with
baseline measures of neurological function. Furthermore,
functional MRI holds great potential for widespread
research and clinical use because it does not require
exposure to ionising radiation. Application of this
technique is best in the chronic phase when the patient
is cooperative and able to comprehend test instructions.
Magnetoencephalograhpy is a new technology that is
based on the detection of magnetic fi eld potentials and
permits real-time direct
electrophysiology. Magnetoencephalography is superior
to standard electroencephalography as it provides more
precise temporal and spatial patterns that are free from
artefacts. The source of the electroencephalography
abnormality can be localised by magnetoencephalography
and registered on a standard MRI. As such, this technique
is not a common imaging technique but provides
a combination of a measure of electrophysiological
dysfunction with anatomical information.137
Magnetoencephalography technology is used as a
clinical diagnostic procedure for epilepsy and experimental
research on sensimotor and language function.138–140 It also
provides useful information for the assessment of
cognitive complaints.141 In a study of head injury patients
with postconcussive symptoms, the combined use of
magnetoencephalography and MRI resulted in the
detection of abnormal activity in 65% of patients compared
with 10% in asymptomatic patients.142 The level of
assessment of brain
http://neurology.thelancet.com Vol 6 August 2007
functional damage in patients with head injuries far
exceeds the area of focal damage depicted with structural
imaging. To date, clinical studies with magneto-
encephalography are limited and it is too early to draw
any conclusions relating to its potential use in head
Additional limitations for its use in a routine setting
include costs and specialised requirements for housing
these systems as a result of the need to shield the
In summary, functional imaging techniques depict
more and larger areas of abnormalities than do structural
imaging techniques in patients with head injury.
Although functional imaging in patients with severe
head injury is of prognostic value, there are few data
from patients with mild-to-moderate head injury.
We have assessed various structural and functional
imaging techniques in a clinical setting to guide
management and to provide prognostic information on
mild-to-moderate head injury (tables 1 and 2). General
problems that apply to imaging in patients with mild-to-
moderate head injury are the heterogeneity of the
population in terms of the extent, type, and location of
injury. Distinction has to be made between management
in the acute phase after injury when the varying
cooperation in agitated or confused patients interferes
Costs Clinical value
WholeLow RestrictedYes Yes Intermediate Not routinely used
Not routinely used
DWI=diff usion-weighted imaging. ADC=apparent diff usion coeffi cient. DTI=diff usion tensor imaging. SPECT=single photon emission computed tomography. MRS=magnetic
Table 1: Imaging techniques in mild-to-moderate traumatic head injury: properties and feasibility
Method Patients Time of imagingOutcome measure Time of outcome assessmentPrognostic value
Naalt van der,
CT GCS 3–15, n=425
GCS 3–15, n=72
GCS 9–14, n=63
Early: 1–3 months
Late: 6–12 months
Early: <39 days
Late: 6–15 months
Early: 3–35 days
Late: 3–11 months
Subarachnoid blood and overall CT appearance
Lesions on early MRI, frontotemporal atrophy on
Total number of lesions on T2*-GRE
Volume of lesions
Fractional anisotropy in internal capsule/splenium
GCS 5–15, n=34
GCS 3–15, n=66
GCS 13–15, n=80
GCS 3–15, n=26
GCS 3–15, n=20
GCS 14–15, n=21
GCS 13–15, n=92
GCS 3–15, n=18
GCS 3–15, n=13
Symptoms and RTW
Modifi ed Rankin score
Modifi ed Rankin score
2 months and 6 months
Discharge, 6 months, and
MRS GCS 3–15, n=26 GOS and DRSLowered NAA/Cr ratio obtained at early MRS
DWI=diff usion weighted imaging. DTI=diff usion tensor imaging. SPECT=single photon emission computed tomography. MRS=magnetic resonance spectroscopy. GCS=Glasgow coma scale. GOS(E)=Glasgow
outcome score (extended). DRS=disability rating scale. RTW=return to work. GRE=gradient-recalled echo. CBV=cerebral blood volume. NAA=N-acetyl aspartate. Cr=creatine.
Table 2: Outcome studies with diff erent methods in mild-to-moderate traumatic head injury
http://neurology.thelancet.com Vol 6 August 2007 707
with rapid assessment and the investigation of symptoms
and abnormalities in the chronic phase.
In the management of head injury, conventional CT is
the imaging modality of fi rst choice in the acute phase.
CT is the most relevant imaging procedure for the
detection of lesions eligible for surgical intervention, and
it is rapidly and easily done. However, a normal CT on
admission does not preclude brain injury and is of limited
prognostic value. Although MRI is superior to CT in
detecting diff use axonal injury and non-haemorrhagic
contusions, this technique is not easily applicable in the
acute phase of head injury owing to the limitations in the
monitoring of patients during MRI and the susceptibility
to motion artefacts related to the long exposure time.
Furthermore, there is no evidence that additional MRI
aff ects neurosurgical management in patients with head
injury. In general, within 1–3 months after injury, MRI
assessment is preferable to other approaches if the
appropriate sequences are used for the detection of post-
traumatic abnormalities. Recently developed MRI
techniques such as diff usion-weighted imaging and
diff usion tensor imaging are promising as they provide
more insight into the pathophysiological mechanisms of
head injury. However, their prognostic value is unknown.
Functional imaging can provide useful information for
determining the extent of ischaemic and metabolic injury
in patients with head injury. The main imaging
techniques dedicated to brain haemodynamics and
metabolism in head injury are MRS, functional MRI,
SPECT, and PET. In general, SPECT and PET seem to be
more sensitive in lesion detection compared with
structural imaging techniques such as CT and MRI. Both
imaging techniques have limited availability and are
mainly used in a research setting. MRS and functional
MRI combine the accuracy of MRI with information on
brain function and the metabolic state of the brain and
are preferably used in the chronic phase after injury. The
use of perfusion MRI and perfusion CT is not extensively
investigated in traumatic head injury. Perfusion MRI
provides better brain coverage than does perfusion CT,
although this latter technique has some promising
qualities, despite its radiation exposure, as it has a low
exposure time and is readily available in most emergency
departments. If it becomes more ready available, magneto-
encephalography might be a promising neuroimaging
technique in the future. This new technique provides
anatomical information that can be related to
neuropsychological and neurobehavioural outcome.
New technologies adding a functional dimension to
structural imaging are likely to improve the relation
between neuroimaging and outcome as they provide an
index of haemodynamic and metabolic function in
addition to anatomy. Additional studies are needed to
assess the extent and duration of abnormalities found in
symptomatic and asymptomatic patients. The potential
ability of new MRI techniques to visualise axonal injury
as the major pathological substrate of traumatic brain
injury is promising. The ability of functional neuro-
imaging to depict brain activity during cognitive tasks
will enable the possibility to determine the effi cacy of
various rehabilitation programmes.
Further studies of mild-to-moderate head injury are
necessary to prove the feasibility of neuroimaging for
this patient group, as management is increasingly
directed by the demand for imaging techniques that
provide information to guide clinical management and
help to determine prognosis.
ZM wrote the fi rst draft. All authors critically revised the paper and
contributed to the fi nal version.
Confl icts of interest
We have no confl ict of interest.
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