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Functional Magnetic Resonance Imaging - Medical Clinical Policy Bulletins | Aetna
(https://www.aetna.com/)
Functional Magnetic Resonance Imaging
Policy History
Last Review
10/31/2020
Effective: 11/09/2007
Next
Review: 08/26/2021
Review History
Definitions
Additional Information
Clinical Policy Bulletin
Notes
Number: 0739
Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB.
Aetna considers functional magnetic resonance imaging
(fMRI) medically necessary to identify the eloquent cortex in
pre-surgical evaluation of persons with brain tumors (except
temporal tumors), epilepsy (except temporal neocortical
epilepsy), or vascular malformations.
Aetna considers fMRI experimental and investigational to
identify the eloquent cortex in pre-surgical evaluation of
persons with temporal neocortical epilepsy or temporal tumors.
Aetna considers fMRI experimental and investigational for the
diagnosis, monitoring, prognosis, or surgical management of
all other indications, including any of the following
conditions/diseases (not an all-inclusive list) because its
effectiveness for these indications has not been established:
▪ Alzheimer's disease
▪ Anxiety disorder
▪ Anoxic-ischemic brain injury
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▪ Attention-deficit hyperactivity disorder
▪ Bipolar disorder
▪ Childhood mal-treatment
▪ Chronic pain (including fibromyalgia)
▪ Disorders of consciousness (e.g., locked-in syndrome,
minimally conscious state (subacute/chronic;
traumatic/non-traumatic), and coma/vegatative state)
▪ Multiple sclerosis
▪ Obsessive-compulsive disorder
▪ Panic disorder
▪ Parkinson's disease
▪ Psychosis
▪ Psychotic depression
▪ Schizophrenia
▪ Stroke/stroke rehabilitation
▪ Trauma (e.g., head injury).
See also CPB 0279 - Magnetic Source
Imaging/Magnetoencephalography (../200_299/0279.html).
Background
Functional magnetic resonance imaging (fMRI) is a type of
functional brain imaging technology. It localizes regions of
activity in the brain by measuring blood flow and/or
metabolism following task activation, and is generally used to
identify the eloquent cortex in the brain. Eloquent cortex refers
to specific cortical areas in the brain that directly controls
function, such as language (e.g., Broca's area, Wernicke's
area) and sensorimotor function (e.g., sensorimotor
cortex). Injury, dissection or removal of that area can result in
major focal neurological deficits (Byrne, 2016). Functional MRI
has been used to map these areas when planning a tumor
resection. Furthermore, fMRI has been employed for the
diagnosis, monitoring, prognosis, or surgical management of
many diseases/conditions (e.g., Alzheimer's disease, brain
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tumors, epilepsy, multiple sclerosis (MS), Parkinson's disease,
stroke, trauma, vascular malformations, and vegetative
state/coma).
The bulk of published evidence concerning the clinical
applications of fMRI centers on its use in pre-surgical
planning. In particular, studies involving language fMRI mainly
address its use in pre-surgical planning for epilepsy, arterio-
venous malformations (AVMs), and brain tumors (Bookheimer,
2007). It has been suggested that fMRI of the brain reduces
the need for invasive testing of seizure disorder patients being
considered for surgical treatment. Woermann et al (2003)
compared the determination of language dominance using
fMRI with results of the Wada test in 100 patients with different
localization-related epilepsies. These investigators found 91
% concordance between both tests. The overall rate of false
categorization by fMRI was 9 %, ranging from 3 % in left-sided
temporal lobe epilepsy (TLE) to 25 % in left-sided extra-
temporal epilepsy. The authors noted that language fMRI
might reduce the necessity of the Wada test for language
lateralization, especially in TLE.
Sabsevitz and colleagues (2003) examined whether pre-
operative fMRI predicts language deficits in patients with
epilepsy undergoing left anterior temporal lobectomy (L-ATL).
A total of 24 patients with L-ATL underwent pre-operative
language mapping with fMRI, pre-operative intra-carotid
sodium amobarbital (Amytal)/Wada testing for language
dominance, as well as pre- and post-operative
neuropsychological testing. Functional MRI laterality indexes
(LIs), reflecting the inter-hemispheric difference between
activated volumes in left and right homologous regions of
interest, were calculated for each patient. Relationships
between the fMRI LI, Wada language dominance, and naming
outcome were examined. Both the fMRI LI (p < 0.001) and the
Wada test (p < 0.05) were predictive of naming outcome.
Functional MRI showed 100 % sensitivity and 73 % specificity
in predicting significant naming decline. Both fMRI and the
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Wada test were more predictive than age at seizure onset or
pre-operative naming performance. The authors concluded
that pre-operative fMRI predicted naming decline in patients
undergoing L-ATL surgery.
Medina et al (2005) prospectively evaluated effect of fMRI on
diagnostic work-up and treatment planning in patients with
seizure disorders who are candidates for surgical treatment. A
total of 60 consecutively enrolled patients (27 females and 33
males; mean age of 15.8 +/- 8.7 years; range of 6.8 to 44.2
years) were examined. Forty-five (75 %) patients were right-
handed, 9 (15 %) were left-handed, and 6 (10 %) had
indeterminate hand dominance. Prospective questionnaires
were used to evaluate diagnostic work-up, counseling, and
treatment plans of the seizure team before and after fMRI.
Confidence level scales were used to determine effect of fMRI
on diagnostic and therapeutic thinking. Paired-t test and 95 %
confidence interval analyses were performed. In 53 patients,
language mapping was performed; in 33, motor mapping; and
in 7, visual mapping. The study revealed change in
anatomical location or lateralization of language-receptive area
-- (Wernicke's area) (28 % of patients) as well as language-
expressive area (Broca's area) (21 % of patients). Statistically
significant increases were found in confidence levels after
fMRI in regard to motor and visual cortical function evaluation.
In 35 (58 %) of 60 patients, the seizure team thought that fMRI
results altered patient and family counseling. In 38 (63 %) of
60 patients, fMRI results helped to avoid further studies,
including the Wada test. In 31 (52 %) and 25 (42 %) of 60
patients, intra-operative mapping and surgical plans,
respectively, were altered because of fMRI results. In 5 (8 %)
patients, two-stage surgery with extra-operative direct
electrocortical stimulation mapping (ESM) was averted, and
resection was accomplished in one-stage. In 4 (7 %) patients,
extent of surgical resection was altered because eloquent
areas were identified close to seizure focus. The authors
concluded that fMRI results influenced diagnostic and
therapeutic decision making of the seizure team; results
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indicated a change in language dominance, an increase in
confidence level in identification of critical brain function areas,
alterations in patient and family counseling as well as intra-
operative mapping and surgical approach.
Functional MRI has been used in pre-surgical planning for
patients with brain tumors as well as vascular malformations.
Pouratian and colleagues (2002) evaluated the utility of pre-
operative fMRI to predict if a given cortical area would be
deemed essential for language processing by ESM. These
investigators studied patients with vascular malformations,
specifically AVMs and cavernous angiomas, in whom blood-
flow patterns are abnormal and in whom a perfusion-
dependent mapping signal may be questionable. A total of 10
patients were studied (7 with AVMs and 3 with cavernous
angiomas). These researchers used a battery of linguistic
tasks, including visual object naming, word generation,
auditory responsive naming, visual responsive naming, and
sentence comprehension, to identify brain regions that were
consistently activated across expression and comprehension
linguistic tasks. In a comparison of ESM and fMRI activations,
the researchers varied the matching criteria (overlapping
activations, adjacent activations, and deep activations) and the
radii of influence of ESM (2.5, 5, and 10 mm) to determine the
effects of these factors on the sensitivity and specificity of
fMRI. The sensitivity and specificity of fMRI were dependent
on the task, lobe, and matching criterion. For the population
studied, the sensitivity and specificity of fMRI activations
during expressive linguistic tasks were found to be up to 100
% and 66.7 %, respectively, in the frontal lobe, and during
comprehension linguistic tasks up to 96.2 % and 69.8 %,
respectively, in the temporal and parietal lobes. The sensitivity
and specificity of each disease population (AVMs and
cavernous angiomas) and of individuals were consistent with
those values reported for the entire population studied. The
authors concluded that pre-operative fMRI is a highly sensitive
pre-operative planning tool for identifying cortical areas that
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are essential for language; and that this imaging modality may
play a future role in pre-surgical planning for patients with
vascular malformations.
Anderson et al (2006) examined the utility of fMRI as a
determinant of lateralization of expressive language in children
with cerebral lesions. Functional MRI language lateralization
was attempted in 35 children (29 with epilepsy) aged 8 to 18
years with frontal or temporal lobe lesions (28 left hemisphere,
5 right hemisphere, and 2 bilateral). Axial and coronal fMRI
scans through the frontal and temporal lobes were acquired at
1.5 Tesla (T) by using a block-design, covert word-generation
paradigm. Activation maps were lateralized by blinded visual
inspection and quantitative asymmetry indices (hemispheric
and inferior frontal regions of interest, at p < 0.001 uncorrected
and p < 0.05 Bonferroni corrected). A total of 30 children
showed significant activation in the inferior frontal gyrus.
Lateralization by visual inspection was left in 21, right in 6, and
bilateral in 3, and concordant with hemispheric and inferior
frontal quantitative lateralization in 93 % of cases.
Developmental tumors and dysplasias involving the inferior left
frontal lobe had activation overlying or abutting the lesion in 5
of 6 cases. Functional MRI language lateralization was
corroborated in 6 children by frontal cortex stimulation or intra-
carotid Amytal testing (IAT) and indirectly supported by
aphasiology in a further 6 cases. In 2 children, fMRI language
lateralization was bilateral, and corroborative methods of
language lateralization were left. Neither lesion lateralization,
patient handedness, nor developmental versus acquired
nature of the lesion was associated with language
lateralization. Involvement of the left inferior or middle frontal
gyri increased the likelihood of atypical language
lateralization. The authors concluded that this study suggests
that fMRI lateralizes language in children with cerebral lesions.
Stancanello et al (2007) attempted to validate a method to
exploit functional information for the identification of functional
organs at risk (fOARs) in CyberKnife radiosurgery treatment
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planning. Five patients affected by AVMs and scheduled to
undergo radiosurgery were scanned prior to treatment using
computed tomography (CT), three-dimensional rotational
angiography (3D-RA), T2 weighted and blood oxygenation
level dependent echo planar imaging MRI. Tasks were
chosen on the basis of lesion location by considering those
areas which could be potentially close to treatment targets.
Functional data were superimposed on 3D-RA and CT used
for treatment planning. The procedure for the localization of
fMRI areas was validated by direct ESM on 38 AVM and tumor
patients undergoing conventional surgery. Treatment plans
studied with and without considering fOARs were significantly
different, in particular with respect to both maximum dose and
dose volume histograms; consideration of the fOARs allowed
quality indices of treatment plans to remain almost constant or
to improve in 4 out of 5 cases compared to plans with no
consideration of fOARs. The authors concluded that the
presented method provides an accurate tool for the integration
of functional information into AVM radiosurgery, which might
help to minimize undesirable side effects and to make
radiosurgery less invasive.
Stippich and colleagues (2007) prospectively evaluated the
feasibility of standardized pre-surgical fMRI for localizing the
Broca and Wernicke areas as well as for lateralizing language
function. A total of 81 patients (36 females, 45 males; aged 7
to 75 years) with different brain tumors underwent blood
oxygen level-dependent fMRI at 1.5 T with two paradigms: (i)
sentence generation (SG), and (ii) word generation (WG).
Functional MRI measurements, data processing, and
evaluation were fully standardized by using dedicated
software. Four regions of interest were evaluated in each
patient: the Broca and Wernicke areas and their anatomical
homologs in the right hemisphere. The SG and WG
paradigms were successfully completed by all (100 %) and 70
(86 %) patients, respectively. Success rates in localizing and
lateralizing language were 96 % for the Broca and Wernicke
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areas with the SG paradigm, 81 % for the Broca area and 80
% for the Wernicke area with the WG paradigm, and 98 % for
both areas when the SG and WG paradigms were used in
combination. Functional localizations were consistent for SG
and WG paradigms in the inferior frontal gyrus (Broca area)
and the superior temporal, supra-marginal, and angular gyri
(Wernicke area). Surgery was not performed in 7 patients (9
%) and was modified in 2 patients (2 %) because of fMRI
findings. The authors concluded that fMRI proved to be
feasible during routine diagnostic neuro-imaging for localizing
and lateralizing language function pre-operatively.
There is evidence for the use of fMRI in pre-surgical planning
for epilepsy and monitoring of language function during tumor
resection.
Roux et al (2003) analyzed the usefulness of pre-operative
language fMRI by correlating fMRI data with intra-operative
ESM results for patients with brain tumors. Naming and verb
generation tasks were used, separately or in combination, for
14 right-handed patients with tumors in the left hemisphere.
Acquired fMRI data were analyzed with statistical parametric
mapping software, with two standard analysis thresholds (p <
0.005 and then p < 0.05). The fMRI data were then registered
in a frameless stereotactic neuro-navigational device and
correlated with direct brain mapping results. These
researchers used a statistical model with the fMRI information
as a predictor, spatially correlating each intra-operatively
mapped cortical site with fMRI data integrated in the neuro-
navigational system (site-by-site correlation). Eight patients
were also studied with language fMRI post-operatively, with
the same acquisition protocol. These investigators observed
high variability in signal extents and locations among patients
with both tasks. The activated areas were located mainly in
the left hemisphere in the middle and inferior frontal gyri (F2
and F3), the superior and middle temporal gyri (T1 and T2),
and the supra-marginal and angular gyri. A total of 426
cortical sites were tested for each task among the 14 patients.
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In frontal and temporo-parietal areas, poor sensitivity of the
fMRI technique was observed for the naming and verb
generation tasks (22 % and 36 %, respectively) with p < 0.005
as the analysis threshold. Although not perfect, the specificity
of the fMRI technique was good in all conditions (97 % for the
naming task and 98 % for the verb generation task). Better
correlation (sensitivity, 59 %; specificity, 97 %) was achieved
by combining the two fMRI tasks. Variation of the analysis
threshold to p < 0.05 increased the sensitivity to 66 % while
decreasing the specificity to 91 %. Post-operative fMRI data
(for the cortical brain areas studied intra-operatively) were in
accordance with brain mapping results for 6 of 8 patients.
Complete agreement between pre- and post-operative fMRI
studies and direct brain mapping results was observed for
only 3 of 8 patients. The authors concluded that with the
paradigms and analysis thresholds used in this study,
language fMRI data obtained with naming or verb generation
tasks, before and after surgery, were imperfectly correlated
with intra-operative brain mapping results. A better correlation
could be obtained by combining the fMRI tasks. The overall
results of this study showed that language fMRI could not be
used to make critical surgical decisions in the absence of
direct brain mapping. Other acquisition protocols are needed
for evaluation of the potential role of language fMRI in the
accurate detection of essential cortical language areas.
Benke and associates (2006) noted that recent studies have
claimed that language fMRI can identify language lateralization
in patients with TLE and that fMRI-based findings are highly
concordant with the conventional assessment procedure of
speech dominance, the IAT. These researchers attempted to
establish the power of language fMRI to detect language
lateralization during pre-surgical assessment and compared
the findings of a semantic decision paradigm with the results of
a standard IAT in 68 patients with chronic intractable right and
left TLE (rTLE, n = 28; lTLE, n = 40) who consecutively
underwent a pre-surgical evaluation program. The patient
group also included 14 (20.6 %) subjects with atypical
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(bilateral or right hemisphere) speech. Four raters used a
visual analysis procedure to determine the laterality of speech-
related activation individually for each patient. Overall
congruence between fMRI-based laterality and the laterality
quotient of the IAT was 89.3 % in rTLE and 72.5 % in lTLE
patients. Concordance was best in rTLE patients with left
speech. In lTLE patients, language fMRI identified atypical,
right hemisphere speech dominance in every case, but missed
left hemisphere speech dominance in 17.2 %. Frontal
activations had higher concordance with the IAT than did
activations in temporo-parietal or combined regions of
interest. Because of methodological problems, recognition of
bilateral speech was difficult. The authors concluded that
these data provide evidence that language fMRI as used in the
present study has limited correlation with the IAT, especially in
patients with lTLE and with mixed speech dominance. They
noted that further refinements regarding the paradigms and
analysis procedures will be needed to improve the contribution
of language fMRI for pre-surgical assessment.
Petrella and colleagues (2006) prospectively evaluated the
effect of pre-operative fMRI localization of language and motor
areas on therapeutic decision making in patients with
potentially resectable brain tumors. A total of 39 consecutive
patients (19 men, 20 women; mean age of 42.2 years) referred
for fMRI for possible tumor resection were evaluated. A pre-
operative diagnosis of brain tumor was made in all patients.
Sentence completion and bilateral hand squeeze tasks were
used to map language and sensorimotor areas.
Neurosurgeons completed questionnaires regarding the
proposed treatment plan before and after fMRI and after
surgery. They also gave confidence ratings for fMRI results
and estimated the effect on surgical time, extent of resection,
and surgical approach. The effect of fMRI on changes in
treatment plan was assessed with the Wilcoxon signed rank
test. Differences in confidence ratings between altered and
un-altered treatment plans were assessed with the Mann-
Whitney U test. The estimated influence of fMRI on surgical
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time, extent of resection, and surgical approach was denoted
with summary statistics. Treatment plans before and after
fMRI differed in 19 patients (p < 0.05), with a more aggressive
approach recommended after imaging in 18 patients. There
were no significant differences in confidence ratings for fMRI
between altered and un-altered plans. Functional MRI
resulted in reduced surgical time (estimated reduction, 15 to
60 minutes) in 22 patients who underwent surgery, a more
aggressive resection in 6, and a smaller craniotomy in 2. The
authors concluded that fMRI enables the selection of a more
aggressive therapeutic approach than might otherwise be
considered because of functional risk. In certain patients,
surgical time may be shortened, the extent of resection
increased, and craniotomy size decreased.
Di et al (2007) assessed the differences in brain activation in
response to presentation of the patient's own name spoken by
a familiar voice (SON-FV) in patients with vegetative state (VS)
and minimally conscious state (MCS). By using fMRI, these
investigators prospectively studied residual cerebral activation
to SON-FV in 7 patients with VS and 4 patients with MCS.
Behavioral evaluation was performed by means of
standardized testing up to 3 months post-fMRI. Two patients
with VS failed to show any significant cerebral activation, while
3 patients with VS showed SON-FV induced activation within
the primary auditory cortex. Finally, 2 patients with VS and
all 4 patients with MCS not only showed activation in primary
auditory cortex but also in hierarchically higher order
associative temporal areas. The 2 patients with VS showing
the most widespread activation subsequently showed clinical
improvement to MCS observed 3 months after their fMRI
scan. The authors concluded that cerebral responses to
patient's own name spoken by a familiar voice as measured by
fMRI might be a useful tool to pre-clinically distinguish MCS-
like cognitive processing in some patients behaviorally
classified as vegetative.
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The American College of Radiology (ACR)'s guideline on
neurological imaging for patients with epilepsy (Karis et al,
2006) noted that the data provided by MRI are essential in the
pre-surgical evaluation of patients with medically refractory
epilepsy, but noted that structurally detectable abnormalities
are absent in many patients. In these patients, functional
studies provide useful information on localization of the seizure
focus. In this regard, functional imaging techniques, including
positron emission tomography, single-photon emission
computed tomography, magnetic source imaging, and fMRI,
have contributed to the pre-surgical evaluation of patients with
epilepsy. The ACR guideline provided appropriateness ratings
(1 = least appropriate; 9 = most appropriate) on fMRI for the
following indications:
▪ Chronic epilepsy, poor therapeutic response. Surgery
candidate (rating = 5; may be helpful in pre-surgical
planning).
▪ New onset of seizure. Ethyl alcohol, and/or drug-related
(rating = 2).
▪ New onset seizure. Aged 18 to 40 years (rating = 2).
▪ New onset seizure. Aged greater than 40 years (rating =
2).
▪ New onset seizure. Focal neurological deficit (rating = 2).
Additionally, the ACR's guideline on neurological imaging for
patients with head trauma (Davis et al, 2006) provided an
appropriateness rating of 2 for patients with sub-acute or
chronic closed head injury with cognitive and/or neurological
deficit(s).
The Ontario Ministry of Health and Long-Term Care's review
on functioning brain imaging (2006) stated that there may be a
role for fMRI in the identification of surgical candidates for
tumor resection. The review also stated that there may be
some clinical utility for fMRI in pre-surgical functional
mapping.
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The assessment by the Ontario Ministry of Health and Long-
Term Care (2006) stated that there is limited clinical utility of
functional brain imaging in the management of patients with
MS at this time. This is in agreement with the European
Federation of Neurological Societies' guideline on the use of
neuro-imaging in the management of MS (Filippi et al, 2006),
which stated that the use of non-conventional MRI techniques
(e.g., fMRI, diffusion tensor MRI, magnetization transfer MRI,
and MR spectroscopy) is not recommended.
Rocca and colleagues (2008) used fMRI to examine the
properties of the mirror neuron system (MNS) in patients with
MS. Using a 3 tesla scanner, these researchers acquired fMRI
in 16 right-handed patients with relapsing-remitting MS and 14
controls. Two motor tasks were studied. The first consisted of
repetitive flexion-extension of the last 4 fingers of the right
hand (simple task) alternated to epochs of rest; the second
(MNS task) consisted of observation of a movie showing the
hand of another subject while performing the same task.
During the simple task, compared to controls, patients with MS
had more significant activations of the contralateral primary
sensori-motor cortex and supplementary motor area. During
the MNS task, both groups showed the activation of several
visual areas, the infra-parietal sulcus, and the inferior frontal
gyrus (IFG), bilaterally. The IFG and the visual areas were
significantly more active in patients than controls. The between-
group interaction analysis showed that in patients with MS,
part of the regions of the MNS were more active also during the
simple task. The authors concluded that the findings of this
study suggested increased activation of the MNS in patients
with MS with a normal level of function and widespread damage
of the central nervous system. The potentialities of this system
in facilitating clinical recovery in patients with MS and other
neurological conditions should be investigated.
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In an editorial that accompanied the afore-mentioned article,
Phillips (2008) stated that fMRI has tremendous potential for
assessing and better understanding MS. He noted that it is
important to remember that fMRI is an indirect measurement of
neuronal activity. Also, it has been reported that there is
altered brain perfusion in patients with MS. Changes in
perfusion may alter the sensitivity and statistical characteristics
of fMRI. Currently, it is unclear to what extent altered tissue
perfusion complicates the interpretation of fMRI in MS.
Furthermore, the enhanced activation patterns observed in MS
have also been shown in other neurological conditions such as
Alzheimer's disease, Parkinson's disease, and stroke.
In a randomized, double-blind, placebo-controlled study, Atri et
al (2011) examined the feasibility and test-retest reliability of
encoding-task fMRI in mild Alzheimer disease (AD). These
investigators studied 12 patients with mild AD (mean [SEM]
Mini-Mental State Examination score, 24.0 [0.7]; mean Clinical
Dementia Rating score, 1.0) who had been taking donepezil
hydrochloride for more than 6 months from the placebo-arm of
a larger 24-week study (n = 24, 4 scans on weeks 0, 6, 12,
and 24, respectively). They performed whole-brain t maps (p
< 0.001, 5 contiguous voxels) and hippocampal regions-of-
interest analyses of extent (percentage of active voxels) and
magnitude (percentage of signal change) for novel-greater-
than-repeated face-name contrasts. These researchers also
calculated intra-class correlation coefficients and power
estimates for hippocampal regions of interest. Task tolerability
and data yield were high (95 of 96 scans yielded favorable-
quality data). Whole-brain maps were stable. Right and left
hippocampal regions-of-interest intraclass correlation
coefficients were 0.59 to 0.87 and 0.67 to 0.74, respectively.
To detect 25.0 % to 50.0 % changes in week-0 to week-12
hippocampal activity using left-right extent or right magnitude
with 80.0 % power (2-sided α = 0.05) requires 14 to 51
patients. Using left magnitude requires 125 patients because
of relatively small signal to variance ratios. The authors
concluded that encoding-task fMRI was successfully
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implemented in a single-site, 24-week, AD randomized
controlled trial. Week 0 to 12 whole-brain t maps were stable,
and test-retest reliability of hippocampal fMRI measures
ranged from moderate to substantial. Right hippocampal
magnitude may be the most promising of these candidate
measures in a leveraged context. These initial estimates of test-
retest reliability and power justify evaluation of encoding- task
fMRI as a potential biomarker for signal of effect in exploratory
and proof-of-concept trials in mild AD. They stated that
validation of these results with larger sample sizes and
assessment in multi-site studies is warranted.
Burgmer and colleagues (2010) stated that studies with
functional neuroimaging support the hypothesis of central pain
augmentation in fibromyalgia syndrome (FMS) with functional
differences in areas of the medial pain system. These
investigators examined if these findings are unique to patients
with FMS. BOLD-signal patterns during and before tonic
experimental pain were compared to healthy controls and
patients with rheumatoid arthritis (RA) as a chronic pain
disorder of somatic origin. These researchers expected
different BOLD-signal patterns in areas of the medial pain
system that were most pronounced in patients with FMS. An
fMRI-block design before, during and after an incision was
performed in patients with FMS (n = 17), RA (n = 16) and in
healthy controls (n = 17). A 2-factorial model of BOLD-signal
changes was designed to explore significant differences of
brain activation between the groups during the pain stimulus.
Additionally, the correlation of brain activity during the
anticipation of pain with the amount of the impending pain was
determined. These researchers observed a FMS-unique
temporal brain activation of the frontal cortex in patients with
FMS. Moreover, areas of the motor cortex and the cingulate
cortex presented a FMS-specific relation between brain activity
during pain anticipation and the magnitude of the subsequent
pain experience. The authors concluded that these findings
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support the hypothesis that central mechanisms of pain
processing in the frontal cortex and cingulate cortex may play
an important role in patients with FMS.
Tregellas et al (2010) noted that 3-(2,4-Dimethoxybenzylidene)
-anabaseine (DMXB-A) is a partial agonist at alpha7-nicotinic
acetylcholine receptors and is now in early clinical
development for treatment of deficits in neurocognition and
sensory gating in schizophrenia. During its initial phase II test,
fMRI studies were conducted to determine whether the drug
had its intended effect on hippocampal inhibitory interneurons.
Increased hemodynamic activity in the hippocampus in
schizophrenia is found during many tasks, including smooth
pursuit eye movements, and may reflect inhibitory
dysfunction. Placebo and 2 doses of drug were administered
in a random, double-blind cross-over design. After the
morning drug/placebo ingestion, subjects underwent fMRI
while performing a smooth pursuit eye movement task. Data
were analyzed from 16 non-smoking patients, including 7
women and 9 men. The 150-mg dose of DMXB-A, compared
with placebo, diminished the activity of the hippocampus
during pursuit eye movements, but the 75-mg dose was
ineffective. The effect at the 150-mg dose was negatively
correlated with plasma drug levels. The findings are
consistent with the previously established function of alpha7-
nicotinic receptors on inhibitory interneurons in the
hippocampus and with genetic evidence for deficits in these
receptors in schizophrenia. Imaging of drug response is useful
in planning future clinical tests of this compound and other
nicotinic agonists for schizophrenia.
Whalley et al (2012) noted that although bipolar disorder (BD)
and schizophrenia (SCZ) have a number of clinical features
and certain susceptibility genes in common, they are
considered separate disorders, and it is unclear which aspects
of pathophysiology are specific to each condition. These
researchers examined the fMRI literature to determine the
evidence for diagnosis-specific patterns of brain activation in
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these 2 patient groups. A systematic search was performed to
identify fMRI studies directly comparing BD and SCZ to
examine evidence for diagnosis-specific activation patterns.
Studies were categorized into (i) those investigating emotion,
reward, or memory, (ii) those describing executive function
or language tasks, and (iii) those looking at the resting state
or default mode networks. Studies reporting estimates of
sensitivity and specificity of classification were also
summarized, followed by studies reporting associations with
symptom severity measures. A total of 21 studies were
identified including patients (n = 729) and healthy subjects (n =
465). Relative over-activation in the medial temporal lobe and
associated structures was found in BD versus SCZ in tasks
involving emotion or memory. Evidence of differences
between the disorders in pre-frontal regions was less
consistent. Accuracy values for assignment of diagnosis were
generally lower in BD than in SCZ. Few studies reported
significant symptom associations; however, these generally
implicated limbic regions in association with manic symptoms.
The authors concluded that although there are a limited
number of studies and a cautious approach is warranted,
activation differences were found in the medial temporal lobe
and associated limbic regions, suggesting the presence of
differences in the neurobiological substrates of SCZ and BD.
They stated that future studies examining symptom
dimensions, risk-associated genes, and the effects of
medication will aid clarification of the mechanisms behind
these differences.
Astrakas et al (2012) stated that the number of individuals
suffering from stroke is increasing daily, and its consequences
are a major contributor to invalidity in today's society. Stroke
rehabilitation is relatively new, having been hampered from the
long-standing view that lost functions were not recoverable.
Nowadays, robotic devices, which aid by stimulating brain
plasticity, can assist in restoring movement compromised by
stroke-induced pathological changes in the brain that can be
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monitored by MRI. Multi-parametric MRI of stroke patients
participating in a training program with a novel Magnetic
Resonance Compatible Hand-Induced Robotic Device
(MR_CHIROD) could yield a promising biomarker that,
ultimately, will enhance the ability to advance hand motor
recovery following chronic stroke. Using state-of-the art MRI in
conjunction with MR_CHIROD-assisted therapy can provide
novel biomarkers for stroke patient rehabilitation extracted by
a meta-analysis of data. Successful completion of such
studies may provide a ground breaking method for the future
evaluation of stroke rehabilitation therapies. Their results will
attest to the effectiveness of using MR-compatible hand
devices with MRI to provide accurate monitoring during
rehabilitative therapy. Furthermore, such results may identify
biomarkers of brain plasticity that can be monitored during
stroke patient rehabilitation. The potential benefit for chronic
stroke patients is that rehabilitation may become possible for a
longer period of time after stroke than previously thought,
unveiling motor skill improvements possible even after 6
months due to retained brain plasticity.
Wager et al (2013) noted that persistent pain is measured by
means of self-report, the sole reliance on which hampers
diagnosis and treatment. Functional magnetic resonance
imaging holds promise for identifying objective measures of
pain, but brain measures that are sensitive and specific to
physical pain have not yet been identified. In 4 studies
involving a total of 114 participants, these researchers
developed an fMRI-based measure that predicts pain intensity
at the level of the individual person. In study 1, they used
machine-learning analyses to identify a pattern of fMRI activity
across brain regions -- a neurologic signature -- that was
associated with heat-induced pain. The pattern included the
thalamus, the posterior and anterior insulae, the secondary
somatosensory cortex, the anterior cingulate cortex, the peri-
aqueductal gray matter, and other regions. In study 2, these
investigators tested the sensitivity and specificity of the
signature to pain versus warmth in a new sample. In study 3,
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they assessed specificity relative to social pain, which
activates many of the same brain regions as physical pain. In
study 4, these researchers evaluated the responsiveness of
the measure to the analgesic agent remifentanil. In study 1,
the neurologic signature showed sensitivity and specificity of
94 % or more (95 % confidence interval [CI]: 89 to 98) in
discriminating painful heat from non-painful warmth, pain
anticipation, and pain recall. In study 2, the signature
discriminated between painful heat and non-painful warmth
with 93 % sensitivity and specificity (95 % CI: 84 to 100). In
study 3, it discriminated between physical pain and social pain
with 85 % sensitivity (95 % CI: 76 to 94) and 73 % specificity
(95 % CI, 61 to 84) and with 95 % sensitivity and specificity in
a forced-choice test of which of 2 conditions was more painful.
In study 4, the strength of the signature response was
substantially reduced when remifentanil was administered.
The authors concluded that it is possible to use fMRI to assess
pain elicited by noxious heat in healthy persons. Moreover,
they state that future studies are needed to assess whether
the signature predicts clinical pain.
Magland and Childress (2014) stated that real-time fMRI is
especially vulnerable to task-correlated movement artifacts
because statistical methods normally available in conventional
analyses to remove such signals cannot be used in the context
of real-time fMRI. Multi-voxel classifier-based methods,
although advantageous in many respects, are particularly
sensitive. These researchers systematically studied various
movements of the head and face to determine to what extent
these can "masquerade" as signal in multi-voxel classifiers. A
total of 10 subjects were instructed to move systematically (12
instructed movements) throughout fMRI exams and data from
a previously published real-time study was also analyzed to
determine the extent to which non-neural signals contributed
to the high reported accuracy in classifier output. Of potential
concern, whole-brain classifiers based solely on movements
exhibited false positives in all cases (p < 0.05). Artifacts were
also observed in the spatial activation maps for 2 of the 12
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movement tasks. In the retrospective analysis, it was
determined that the relatively high reported classification
accuracies were (fortunately) mostly explainable by neural
activity, but that in some cases performance was likely
dominated by movements. The authors concluded that
movement tasks of many types (including movements of the
body, eyes, and face) can lead to false positives in classifier-
based real-time fMRI paradigms.
The University of Michigan Health System’s clinical guideline
on “Attention-deficit hyperactivity disorder” (2013) listed
functional magnetic resonance imaging as one of the search
terms for the update of a previous version of this guideline.
Moreover, the updated guideline stated that “Diagnosis is
based on the Diagnostic and Statistical Manual of Mental
Disorders, fourth edition (DSM-IV-TR) criteria. The three main
types are primary hyperactive, primary inattentive, and
combined. No specific test can make the diagnosis”.
Furthermore, UpToDate reviews on “Attention deficit
hyperactivity disorder in children and adolescents: Clinical
features and evaluation” (Krull, 2014) and “Adult attention
deficit hyperactivity disorder in adults: Epidemiology,
pathogenesis, clinical features, course, assessment, and
diagnosis” (Bukstein, 2014) do not mention the use of fMRI as
a diagnostic tool.
Wager and colleagues (2013) noted that persistent pain is
measured by means of self-report, the sole reliance on which
hampers diagnosis and treatment. Functional MRI holds
promise for identifying objective measures of pain, but brain
measures that are sensitive and specific to physical pain have
not yet been identified. In 4 studies involving a total of 114
participants, these researchers developed an fMRI-based
measure that predicts pain intensity at the level of the
individual person. In study 1, they used machine-learning
analyses to identify a pattern of fMRI activity across brain
regions -- a neurologic signature -- that was associated with
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heat-induced pain. The pattern included the thalamus, the
posterior and anterior insulae, the secondary somatosensory
cortex, the anterior cingulate cortex, the periaqueductal gray
matter, and other regions. In study 2, these researchers
tested the sensitivity and specificity of the signature to pain
versus warmth in a new sample. In study 3, they assessed
specificity relative to social pain, which activates many of the
same brain regions as physical pain. In study 4, these
investigators assessed the responsiveness of the measure to
the analgesic agent remifentanil. In study 1, the neurologic
signature showed sensitivity and specificity of 94 % or more
(95 % CI: 89 to 98) in discriminating painful heat from non-
painful warmth, pain anticipation, and pain recall. In study 2,
the signature discriminated between painful heat and non-
painful warmth with 93 % sensitivity and specificity (95 % CI:
84 to 100). In study 3, it discriminated between physical pain
and social pain with 85 % sensitivity (95 % CI: 76 to 94) and
73 % specificity (95 % CI: 61 to 84) and with 95 % sensitivity
and specificity in a forced-choice test of which of 2 conditions
was more painful. In study 4, the strength of the signature
response was substantially reduced when remifentanil was
administered. The authors concluded that it is possible to use
fMRI to assess pain elicited by noxious heat in healthy
persons. Moreover, they stated that future studies are needed
to assess whether the signature predicts clinical pain.
Furthermore, the Work Loss Data Institute’s guideline on “Pain
(chronic)” (2013) listed fMRI as one of the interventions that
were considered, but are not recommended.
Stender et al (2014) stated that bedside clinical examinations
can have high rates of misdiagnosis of unresponsive
wakefulness syndrome (vegetative state) or minimally
conscious state. The diagnostic and prognostic usefulness of
neuroimaging-based approaches has not been established in
a clinical setting. These researchers carried out a validation
study of 2 neuroimaging-based diagnostic methods: (i) PET
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imaging and (ii) functional MRI (fMRI). For this clinical
validation study, these investigators included patients referred
to the University Hospital of Liege, Belgium, between January,
2008, and June, 2012, who were diagnosed by the authors’
unit with unresponsive wakefulness syndrome, locked-in
syndrome, or minimally conscious state with traumatic or non-
traumatic causes. They did repeated standardized clinical
assessments with the Coma Recovery Scale-Revised
(CRS-R), cerebral (18)F-fluorodeoxyglucose (FDG) PET, and
fMRI during mental activation tasks. They calculated the
diagnostic accuracy of both imaging methods with CRS-R
diagnosis as reference. They assessed outcome after 12
months with the Glasgow Outcome Scale-Extended. The
authors included 41 patients with unresponsive wakefulness
syndrome, 4 with locked-in syndrome, and 81 in a minimally
conscious state (48 = traumatic, 78 = non-traumatic; 110 =
chronic, 16 = subacute). (18)F-FDG PET had high sensitivity
for identification of patients in a minimally conscious state (93
%, 95 % CI: 85 to 98) and high congruence (85 %, 77 to 90 %)
with behavioral CRS-R scores. The active fMRI method was
less sensitive at diagnosis of a minimally conscious state (45
%, 30 to 61 %) and had lower overall congruence with
behavioral scores (63 %, 51 to 73 %) than PET imaging. (18)
F-FDG PET correctly predicted outcome in 75 of 102 patients
(74 %, 64 to 81 %), and fMRI in 36 of 65 patients (56 %, 43 to
67 %); 13 of 41 (32 %) of the behaviorally unresponsive
patients (i.e., diagnosed as unresponsive with CRS-R) showed
brain activity compatible with (minimal) consciousness (i.e.,
activity associated with consciousness, but diminished
compared with fully conscious individuals) on at least 1
neuroimaging test; 69 % of these (9 of 13) patients
subsequently recovered consciousness. The authors
concluded that cerebral (18)F-FDG PET could be used to
complement bedside examinations and predict long-term
recovery of patients with unresponsive wakefulness syndrome.
Moreover, they stated that active fMRI might also be useful for
differential diagnosis, but seems to be less accurate.
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UpToDate reviews on “Locked-in syndrome’ (Caplan, 2015)
and “Stupor and coma in adults” (Young, 2015) do not mention
functional MRI as a management tool.
Furthermore, an UpToDate review on “Treatment and
prognosis of coma in children’ (Thompson and Williams, 2015)
states that “Other neuroimaging modalities, MR spectroscopy,
functional MRI, positron emission tomography are not useful in
the evaluation of coma prognosis]. Studies, awaiting
validation, suggest that these tools may help discriminate
between persistent vegetative state, minimally conscious state
and other states of impaired consciousness”.
Anoxic-Ischemic Brain Injury
An UpToDate review on “Hypoxic-ischemic brain injury:
Evaluation and prognosis” (Weinhouse and Young, 2016)
states that “In the future, larger studies may find a role for
standard MRI as well as functional neuroimaging, such as
positron emission tomography (PET) and functional MRI
(fMRI), in the prognostic assessment of adults with anoxic-
ischemic brain injury …. fMRI studies have the potential to
detect network processing of sensory and motor responses,
showing some evidence of awareness in a small proportion of
behaviorally unresponsive patients. However, the
performance and interpretation of these studies remains
complex and is still investigational. There are also ethical
issues regarding quality of life in decision-making that need to
be resolved, namely whether patients who can generate such
binary responses can participate in a decision-making
process”.
Psychotic Depression
O'Connor and Agius (2015) stated that psychotic depression is
widely accepted as a specific subtype of unipolar major
depression. Magnetic resonance imaging studies have begun
to investigate the neurobiological changes that differentiate
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this subtype of major depression from non-psychotic
depression. Any differences may eventually be useful in
aiding diagnosis patients for whom there is diagnostic
uncertainty. This review collated the currently available
evidence. These investigators performed a systematic search
of the Medline, PubMed, Embase & Web of Science
databases was used to identify all articles comparing structural
grey matter or fMRI differences between adults (18 years or
older) with previously diagnosed psychotic and non-psychotic
depression in pre-defined regions of interest (hippocampus,
amygdala, cingulate, insula and frontal cortices). The results
were collated and organized according to brain region. There
was a paucity of studies addressing structural and functional
changes differentiating these 2 disorders and
recommendations regarding use of these modalities in
diagnosis cannot be made. From the available studies
decreases in frontal cortex grey matter volumes may
differentiate psychotic from non-psychotic depression while
further studies are needed to confirm decreases in insula
cortex volumes. Functional MRI studies showed associations
between altered activity in these 2 regions and cognitive
impairments in patients with psychotic depression. The
volumes of putative emotional processing regions including the
amygdala, hippocampus and anterior cingulate showed no
difference between psychotic and non-psychotic depression.
The authors concluded that structural and functional changes
in the higher associative regions of the frontal and insular
cortices appeared to differentiate psychotic and non-psychotic
depression to a greater degree than changes in putative
emotional processing regions. The quality of the evidence
both in terms of numbers of studies available and sample
sizes involved was very poor; but in regard to directing future
study, understanding the neurobiology of psychotic depression
may benefit from a more detailed assessment of these 2
regions.
Temporal Neocortical Epilepsy and Temporal Tumors
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On behalf of the American Academy of Neurology (AAN),
Szaflarski and colleagues (2017) evaluated the diagnostic
accuracy and prognostic value of fMRI in determining
lateralization and predicting post-surgical language and
memory outcomes. An 11-member panel rated available
evidence according to the 2004 AAN process. At least 2
panelists reviewed the full text of 172 articles and selected 37
for data extraction. Case reports, reports with less than 15
cases, meta-analyses, and editorials were excluded. The
authors concluded that the use of fMRI may be considered an
option for lateralizing language functions in place of
intracarotid amobarbital procedure (IAP) in patients with
medial temporal lobe epilepsy (MTLE; Level C), temporal
epilepsy in general (Level C), or extra-temporal epilepsy (Level
C). For patients with temporal neocortical epilepsy or temporal
tumors, the evidence is insufficient (Level U). They stated that
fMRI may be considered to predict post-surgical language
deficits after anterior temporal lobe resection (Level C). The
use of fMRI may be considered for lateralizing memory
functions in place of IAP in patients with MTLE (Level C), but is
of unclear utility in other epilepsy types (Level U). Moreover,
they stated that fMRI of verbal memory or language encoding
should be considered for predicting verbal memory outcome
(Level B); and fMRI using non-verbal memory encoding may
be considered for predicting visuospatial memory outcomes
(Level C). These investigators noted that pre-surgical fMRI
could be an adequate alternative to IAP memory testing for
predicting verbal memory outcome (Level C).
Anxiety Disorder
Wang and colleagues (2018) noted that impairments in
emotion regulation, and more specifically in cognitive re-
appraisal, are thought to play a key role in the pathogenesis of
anxiety disorders. However, the available evidence on such
deficits is inconsistent. To further illustrate the neurobiological
underpinnings of anxiety disorder, the present meta-analysis
summarized fMRI findings for cognitive re-appraisal tasks and
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investigated related brain areas. These investigators
performed a comprehensive series of meta-analyses of
cognitive reappraisal fMRI studies contrasting patients with
anxiety disorder with healthy control (HC) subjects, employing
an anisotropic effect-size signed differential mapping
approach. They also conducted a subgroup analysis of
medication status, anxiety disorder subtype, data-processing
software, and MRI field strengths. Meta-regression was used
to explore the effects of demographics and clinical
characteristics. A total of 8 studies, with 11 datasets including
219 patients with anxiety disorder and 227 HC, were
identified. Compared with HC, patients with anxiety disorder
showed relatively decreased activation of the bilateral
dorsomedial prefrontal cortex (dmPFC), bilateral dorsal
anterior cingulate cortex (dACC), bilateral supplementary
motor area (SMA), left ventromedial prefrontal cortex
(vmPFC), bilateral parietal cortex, and left fusiform gyrus
during cognitive re-appraisal. The subgroup analysis,
jackknife sensitivity analysis, heterogeneity analysis, and
Egger's tests further confirmed these findings. The authors
concluded that they identified the most robust functional
neuroimaging findings on cognitive re-appraisal in anxiety
disorder. The results demonstrated that patients with anxiety
disorder could not recruit the prefronto-parietal network,
including the dmPFC, dACC, SMA, vmPFC, and parietal
cortex, to down-regulate their emotion response. These
findings provided robust evidence that impairment of prefronto-
parietal neuronal circuits may play an important role in the
pathogenesis of anxiety disorder. This finding may provide
novel targets for medical or cognitive-behavioral interventions
and neuromodulation approaches (e.g., transcranial magnetic
stimulation). These researchers stated that with longitudinal
data, future investigations should further explore whether
these functional abnormities are associated with structural
changes or influenced by disease severity and medication
status.
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The authors stated that this study had several drawbacks.
First, the number of fMRI studies included was small; the
literature search yielded only 8 studies with 11 relevant
patients versus controls comparisons. This could affect the
generalizability of these findings, particularly in the subgroup
meta-analyses and meta-regressions analyses. Second, this
meta-analysis was based on co-ordinates from published
studies rather than raw statistical maps, which might reduce its
accuracy. Third, the heterogeneity of the data acquisition and
analysis techniques, including MRI field strengths, slice
thickness, voxel size, and data-processing software, may
reduce the accuracy of these results. Fourth, this meta-
analysis included studies of medicine-naive patients who had
undergone a medication wash-out period before scanning, so
that longer-term influences of medication on brain function
could not be completely excluded. Although these
researchers conducted a subgroup meta-analysis of the
medicine-naive, these results should be interpreted with
caution. Finally, some patients with anxiety disorder had co-
morbid major depression. Anxiety and major depressive
disorders may have different disorder-specific deficits in the
neural mechanisms of cognitive re-appraisal. Although the
patients fulfilled their criteria for co-morbid major depression
with anxiety disorder being the primary diagnosis, the
influence of major depression could not be completely ruled
out.
Childhood Mal-Treatment
Heany and associates (2018) stated that childhood mal-
treatment, including abuse and neglect, may have sustained
effects on the integrity and functioning of the brain, alter
neurophysiological responsivity later in life, and pre-dispose
individuals toward psychiatric conditions involving socio-
affective disturbances. This meta-analysis quantified
associations between self-reported childhood mal-treatment
and brain function in response to socio-affective cues in
adults. A total of 17 fMRI studies reporting on data from 848
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individuals examined with the Childhood Trauma
Questionnaire were included in a meta-analysis of whole-brain
findings, or a review of region of interest findings. The spatial
consistency of peak activations associated with mal-treatment
exposure was tested using activation likelihood estimation,
using a threshold of p < 0.05 corrected for multiple
comparisons. Adults exposed to childhood mal-treatment
showed significantly increased activation in the left superior
frontal gyrus and left middle temporal gyrus, and decreased
activation in the left superior parietal lobule and the left
hippocampus. Although hyper-responsivity to socio-affective
cues in the amygdala and ventral anterior cingulate cortex in
correlation with mal-treatment severity was a replicated finding
in region of interest studies, null results were reported as well.
The authors concluded that these findings suggested that
childhood mal-treatment had sustained effects on brain
function into adulthood, and high-lighted potential mechanisms
for conveying vulnerability to development of
psychopathology. These findings need to be further
investigated.
Obsessive-Compulsive Disorder
Lu and co-workers (2018) presented a study protocol for a
single-blind, randomized controlled trial (RCT) to examine the
feasibility and efficacy of mindfulness-based cognitive therapy.
A total of 120 un-medicated Chinese obsessive-compulsive
disorder (OCD) patients will be randomized to the mindfulness-
based cognitive therapy group, the selective serotonin
reuptake inhibitor group or the psycho-education group for 11
sessions in 10 weeks. A range of scales for clinical symptoms
and fMRI will be completed at baseline (week 0), mid-
intervention (week 4), post-intervention (week 10) and the
6- month follow-up (weeks 14, 22 and 34). The authors stated
that this study will have relevance to decisions about
therapeutic options for un-medicated OCD patients.
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Panic Disorder
Ni and colleagues (2020) stated that panic disorder (PD) is a
prevalent anxiety disorder, however, its neurobiology remains
poorly understood. It has been proposed that the
pathophysiology of PD is related to an abnormality in a
particular neural network. However, most studies investigating
resting-state functional connectivity (FC) have relied on a priori
restrictions of seed regions, which may bias observations.
These investigators examined changes in intra- and inter-
network FC in the whole brain of patients with PD using resting-
state fMRI. A voxel-wise data-driven independent component
analysis was performed on 26 PD patients and 27 healthy
controls (HCs). They compared the differences in the intra- and
inter-network FC between the 2 groups of subjects using
statistical parametric mapping with 2-sample t-tests. PD
patients exhibited decreased intra-network FC in the right
anterior cingulate cortex (ACC) of the anterior default mode
network, the left pre-central and post-central gyrus of the
sensori-motor network, the right lobule V/VI, the cerebellum
vermis, and the left lobule VI of the cerebellum network
compared with the HCs. The intra-network FC in the right
ACC was negatively correlated with symptom severity. None
of the pairs of resting state networks showed significant
differences in functional network connectivity between the 2
groups. The authors concluded that these results suggested
that the brain networks associated with emotion regulation,
interoceptive awareness, and fear and somatosensory
processing may play an important role in the pathophysiology
of PD.
Furthermore, an UpToDate review on “Panic disorder in adults:
Epidemiology, pathogenesis, clinical manifestations, course,
assessment, and diagnosis” (Roy-Byrne, 2020) does not
mention functional MRI as a management option.
Psychosis
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Gonzalez-Vivas and colleagues (2019) noted that little is
known regarding changes in brain functioning after 1st-
episode psychosis (FEP). Such knowledge is important for
predicting the course of disease and adapting interventions.
and fMRI has become a promising tool for examining brain
function at the time of symptom onset and at follow-up. These
researchers carried out a systematic review of longitudinal
fMRI studies with FEP patients according to PRISMA
guidelines. Resting-state and task-activated studies were
considered together. A total of 11 studies were included; they
reported on a total of 236 FEP patients who were evaluated by
2 fMRI scans and clinical assessments; 5 studies found hypo-
activation at baseline in prefrontal cortex areas, 2 studies
found hypo-activation in the amygdala and hippocampus, and
3 others found hypo-activation in the basal ganglia. Other hypo-
activated areas were the anterior cingulate cortex, thalamus and
posterior cingulate cortex; 10 out of 11 studies reported (partial)
normalization by increased activation after anti-psychotic
treatment. A minority of studies observed
hyper-activation at baseline. The authors concluded that this
review of longitudinal FEP samples studies showed a pattern
of predominantly hypo-activation in several brain areas at
baseline that may normalize to a certain extent following
treatment. These investigators stated that these findings
should be interpreted with caution given the small number of
studies and their methodological and clinical heterogeneity.
Language and Memory Decline (Evaluation After Epilepsy Surgery)
Schmid and colleagues (2018) noted that the European Union-
funded E-PILEPSY project was launched to develop
guidelines and recommendations for epilepsy surgery. In a
systematic review, these investigators evaluated the diagnostic
accuracy of fMRI, Wada test, magnetoencephalography
(MEG), and functional transcranial Doppler sonography (fTCD)
for language and memory decline after surgery. They carried
out a literature search using PubMed, Embase, and
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CENTRAL. The diagnostic accuracy was expressed in terms
of sensitivity and specificity for post-operative language or
memory decline, as determined by pre- and post-operative
neuropsychological assessments. If 2 or more estimates of
sensitivity or specificity were extracted from a study, 2 meta-
analyses were conducted, using the maximum ("best case")
and the minimum ("worst case") of the extracted estimates,
respectively. A total of 28 papers were eligible for data
extraction and further analysis. All tests for heterogeneity
were highly significant, indicating large between-study
variability (p < 0.001). For memory outcomes, meta-analyses
were conducted for Wada tests (n = 17) using both memory
and language laterality quotients. In the best case, meta-
analyses yielded a sensitivity estimate of 0.79 (95 % CI: 0.67
to 0.92) and a specificity estimate of 0.65 (95 % CI: 0.47 to
0.83). For the worst case, meta-analyses yielded a sensitivity
estimate of 0.65 (95 % CI: 0.48 to 0.82) and a specificity
estimate of 0.46 (95 % CI: 0.28 to 0.65). The overall quality of
evidence, which was assessed using Grading of
Recommendations Assessment, Development, and Evaluation
(GRADE) methodology, was rated as very low. Meta-analyses
concerning diagnostic accuracy of fMRI, fTCD, and MEG were
not feasible due to small numbers of studies (fMRI, n = 4;
fTCD, n = 1; MEG, n = 0). This also applied to studies
concerning language outcomes (Wada test, n = 6; fMRI, n = 2;
fTCD, n = 1; MEG, n = 0). The authors concluded that meta-
analyses could only be conducted in a few subgroups for the
Wada test with low-quality evidence. Thus, more evidence
from high-quality studies and improved data reporting are
needed. Moreover, these researchers stated that the large
between-study heterogeneity underlined the necessity for
more homogeneous and thus comparable studies in future
research.
CPT Codes / HCPCS Codes / ICD-10 Codes
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Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":
Code Code Description
CPT codes covered if selection criteria are met:
70554 Magnetic resonance imaging, brain, functional
MRI; including test selection and administration
of repetitive body part movement and/or visual
stimulation, not requiring physician or
psychologist administration
70555 requiring physician or psychologist
administration of entire neurofunctional testing
ICD-10 codes covered if selection criteria are met:
C71.0 -
C71.9
Malignant neoplasm of brain
C79.31 -
C79.49
Secondary malignant neoplasm of brain and
other parts of nervous system
D33.0 -
D33.2
Benign neoplasm of brain
D43.0 -
D43.2,
D43.4
Neoplasm of uncertain behavior of brain and
spinal cord
G40.001 -
G40.919
Epilepsy and recurrent seizures
Q28.2 -
Q28.3
Arteriovenous and other malformations of
cerebral vessels
R56.1 Post traumatic seizures
R56.9 Unspecified convulsions
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
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Code Code Description
F20.0
F20.9
F25.0
F25.9
Schizophrenia
F29 Unspecified psychosis not due to a substance
or known physiological condition
F30.10 -
F31.9
Bipolar I disorder
F32.3 Major depressive disorder, single episode,
severe with psychotic features
F33.3 Major depressive disorder, recurrent, severe
with psychotic symptoms
F41.0 -
F41.9
Other anxiety disorders
F42.2 -
F42.9
Obsessive-compulsive disorder
F90.1 -
F90.9
Attention-deficit hyperactivity disorder,
G20 -
G21.9
Parkinson's disease and secondary
parkinsonism
G30.0 -
G30.9
Alzheimer's disease
G35 Multiple sclerosis
G45.0
G45.2
G45.4
G45.9
Transient cerebral ischemic attacks and related
syndromes
G89.21 -
G89.29
Chronic pain
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Code Code Description
G93.1 Anoxic brain damage, not elsewhere classified
G93.81 -
G93.89
Other specified disorders of brain [Locked-in
syndrome]
I63.00 -
I66.9
Cerebral infarction, occlusion and stenosis of
cerebral and precerebral arteries not resulting
in cerebral infarction
I67.1 -
I69.998
Cerebovascular diseases and disorders
M79.7 Fibromyalgia
R40.20 -
R40.236+
Coma
R40.3 Persistent vegetative state
S01.00x+
-
S02.92x+
Open wound of head and fracture of skull and
facial bones
S05.20x+
-
S05.92x+
Injury of eye and orbit
S06.0x0+
-
S06.9x9+
Intracranial injury
S08.0xx+
-
S08.89x+
Avulsion and traumatic amputation of part of
head
S09.20x+
-
S09.90x+
Other and unspecified injuries of head
Functional Magnetic Resonance Imaging - Medical Clinical Policy Bulletins | Aetna Page 34 of 42
Code Code Description
T74.12xA
-
T74.12xS
Child physical abuse, confirmed
T74.92xA
-
T74.92xS
Unspecified child maltreatment, confirmed
T76.12xA
-
T76.12xS
Child physical abuse, suspected
T76.92xA
-
T76.92xS
Unspecified child maltreatment
Functional Magnetic Resonance Imaging - Medical Clinical Policy Bulletins | Aetna Page 35 of 42
The above policy is based on the following references:
1. Alustiza I, Radua J, Pla M, et al. Meta-analysis of
functional magnetic resonance imaging studies of
timing and cognitive control in schizophrenia and
bipolar disorder: Evidence of a primary time deficit.
Schizophr Res. 2017;188:21-32.
2. Anderson DP, Harvey AS, Saling MM, et al. FMRI
lateralization of expressive language in children with
cerebral lesions. Epilepsia. 2006;47(6):998-1008.
3. Astrakas LG, Naqvi SH, Kateb B, Tzika AA. Functional
MRI using robotic MRI compatible devices for
monitoring rehabilitation from chronic stroke in the
molecular medicine era (Review). Int J Mol Med.
2012;29(6):963-973.
4. Atri A, O'Brien JL, Sreenivasan A, et al. Test-retest
reliability of memory task functional magnetic
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Functional Magnetic Resonance Imaging - Medical Clinical Policy Bulletins | Aetna Page 36 of 42
resonance imaging in Alzheimer disease clinical trials.
Arch Neurol. 2011;68(5):599-606.
5. Augustovski F, Pichon Riviere, A, Alcaraz A, et al.
Functional magnetic resonance imaging for brain
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Health Policy (IECS); 2005.
6. Benke T, Köylü B, Visani P, et al. Language
lateralization in temporal lobe epilepsy: A comparison
between fMRI and the Wada Test. Epilepsia. 2006;47
(8):1308-1319.
7. Bookheimer S. Pre-surgical language mapping with
functional magnetic resonance imaging. Neuropsychol
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8. Bukstein O. Adult attention deficit hyperactivity
disorder in adults: Epidemiology, pathogenesis, clinical
features, course, assessment, and diagnosis.
UpToDate [online serial]. Waltham, MA: UpToDate;
reviewed July 2014.
9. Burgmer M, Pogatzki-Zahn E, Gaubitz M, et al.
Fibromyalgia unique temporal brain activation during
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10. Byrne RW. Mapping of eloquent cortex in focal
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11. Canu E, Sarasso E, Filippi M, Agosta F. Effects of
pharmacological and nonpharmacological treatments
on brain functional magnetic resonance imaging in
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13. Cirstea CM, Brooks WM, Craciunas SC, et al. Primary
motor cortex in stroke: A functional MRI-guided proton
MR spectroscopic study. Stroke. 2011;42(4):1004-1009.
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patient's own name in the vegetative and minimally
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17. Filippi M, Rocca MA, Arnold DL, et al. EFNS guidelines
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21. Heany SJ, Groenewold NA, Uhlmann A, et al. The
neural correlates of childhood trauma questionnaire
scores in adults: A meta-analysis and review of
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22. Ibanez V, Deiber MP. Functional imaging in mild
cognitive impairment and early Alzheimer's disease: Is
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Functional Magnetic Resonance Imaging - Medical Clinical Policy Bulletins | Aetna Page 38 of 42
23. Karis JP, Seidenwurm DJ, Davis PC, et al.; Expert Panel
on Neurologic Imaging. Epilepsy. ACR Appropriateness
Criteria. Reston, VA: American College of Radiology
(ACR); 2006.
24. Krull KR. Attention deficit hyperactivity disorder in
children and adolescents: Clinical features and
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UpToDate; reviewed July 2014.
25. Lu L, Zhang T, Gao R, et al. Mindfulness-based
cognitive therapy for obsessive-compulsive disorder:
Study protocol for a randomized controlled trial with
functional magnetic resonance imaging and a 6-month
follow-up. J Health Psychol. 2018 Jul 1 [Epub ahead of
print].
26. Magland JF, Childress AR. Task-correlated facial and
head movements in classifier-based real-time fMRI. J
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27. Matchar DB, Kulasingam SL, Huntington A, et al.
Positron emission tomography, single photon
emission computed tomography, computed
tomography, functional magnetic resonance imaging,
and magnetic resonance spectroscopy and for the
diagnosis and management of Alzheimer's dementia.
Technology Assessment. Prepared by the Duke Center
for Clinical Health Policy Research and Evidence Based
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Quality (AHRQ). Contract No. 290-02-0025, Task Order
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28. Medina LS, Bernal B, Dunoyer C, et al. Seizure
disorders: Functional MR imaging for diagnostic
evaluation and surgical treatment – prospective study.
Radiology. 2005;236(1):247-253.
29. Ni M-F, Zhang B-W, Chang Y, et al. Altered resting-state
network connectivity in panic disorder: An
independent component analysis. Brain Imaging
Behav. 2020 Aug 3 [Online ahead of print].
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Functional Magnetic Resonance Imaging - Medical Clinical Policy Bulletins | Aetna Page 39 of 42
30. O'Connor S, Agius M. A systematic review of structural
and functional MRI differences between psychotic and
nonpsychotic depression. Psychiatr Danub. 2015;27
Suppl 1:S235-S239.
31. Ontario Ministry of Health and Long-Term Care,
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Ontario Ministry of Health and Long-Term Care;
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32. Petrella JR, Shah LM, Harris KM, et al. Preoperative
functional MR imaging localization of language and
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33. Phillips MD. Functional faults: fMRI in MS. Neurology.
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34. Pouratian N, Bookheimer SY, Rex DE, et al. Utility of
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MA. Last reviewed July 2020.
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Functional Magnetic Resonance Imaging - Medical Clinical Policy Bulletins | Aetna Page 40 of 42
39. Sabsevitz DS, Swanson SJ, Hammeke TA, et al. Use of
preoperative functional neuroimaging to predict
language deficits from epilepsy surgery. Neurology.
2003;60(11):1788-1792.
40. Schmid E, Thomschewski A, Taylor A, et al; E-PILEPSY
consortium. Diagnostic accuracy of functional
magnetic resonance imaging, Wada test,
magnetoencephalography, and functional transcranial
Doppler sonography for memory and language
outcome after epilepsy surgery: A systematic review.
Epilepsia. 2018;59(12):2305-2317.
41. Stancanello J, Cavedon C, Francescon P, et al. BOLD
fMRI integration into radiosurgery treatment planning
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Functional Magnetic Resonance Imaging - Medical Clinical Policy Bulletins | Aetna Page 41 of 42
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49. Wang HY, Zhang XX, Si CP, et al. Prefrontoparietal
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)
Functional Magnetic Resonance Imaging - Medical Clinical Policy Bulletins | Aetna Page 42 of 42
Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan
benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,
general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care
services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors
in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely
responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is
subject to change.
Copyright © 2001-2020 Aetna Inc.
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AETNA BETTER HEALTH® OF PENNSYLVANIA
Amendment to Aetna Clinical Policy Bulletin Number: 0739 Functional
Magnetic Resonance Imaging
There are no amendments for Medicaid.
revised 10/29/2020
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