0739 functional magnetic resonance imaging (3)

of 42

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

Proprietary

https://www.aetna.com/

Functional Magnetic Resonance Imaging - Medical Clinical Policy Bulletins | Aetna of 42

▪ 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

Proprietary


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

Proprietary


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

Proprietary


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

Proprietary


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

Proprietary


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

Proprietary


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.

Proprietary


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

Proprietary


(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

Proprietary


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.

Proprietary


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.

Proprietary


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.

Proprietary


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

Proprietary


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

Proprietary


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

Proprietary


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

Proprietary


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,

Proprietary


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

Proprietary

Proprietary

http://aetnet.aetna.com/mpa/cpb/700_799/0739.html 12/23/2020


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

http://aetnet.aetna.com/mpa/cpb/700_799/0739.html

Proprietary



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


Proprietary



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.


Proprietary



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


Proprietary



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


Proprietary



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


Proprietary



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.


Proprietary



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


Proprietary



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.


Proprietary



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


Proprietary



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


Proprietary



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


Proprietary



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):


Proprietary



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



Proprietary



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




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


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

Proprietary



Proprietary



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

pathologies [summary]. Report IRR No. 50. Buenos

Aires, Argentina: Institute for Clinical Effectiveness and

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

Rev. 2007;17(2):145-155.

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

experimental pain: A controlled fMRI Study. J Neural

Transm. 2010;117(1):123-131.

10. Byrne RW. Mapping of eloquent cortex in focal

epilepsy with intracranial electrodes. In: Byrne RW,

eds. Functional Mapping of the Cerebral Cortex: Safe

Surgery in Eloquent Brain. New York, NY; Springer

International; 2016.

11. Canu E, Sarasso E, Filippi M, Agosta F. Effects of

pharmacological and nonpharmacological treatments

on brain functional magnetic resonance imaging in

Alzheimer's disease and mild cognitive impairment: A

critical review. Alzheimers Res Ther. 2018;10(1):21.

12. Caplan LR. Locked-in syndrome. UpToDate [online

serial]. Waltham, MA: UpToDate; reviewed July 2015.


Proprietary



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.

14. Corabian P, Hailey D. Functional diagnostic imaging in

epilepsy. Health Technology Assessment Series.

Edmonton, AB: Alberta Heritage Foundation for

Medical Research (AHFMR); 1998.

15. Davis PC, Seidenwurm DJ, Brunberg JA, et al.; Expert

Panel on Neurologic Imaging. Head trauma. ACR

Appropriateness Criteria. Reston, VA: American College

of Radiology (ACR); 2006.

16. Di HB, Yu SM, Weng XC, et al. Cerebral response to

patient's own name in the vegetative and minimally

conscious states. Neurology 2007; 68:895-899.

17. Filippi M, Rocca MA, Arnold DL, et al. EFNS guidelines

on the use of neuroimaging in the management of

multiple sclerosis. Eur J Neurol 2006;13(4):313-325.

18. Gaillard WD, Berl MM, Duke ES, et al. fMRI language

dominance and FDG-PET hypometabolism. Neurology.

2011;76(15):1322-1329.

19. Gaillard WD, Chiron C, Cross JH, et al; ILAE, Committee

for Neuroimaging, Subcommittee for Pediatric.

Guidelines for imaging infants and children with recent-

onset epilepsy. Epilepsia. 2009;50(9):2147-2153.

20. Gonzalez-Vivas C, Soldevila-Matias P, Sparano O, et al.

Longitudinal studies of functional magnetic resonance

imaging in first-episode psychosis: A systematic

review. Eur Psychiatry. 2019;59:60-69.

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

functional magnetic resonance imaging studies. Dev

Psychopathol. 2018;30(4):1475-1485.

22. Ibanez V, Deiber MP. Functional imaging in mild

cognitive impairment and early Alzheimer's disease: Is

it pertinent? Front Neurol Neurosci. 2009;24:30-38.


Proprietary



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

evaluation. UpToDate [online serial]. Waltham, MA:

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

Neuroimaging. 2014;24(4):371-378.

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

Center for the Agency for Healthcare Research and

Quality (AHRQ). Contract No. 290-02-0025, Task Order

# 1. Rockville, MD: AHRQ; April 30, 2004.

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].


Proprietary



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,

Medical Advisory Secretariat. Functional brain imaging.

Health Technology Policy Assessment. Toronto, ON:

Ontario Ministry of Health and Long-Term Care;

December 2006.

32. Petrella JR, Shah LM, Harris KM, et al. Preoperative

functional MR imaging localization of language and

motor areas: Effect on therapeutic decision making in

patients with potentially resectable brain tumors.

Radiology. 2006;240(3):793-802.

33. Phillips MD. Functional faults: fMRI in MS. Neurology.

2008;70(4):248-249.

34. Pouratian N, Bookheimer SY, Rex DE, et al. Utility of

preoperative functional magnetic resonance imaging

for identifying language cortices in patients with

vascular malformations. J Neurosurg. 2002;97(1):21-32.

35. Prodoehl J, Burciu RG, Vaillancourt DE. Resting state

functional magnetic resonance imaging in Parkinson's

disease. Curr Neurol Neurosci Rep. 2014;14(6):448.

36. Rocca MA, Tortorella P, Ceccarelli A, et al. The 'mirror

neuron system' in MS: A 3 tesla fMRI study. Neurology.

2008;70(4):255-262.

37. Roux FE, Boulanouar K, Lotterie JA, et al. Language

functional magnetic resonance imaging in

preoperative assessment of language areas:

Correlation with direct cortical stimulation.

Neurosurgery. 2003;52(6):1335-1345; discussion 1345

1347.

38. Roy-Byrne PP. Panic disorder in adults: Epidemiology,

pathogenesis, clinical manifestations, course,

assessment, and diagnosis. UpToDate Inc., Waltham,

MA. Last reviewed July 2020.


Proprietary



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

of cerebral vascular malformations. Med Phys. 2007;34

(4):1176-1184.

42. Stender J, Gosseries O, Bruno MA, et al. Diagnostic

precision of PET imaging and functional MRI in

disorders of consciousness: A clinical validation study.

Lancet. 2014;384(9942):514-522.

43. Stippich C, Rapps N, Dreyhaupt J, et al. Localizing and

lateralizing language in patients with brain tumors:

Feasibility of routine preoperative functional MR

imaging in 81 consecutive patients. Radiology.

2007;243(3):828-836.

44. Szaflarski JP, Gloss D, Binder JR, et al. Practice guideline

summary: Use of fMRI in the presurgical evaluation of

patients with epilepsy: Report of the Guideline

Development, Dissemination, and Implementation

Subcommittee of the American Academy of

Neurology. Neurology. 2017;88(4):395-402.

45. Thompson L, Williams E. Treatment and prognosis of

coma in children. UpToDate [online serial]. Waltham,

MA: UpToDate; reviewed July 2015.

46. Tregellas JR, Olincy A, Johnson L, et al. Functional

magnetic resonance imaging of effects of a nicotinic

agonist in schizophrenia. Neuropsychopharmacology.

2010;35(4):938-942.


Proprietary



47. University of Michigan Health System. Attention-deficit

hyperactivity disorder. Ann Arbor, MI: University of

Michigan Health System. April 2013.

48. Wager TD, Atlas LY, Lindquist MA, et al. An fMRI-based

neurologic signature of physical pain. N Engl J Med.

2013;368(15):1388-1397.

49. Wang HY, Zhang XX, Si CP, et al. Prefrontoparietal

dysfunction during emotion regulation in anxiety

disorder: A meta-analysis of functional magnetic

resonance imaging studies. Neuropsychiatr Dis Treat.

2018;14:1183-1198.

50. Weinhouse GL, Young GB. Hypoxic-ischemic brain

injury: Evaluation and prognosis. UpToDate [online

serial]. Waltham, MA: UpToDate; reviewed June 2016.

51. Whalley HC, Papmeyer M, Sprooten E, et al. Review of

functional magnetic resonance imaging studies

comparing bipolar disorder and schizophrenia. Bipolar

Disord. 2012;14(4):411-431.

52. Woermann FG, Jokeit H, Luerding R, et al. Language

lateralization by Wada test and fMRI in 100 patients

with epilepsy. Neurology. 2003;61(5):699-701.

53. Work Loss Data Institute. Pain (chronic). Encinitas, CA:

Work Loss Data Institute. November 14, 2013.

54. Young CB. Stupor and coma in adults.

UpToDate [online serial]. Waltham, MA:

UpToDate; reviewed July 2015.


)


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.

Proprietary



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

Proprietary

0739 functional magnetic resonance imaging (3)

Documents