individuals exposed to a traumatic event may develop post - traumatic stress disorder ( ptsd ) with debilitating post - traumatic stress symptoms , including intrusive memories , avoidance behavior , emotional numbing , and hyperarousal ( american psychiatric association , 2004 ) . is particularly prevalent among military service members who have served in combat ( dohrenwend et al . , 2006 ; the recent conflicts in iraq and afghanistan have been no exception , with combat veterans returning with elevated rates of ptsd ( hoge et al . , 2004 ; smith et al . , 2008 ; tanielian and jaycox , 2008 ) . in light of these findings , much effort has been focused on determining symptom etiology and the associated neural mechanisms of ptsd . the development of neurocircuitry models of ptsd has relied strongly on findings from pre - clinical studies of fear conditioning . evidence from lesion studies , pharmacological manipulations , and electrophysiology in animals and humans suggest that interactions between the amygdala , ventromedial prefrontal cortex ( vmpfc ) , and hippocampus control different aspects of fear processing ( hartley and phelps , 2010 ; rosen and lilienfeld , 2008 ) . the amygdala is involved in acquisition of fear conditioning and extinction learning , whereas the vmpfc is thought to mediate memory storage and retrieval during extinction learning . hippocampal connections to the amygdala and vmpfc may support processing contextual information of threat - related stimuli . amygdala , vmpfc , and hippocampal regions implicated in pre - clinical fear processing are thought to be dysfunctional in ptsd ( rauch et al . functional neuroimaging findings using positron emission topography ( pet ) and functional magnetic resonance imaging ( fmri ) suggest that individuals with ptsd exhibit hyperresponsive amygdala activity to trauma or fear - related stimuli ( shin and liberzon , 2010 ) , during emotionally neutral tasks ( bryant et al . , 2005 ; shin et al . , 2004b ) , and even at rest ( chung et al . , 2006 ; a hyperresponsive amygdala contributes to the exaggerated fear response characteristic of ptsd ( anderson et al . , conversely , ptsd has been associated with a hyporesponsive vmpfc ( hughes and shin , 2011 ) . a hyporesponsive pfc , as well as reduced connectivity to the amygdala ( jin et al . , 2013 ; shin et al . , 2004a ) may indicate insufficient inhibitory control over exaggerated fear responses . lastly , abnormal hippocampal function ( corcoran and maren , 2001 ) and reduced connectivity to the amygdala ( dolcos et al . , 2004 ; mcgaugh , 2004 ) may be associated impairments in contextual memory processing and the ability to inhibit intrusive memories ( shin et al . , 2004a ) , although findings have been mixed ( hughes and shin , 2011 ) . a recent resting - state fmri study showed increased activity in amygdala and reduced spontaneous neural activity in the dlpfc , but no abnormal decrease of resting - state fmri activity in the vmpfc ( yan et al . , 2013 ) . neuroimaging studies using pet and fmri have contributed greatly to understanding ptsd neurocircuitry in humans ; however , these techniques measure metabolic and hemodynamic changes which reflect neuronal activity indirectly ( logothetis , 2003 ) . in addition , pet and fmri techniques have limited temporal resolution ( minutes to seconds ) and consequently limited coverage and resolution in the frequency domain . since neurons communicate to each other via exchanging electric current signals , direct electrophysiological measures are required to study neurophysiological processes that are associated with these hemodynamic signals ( scholvinck et al . , 2013 ) . pet and fmri studies also have implicated different neural pathways that may be hyporesponsive in ptsd ; thus , there is some remaining discrepancy whether ptsd is associated with reduced activity in the vmpfc or dlpfc pathways . furthermore , although the orbitofrontal cortex ( ofc ) is usually considered to be part of the extended limbic system , the contribution of ofc to ptsd has not been fully elucidated . electromagnetic measures such as magnetoencephalography ( meg ) provide direct measurements of neuronal activity with millisecond temporal resolution . using a single dipole model , kolassa and colleagues reported elevated production of focally generated slow waves ( 14  hz ) in ptsd , particularly in left temporal brain regions , with peak activities in the region of the insula . using a meg sensor - space synchronous neural interactions analysis , georgopoulos , engdahl , and their colleagues correctly classified individuals with ptsd and healthy control subjects with > 90% overall accuracy of classification ( georgopoulos et al . , 2010 ) . they also found differences in meg communication measures between temporal and parietal and/or parieto - occipital right hemispheric areas with other brain areas in ptsd ( engdahl et al . , 2010 ) . however in sensor space , it is difficult to determine whether the structures identified by pet and fmri in ptsd neurocircuitry generate abnormal electromagnetic activity . namely , whether electromagnetic - based source imaging techniques will lead to similar or different findings from those obtained in pet and fmri in ptsd neurocircuitry has largely been unexplored . in the current study , we examined neural activity associated with ptsd using resting - state meg . meg is a non - invasive functional imaging technique that directly measures magnetic signals generated by neuronal current in gray matter with high temporal resolution ( < 1  ms ) and spatial localization accuracy ( 23  mm at cortical level ) ( leahy et al . , 1998 ) . meg 's high temporal resolution directly translates into a wide range of coverage for the neuronal magnetic signals in the frequency domain , which is usually divided into different frequency bands . meg 's insensitivity to the electric conductivity profile of the head tissue makes it a better technique than electroencephalography ( eeg ) in localizing neuronal sources . our newly developed high - resolution meg source imaging method called fast - vestal allowed us to perform voxel - wise whole - brain source imaging of human brain rhythms in healthy volunteers ( huang et al . , 2014a ) , and makes meg source imaging a good candidate for localizing abnormal electromagnetic signals in disorders such as ptsd . the primary goal for this study was to examine if the existing ptsd neurocircuitry model including the amygdala , vmpfc , and hippocampus can account for abnormalities detected directly by electromagnetic - based source imaging techniques in resting - state . to achieve this goal , we used high - resolution meg source imaging technique for direct examination of neuronal activity in ptsd , especially in the areas that we think to be abnormal , i.e. amygdala , vmpfc , ofc , hippocampus , dlpfc , dmpfc including dorsal anterior cingulate cortex ( dacc ) , insular cortex , and precuneous . in addition , using meg , we are able to explore potential meg abnormalities in different frequency bands which are associated with different neuronal mechanisms ( see discussion ) , and compare meg findings with previously published results from other functional imaging techniques that have been used to study ptsd . twenty - five participants ( 24 males , 1 female ; mean [ sd ] age : 31.0 [ 5.5 ] ) with ptsd took part in this study . among these participants , 10 were active - duty marines and sailors from camp pendleton and naval medical center in san diego , and 15 were adult outpatient oef / oif veterans recruited from va san diego healthcare system . mean [ sd ] years of education for the participants with ptsd were 13.2 [ 1.4 ] . all participants gave written informed consent for study procedures , which were reviewed and approved by institutional review boards of the va san diego healthcare system and naval health research center at san diego . the informed consent followed the ethical guidelines of the declarations of helsinki ( 1975 ) and additional research requirements for active - duty military personnel and veterans . symptoms of ptsd were assessed using the clinician administered ptsd scale ( caps ) ( blake et al . , 1995 ) or the post - traumatic stress disorder checklist ( pcl ) ( weathers et al . , 1999 ) in accordance with the criteria from the diagnostic and statistical manual of mental disorders iv - tr ( american psychiatric association , 2000 ) . a total of 18 participants met the criteria for ptsd and 7 met the criteria for partial ptsd . participants who completed the caps met the criteria for ptsd ( n  =  14 ) if they reported at least 1 re - experiencing symptom , 3 avoidance symptoms , and 2 hyperarousal symptoms ; patients met the criteria for partial ptsd ( n  =  5 ) if they reported at least 1 re - experiencing symptom and either 3 avoidance symptoms or 2 hyperarousal symptoms ( blanchard et al . , symptoms must have occurred at least once within the past month ( frequency   1 ) and have caused a moderate amount of distress ( intensity    2 ) ( weathers et al . , 1999 , 2001 ) . participants who completed the pcl questionnaire and had a minimum total score of 50 met the criteria for ptsd ( n  =  3 ) , and those with scores from 39 to 49 met the criteria for partial ptsd ( n  =  2 ) ( hoge et al . , 2008 ; iversen et al . , 2008 ; study participants with partial ptsd and ptsd were analyzed together ( n  =  25 ) to maintain statistical power and to examine broad group differences in ptsd neurocircuitry . all had discontinued any psychotropic medications prior to the scan , and at least at 5-day wash - out . we recruited thirty healthy volunteers ( 29 male , 1 female ; mean [ sd ] age : 29.8 [ 6.4 ] ) with no history of neurological or psychiatric disorders assessed by structured clinical interview for dsm - iv . among these healthy volunteers , there were no statistically significant differences in age or education between the healthy volunteer and ptsd groups . exclusion criteria for study participation were as follows : 1 ) other neurological , developmental or psychiatric disorders ( e.g. , brain tumor , stroke , epilepsy , alzheimer 's disease , or schizophrenia , bipolar disorder , history of learning disability , or lesions visible in structural mri ) ; 2 ) substance or alcohol abuse according to dsm - iv criteria within the 6  months prior to the study ; 3 ) history of metabolic or other diseases known to affect the central nervous system ( dikmen et al . , 1995 ) ; and 4 ) extensive metal dental hardware ( e.g. , braces and large metal dentures ; fillings are permitted ) or other metal objects in the head , neck , or face areas that cause non - removable meg artifacts . resting - state meg data ( spontaneous recording for detecting meg slow - wave signals ) were collected at the ucsd meg center using the vectorview whole - head meg system ( elekta - neuromag , helsinki , finland ) with 306 meg channels . participants sat inside a multi - layer magnetically - shielded room ( imedco - ag ) ( cohen et al . , 2002 ) . precautions were taken to ensure head stability ; foam wedges were inserted between the participant 's head and the inside of the unit , and a velcro strap was placed under the participant 's chin and anchored in superior and posterior axes . meg recording was divided into two 5-minute blocks with eyes closed , alternating with two 5-minute blocks with eyes open . in the eyes - closed condition , the participant was instructed to keep his / her eyes closed and empty his / her mind . in the eyes - open condition , the participant was instructed to fix his / her eyes on a fixation point and empty his / her mind . data were sampled at 1000  hz and were run through a high - pass filter with a 0.1  hz cut - off , and a low - pass filter with a 300  hz cut - off . the filter associated with meg data acquisition is a first - order time - domain filter with 3  db around the cut - off points . eye blinks , eye movements , and heart signals were monitored . since the meg eyes - open data were contaminated with eye - blinks in many participants , we focused on analyzing the eyes - closed data in the present study . substantial efforts were taken to help ensure that participants were alert during the meg recordings . prior to all of the study sessions , participants completed a questionnaire about the number of hours they slept the previous night , how rested they felt , and if there was any reason that they might not be attentive and perform to the best of their abilities ( due to headache , pain , etc . ) . sessions alternated between eyes - closed and eyes - open conditions , and eye blinking and movement were monitored . during meg recording , participants were viewed on camera while technicians also monitored alpha band oscillations , which are consistently associated with tonic alertness ( oken et al . , 2006 ) . eyes - closed meg data were first run through maxfilter , also known as signal space separation ( song et al . , 2008 ; taulu et al . , 2004a , b ) to remove external sources of interference ( e.g. , magnetic artifacts due to metal objects , strong cardiac signals , environment noises ) , and to co - register the meg data by removing the small head movements across the two 5-minute eyes - closed sessions . next , residual artifacts due to eye movements and residual cardiac signals were removed using independent component analysis using our customized version of icalab software ( www.bsp.brain.riken.jp/icalab/ ) . structural mri of the participant 's head was collected using a general electric 1.5  t excite mri scanner . the acquisition contains a standard high - resolution anatomical volume with a resolution of 0.94    0.94    1.2  mm using a t1-weighted 3d - ir - fspgr pulse sequence . to co - register the meg with mri coordinate systems , three anatomical landmarks ( i.e. , left and right pre - auricular points , and nasion ) were measured for each participant using the probe position identification system ( polhemus , usa ) . by using mrilab ( elekta / neuromag ) to identify the same three points on the participant 's mr images , a transformation matrix involving both rotation and translation between the meg and mr coordinate systems was generated . to increase the reliability of the meg mr co - registration , approximately 80 points on the scalp were digitized with the polhemus system , in addition to the three landmarks , and those points were co - registered onto the scalp surface of the mr images . the t1-weighted images were also used to extract the brain volume and innermost skull surface ( seglab software developed by elekta / neuromag ) . realistic boundary element method ( bem ) head model was used for meg forward calculation ( huang et al . the bem mesh was constructed by tessellating the inner skull surface from the t1-weighted mri into ~6000 triangular elements with ~5  mm size . a cubic source grid with 5  mm size was used for calculating the meg gain ( i.e. , lead - field ) matrix , which leads to a grid with ~10,000 nodes covering the whole brain . other conventional mri sequences typical for identifying structural lesions were also performed : 1 ) axial t2 * -weighted ; 2 ) axial fast spin - echo t2-weighted ; and 3 ) axial flair . subjects with lesions visible in mri were excluded from the study ( see exclusion criteria ) . the voxel - wise meg source magnitude images were obtained using our recent high - resolution fast - vestal meg source imaging method ( huang et al . , 2014a ) . the second 5-minute resting - state meg sensor - waveform dataset was registered to the first 5-minute resting - state dataset using maxfilter . the artifact - free , eyes - closed , resting - state meg sensor - waveform datasets were divided into 2.5  s epochs . the data in each epoch were first dc - corrected and then run through band - pass filters for the following frequency bands : alpha band ( 812  hz ) , beta band ( 1530  hz ) , gamma band ( 3080  hz ) , high - gamma band ( 80150  hz ) , and low - frequency band ( 17  hz ) that combined delta ( 14  hz ) and theta bands ( 47  hz ) . notch filters at 60  hz and 120  hz were applied to remove the power line signals and their second harmonics . frequency - domain band - pass filter with zero phase - shift via discrete fourier transform was used . at each end of the band - pass filter , the transition of the hanning window in the filter was selected to be at 10% of the associated cut - off frequency . waveforms from all 306 sensors including 204 planar - gradiometers and 102 magnetometers were used in the analysis . for each frequency band , sensor - waveform covariance matrices were calculated for individual epochs after the band - pass filtering , then , the final sensor - waveform covariance matrix was obtained by averaging the covariance matrices across individual epochs for the 10-minute resting - state data . using such a covariance matrix , meg slow - wave source magnitude images that cover the whole brain were obtained for each participant following the fast - vestal procedure ( huang et al . , 2014a ) for a given frequency band . the brain volume is pre - divided into a grid of dipoles with p nodes . let r be the m    m sensor - waveform meg covariance matrix where m is the number of meg sensors for a given frequency band ( e.g. , beta band ) and time - window ( e.g. , length of an epoch ) ; and g be the m    2p gain ( lead - field ) matrix calculated from meg forward modeling for the pre - defined source grid with p dipole locations , with each dipole location having two orthogonal orientations ( i.e. ,  and  ) . in the spherical meg forward head model ,  and  represent the two tangential orientations for each dipole location , whereas in a realistic meg forward model using the boundary element method ( bem ) , the  and -orientations are obtained as the two dominant orientations from the singular - value decomposition ( svd ) of the m    3 lead - field matrix for each dipole , as previously documented ( huang et al . , 2006 ) . eigen - value decomposition is performed for the sensor - waveform covariance matrix:(1)r = ubbubt = ubsbsbtubt where the diagonal elements in sb are simply the square root ( sqrt ) of the corresponding eigenvalues of r which are the diagonal elements in b . next , svd is performed for the gain matrix g:(2)g = ugsgvgt the dimensions for ug , sg , and vg are m    m , m    2p , and 2p    2p , respectively . following the procedure in ( huang et al . , 2014a ) , a distributed source solution for eq . 2 can be expressed as:(3)ubsb = ugsgvgth the 2p    m matrix h is called the distributed source spatial map matrix . the goal of meg inverse source imaging is to obtain h for given r in eq . 3 . however , eq .  3 is under - determined , with the number of unknown variables in each column of h  =  [ h1,h2,  ,hk,  ,hm ] ( i.e. , 2p ) much larger than the number of measurements in each column of ubsb =  [ s1u1,s2u2,  ,skuk,  ,smum , ] ( i.e. , m ) , so additional constraint(s ) are needed to obtain a unique solution for eq .  3 . here , the number of signal ( dominant ) spatial modes k is usually much smaller than the number of meg sensor measurements m. after multiplying from the left side with ugt , for individual dominant spatial modes of eq .  3 , eq . ,k where i  =  1,2,  ,k are the indices of spatial modes in sensor space . by introducing additional minimum l1-norm constraints ( huang et al . , 2014a ) to eq .  4 , one can obtain the fast - vestal solution for hi:(5)min(wt|hi| ) ,  subject  to  constraints  sgvgthiugtuisi , i=1,2,  ,k where the 2p    1 vector hi is the source imaging map associated with the dominant spatial mode vector ui ( dimension m 1 ) of the sensor - domain . in eq .  5 , w = diag(vgvgt ) is a 2p    1 weighting vector chosen to remove potential bias towards grid nodes at the superficial layer ( huang et al . , after solving for hi and hence h using eq .  5 , the fast - vestal source imaging result can be obtained on the source grid as:(6)a = diag(hht ) which is the 2p    1 source magnitude value across grid nodes . the main feature of a , the fast - vestal - based distributed source solution , is that it is highly sparse , with many of its elements being either zero or close to zero , as a direct consequence of l1-norm minimization . an objective pre - whitening method was applied to remove correlated environmental noise and objectively select the dominant eigen - modes ( i.e. , k ) of sensor - waveform covariance matrix ( huang et al . , 2014a ) . meg source magnitude imaging volumes obtained from fast - vestal that cover the whole brain from all healthy control and ptsd participants were first spatially smoothed using a gaussian kernel with 3  mm full width half maximum ( fwhm ) , and then co - registered to an mni-152 brain - atlas template using flirt program in fsl software package ( http://www.fmrib.ox.ac.uk/fsl/ ) . for each voxel in the mni space a two - tailed t - test was performed to assess the group difference for each voxel of the brain volume in the mni space . false discovery rate ( fdr ) was used to control the family - wise error ( benjamini and hochberg , 1995 ) with q  <  .05 . the above procedure was performed for each of the frequency bands separately . for brain areas that showed group differences within a specific frequency band , we were specifically interested in the rois that covered amygdala , vmpfc , ofc , precuneous , and dlpfc . within each roi the analyses were performed in the 20 participants with ptsd or partial ptsd as measured by caps total score . the remaining 5 participants with ptsd or partial ptsd as measured by pcl were not included in this correlational analysis . fig .  1 shows group differences between participants with ptsd and healthy volunteers in resting - state meg source magnitude for the beta - band ( 1530  hz ) . increased beta - band activity in ptsd ( hyperactivity , ptsd  >  controls ) was generated from bilateral amygdala and left anterior hippocampus ( white arrows ) , left and right posterolateral ofc ( magenta arrows ) , several regions within the right insular cortex , bilateral middle temporal gyri , right posterior cingulate cortex ( pcc , brown arrow ) , bilateral junctions of pcc and lingual gyri , and left occipito - temporal  parietal junction . 1 shows decreased beta - band activity in ptsd ( hypoactivity , ptsd < controls ) from vmpfc ( green arrows ) including rostral anterior cingulate cortex ( racc ) and medial ofc , bilateral fps ( more r than l ) , bilateral caudate , bilateral dlpfc ( more r than l ) , right superior frontal gyrus , mid - line supplementary motor areas ( sma ) , right anterior aspect of superior temporal gyrus , bilateral precuneous cortices , and bilateral sensorimotor cortices ( more r than l ) . for a region , an asymmetry is reported when one hemisphere has twice or more voxels being significant than the equivalent region in the opposite hemisphere . 2 shows increased gamma - band ( 3080  hz ) activity in ptsd compared to the healthy control group that was generated from left and right posterolateral ofc ( magenta arrows , more l than r ) , bilateral dmpfc including the dorsal paracingulate cortices and dorsal anterior cingulate cortex ( dacc ) ( more l than r ) , several regions within the bilateral insular cortices , bilateral occipito - temporal  parietal junctions ( more l than r ) , bilateral temporal  occipital fusiform cortices ( more r than l ) , left occipital fusiform gyrus and right lingual gyrus , and right dorsomedial occipital cortex . 2 also shows decreased gamma - band activity in ptsd compared to the control group from vmpfc ( green arrows ) including racc and medial ofc , bilateral fps ( more r than l ) , right dlpfc , mid - line sma , and right sensorimotor cortices . 2 shows increased high - gamma - band ( 80150  hz ) activity in ptsd from left amygdala and hippocampus ( white arrows ) , left posterolateral ofc ( magenta arrows ) , right dacc , left fp , several regions within the bilateral insular cortices , bilateral occipito - temporal  parietal junctions ( more l than r ) , and right dorsomedial occipital cortex . 2 also shows decreased high - gamma - band activity in ptsd from mid - line vmpfc ( green arrows ) including racc and medial ofc , right dlpfc , and right sensorimotor cortices . although ptsd was associated with both hyper- and hypoactivity in the beta , gamma , and high - gamma bands , alpha band meg activity was largely hypoactive in ptsd when compared with the healthy volunteers . 3 shows significantly decreased alpha - band activity in ptsd generated from bilateral fps , bilateral dlpfc ( more r than l ) , right superior frontal gyrus , bilateral anterior aspects of superior temporal gyri ( more r than l ) , bilateral precuneous cortices , and bilateral sensorimotor cortices ( more r than l ) . in contrast , only the left occipito - temporal  parietal junction showed increased alpha - band activity in ptsd . ptsd was also strongly associated with hypoactivity in the low - frequency band compared to the healthy volunteers . 3 shows significantly decreased alpha - band activity in ptsd generated from bilateral fps , bilateral dlpfc ( more r than l ) , bilateral anterior aspects of superior temporal gyri ( more r than l ) , bilateral precuneous cortices , and bilateral sensorimotor cortices ( more r than l ) . similar to the patterns observed in the alpha band , only the left occipito - temporal  parietal junction showed increased low - frequency - band activity in ptsd . positive correlations between resting - state meg activity and caps total symptom scores were found in left amygdala ( beta band , r  =  + 0.51 , p  <  .05 ) and left posterolateral ofc ( also in beta band , r  =  + 0.55 , p  <  .05 ) , indicating the stronger the resting - state meg activity in these areas , the more severe the ptsd symptoms . in addition , negative correlations between resting - state meg activity and total caps symptom scores were found in midline vmpfc ( beta band , r  =  0.58 , p  <  .01 ; gamma band , r  =  0.63 , p  <  .01 ; and high - gamma band , r  =  0.60 , p  <  .01 ) , and midline precuneous ( alpha band , r  =  0.48 , p  <  .05 ) , indicating the weaker the resting - state meg activity in these areas , the more severe the ptsd symptoms . for the first time to our knowledge , the present study shows that individuals with ptsd have abnormal electromagnetic activity that can be directly imaged by resting - state meg source imaging technique for all frequency bands . ptsd was associated with : 1 ) meg hyperactivity from amygdala , hippocampus , posterolateral ofc , dmpfc , insular cortex , and pcc in high frequency bands ( i.e. , beta , gamma , and high gamma bands ) ; 2 ) meg hypoactivity from vmpfc , fp , and dlpfc in the high frequency bands ; 3 ) extensive meg hypoactivity from dlpfc , fp , anterior temporal lobes , precuneous cortex , and sensorimotor cortex in alpha and low - frequency bands , with dlpfc and sensorimotor cortex hypoactivity more prominent in right versus left hemispheres ; and 4 ) resting - state meg activity in left amygdala and posterolateral ofc positively correlated with ptsd symptom scores , whereas meg activity in vmpfc and precuneous correlated negatively with the ptsd symptoms . thalamo - cortical interactions are essential for alpha rhythms , and normal alpha - band activity is associated with functional inhibition ; specifically , increased alpha - band power in a brain area was linked to reduced functional connectivity with other brain areas ( de munck et al . , activity in the beta band is associated with communication between remote brain structures , whereas gamma synchrony promotes local computations ( kopell et al . , although the gamma band electromagnetic signals are generated locally , non - local brain areas can still show significant functional connectivity as measured by coherence related to the gamma band signals . using combined electrophysiological and fmri measurements , studies in both human and animals showed that gamma - band power exhibits spatial coherence over long timescales with the strongest coherence between functionally related areas that are not necessarily local ( he et al . , 2008 ; nir et al . , 2008 ; scholvinck et al . , 2010 , 2013 ; shmuel and leopold , 2008 ) . unlike alpha - band activity , beta and gamma - band activity does not necessarily have to involve thalamus . theta - band signals have been reported in previous eeg studies , although these signals were predominantly task - activated ( e.g. , problem solving ) ( mizuki et al . , 1980 , 1984 , 1992 ; niedermeyer and lopes da silva , 2005 ; takahashi et al . , 1997 ) . increased low - frequency brain rhythms in delta band were often seen in individuals with neurological disorders , e.g. epilepsy and traumatic brain injury ( baayen et al . , 2003 ; de jongh et al . , 2003 ; decker and knott , 1972 ; huang et al . , 2009 , 2012 , 2014b ; lewine et al . , 1999 ; lewine and orrison , 1995 ; nagata et al . , 1985 ; vieth et al . , 1996 when examining the mechanism of abnormal delta rhythms , electrophysiological studies in animals show that abnormal delta activity is from gray matter neurons that have experienced deafferentation due to neurological injuries in underlying white matter , resulting from axonal injury or blockage / limitation in the cholinergic pathways ( ball et al . our meg findings are consistent with previous pet and fmri findings of hyperresponsive amygdala activity in ptsd ( rauch et al . , 1998 , 2006 ) , which is one of the most robust functional neuroimaging findings in ptsd ( hughes and shin , 2011 ) . the amygdala is involved in processing threat - related stimuli ( davis and whalen , 2001 ; morris et al . , 1998 ; whalen et al . , 1998 , 2001 ) and is necessary for fear conditioning ( davis and whalen , 2001 ; ledoux , 2000 ; shin et al . , 2006 ) . moreover , the amygdala is a key component in the neurocircuitry model of ptsd ( rauch et al . , 2006 ) . the present meg study shows that the amygdala hyperactivity in ptsd can also be detected using electromagnetic source imaging measures , which increases the confidence in our meg technique for detecting new abnormalities in ptsd . furthermore , we demonstrate that amygdala hyperactivity was only observable in the high frequency bands ( i.e. , beta and high - gamma bands ) . in addition , the meg hyperactivity in ptsd from left hippocampus in beta and high - gamma bands is also consistent with the current ptsd neurocircuitry model ( rauch et al . , 2006 ) , although the findings from previous pet and fmri in this region have been mixed ( hughes and shin , 2011 ) . the meg gamma - band hyperactivity from dmpfc , including the dacc , in ptsd was also consistent with prior pet and fmri findings ( bremner et al . pannu et al . , 2009 ; shin et al . , 2001 , 2007 , 2011 ) . the dmpfc , including the dacc , is thought to play an important role in a variety of cognitive processes such as performance monitoring , response selection , error detection , and decision making ( shin et al . , 2011 ) . our findings are consistent with studies that used trauma - event - script - driven imagery with spect ( lindauer et al . , 2008 ) and fmri ( lanius et al . , 2007 ) , as well as with studies that used emotional and trauma - unrelated stimuli with pet and fmri ( hughes and shin , 2011 ) . painful stimuli have also been shown to increase insular activity in ptsd ( geuze et al . the insular cortex processes information about the body 's internal state and contributes to the autonomic component of the overall pain response . it has been suggested that the insular cortex integrates the sensory , affective , and cognitive components necessary for normal responses to pain ( kandel et al . , 2000 ) . abnormal insular activity in ptsd may reflect a deficit in integrating these components , thereby contributing to an abnormal pain response ( nagai et al . , 2007 ) . meg hypoactivity from vmpfc in ptsd was consistent with findings from pet and fmri studies ( hughes and shin , 2011 ; rauch et al . hyporesponsive vmpfc is another key component in the current neurocircuitry model of ptsd ( rauch et al . , 2006 ) , which suggests that hyporesponsive vmpfc fails to suppress the amygdala ( rauch et al . , 2006 the vmpfc is connected to and receives input from the ventral tegmental area , amygdala , temporal lobe , olfactory system , and dorsomedial thalamus . in turn , vmpfc sends signals to amygdala , temporal lobe , lateral hypothalamus , hippocampal formation , cingulate cortex , and certain other regions of the prefrontal cortex ( carlson , 2013 ) . in the present study , hypoactivity in vmpfc associated with ptsd was evident in beta , gamma , and high - gamma bands , but not the lower frequency bands . these findings suggest that the beta- and gamma - band interactions between vmpfc and amygdala may not involve thalamus , as evidenced by the lack of group differences in vmpfc in thalamus - dependent alpha band activity ( hindriks and van putten , 2013 ) . we used a resting - state protocol that is insensitive to stimulus features and participant performance . furthermore , we focused on examining meg source - magnitude images rather than functional connectivity ( jin et al . , our protocol was similar to a recent resting - state fmri study of combat - related ptsd that used a magnitude imaging approach ( yan et al . , 2013 ) . our findings are consistent with yan and colleagues , who also found that individuals with ptsd showed increased activity in amygdala , insular cortex , and ofc , as well as decreased activity in dlpfc , superior frontal gyrus , and precuneous cortex . despite these similarities , participants with ptsd in the present study showed decreased meg activity in vmpfc ( beta , gamma , and high - gamma bands , see fig .  1 , fig .  2 ) and bilateral fp areas ( fig .  1 , fig .  2 , fig . 3 ) , whereas yan and colleagues , in their fmri study showed increased activity in a similar region ( yan et al . , 2013 ) . although it is known that the fmri measurements in ventral frontal lobe areas are challenging to obtain due to signal loss , imaging distortion , and susceptibility artifacts ( czervionke et al . , 1988 ; domsch et al . , 2013 ) , the exact reason of the decreased meg versus increased fmri resting - state activity in vmpfc is unknown . overall , the beta - band meg source imaging maps are similar to the fmri maps of yan and colleagues , except for the activity in vmpfc . such a degree of similarity across two different imaging modalities ( i.e. , electromagnetic measures from meg and hemodynamic measures from fmri ) is likely due to beta - band synchronization over long conduction delays , which corresponds to signals traveling a significant distance across brain regions . electrophysiological studies of the rat hippocampus have shown that the beta rhythm allows neuronal synchrony at large time delays , while the gamma band allows such synchrony at short delays . thus , beta synchrony promotes communication between remote structures , whereas gamma synchrony promotes local computations ( kopell et al . interestingly , more recent work in identifying meg correlates of fmri resting - state networks has found that power fluctuations in the beta band produce spatial networks very similar to fmri resting - state networks ( brookes et al . , 2011b ) . our findings suggest that abnormal beta - band neuronal activity in ptsd is likely a candidate for the abnormal fmri signal observed by yan and colleagues ( yan et al . , 2013 ) . the consistent finding of decreases of resting - state activity in precuneous and dlpfc associated with ptsd in the present meg study ( in beta , alpha , and low - frequency bands ) and in the fmri study by yan et al . ( yan et al . , 2013 ) highlight the contribution of these regions in ptsd neurocircuitry . the precuneous is a key region of the  default - mode network ( dmn )  in resting brain which has been detected by fmri ( fransson and marrelec , 2008 ) and meg ( brookes et al . , 2011b ) . furthermore , the precuneous plays a pivotal role in how intrinsic activity is mediated throughout the dmn , and helps sustain a sense of self - consciousness in self - referential mental thoughts during rest ( cavanna and trimble , 2006 ; fransson and marrelec , 2008 ) . non - trauma related words elicit decreased precuneous fmri activity in ptsd , and the decrease in precuneous activity is correlated with caps scores ( geuze et al . , 2008 ) . dissociative symptoms of patients with ptsd may play a role in the decreased activation of precuneous ( geuze et al . , 2008 ) . the dlpfc is a key region for a variety of executive brain functions such as working memory , attention , and other executive functions . it facilitates goal - directed behavior through indirect modulation of the amygdala response to threat , possibly through connections with the temporal cortex ( bishop , 2008 ; gold et al . , 2014 ; mitchell , 2011 ) . in the present study , meg hyperactivity in both right dlpfc and anterior temporal lobe in alpha , beta , gamma , and low - frequency ( fig .  1 , fig .  2 , fig .  3 ) is consistent with the modulation deficit of the dlpfc anterior temporal - amygdala pathway in ptsd . using a task involving cognitive regulation of negative affect via reappraisal , rabinak and colleagues found that ptsd patients engaged the dlpfc during cognitive reappraisal , albeit to a lesser extent than the control participants ( rabinak et al . , 2014 ) . in a longitudinal cortical thickness study , individuals with ptsd showed greater dlpfc thickness in a follow - up exam about 1  year after the trauma than in the acute exam , and greater dlpfc thickness was associated with greater ptsd symptom reductions and better recovery ( lyoo et al . , 2011 ) . on the other hand , healthy volunteers showed greater dlpfc activation and increased amygdala connectivity to threats compared to non - threat condition ( gold et al . , 2014 ) . elevated activity in dlpfc was also observed in ptsd during a maintenance period of working memory in an fmri test ( moores et al . , 2008 ) . future functional imaging studies of ptsd are needed to examine the association between resting - state dlpfc activity and dlpfc responses to different types of working memory and/or attention stimuli . in an event related potential ( erp ) study of combat veterans with ptsd after mild tbi by shu and colleagues , pcc and precuneous areas exhibit greater erps evoked by emotional facial stimuli ( shu et al . , 2014 ) . in the present study , pcc also showed hyperactivity in the beta - band resting - state meg source image ( brown arrow in fig .  1 ) , a finding consistent with the above erp study . however , the hypoactive precuneous is seen in our resting - state meg source image across many frequency bands , also observed in resting - state fmri by yan and colleagues ( yan et al . , 2013 ) , seems to be different from the greater erps in precuneous found by shu and colleagues using emotional stimuli . additional studies are needed to directly examine the association between resting - state electromagnetic signal and evoked responses , as well as the impact of mild tbi on ptsd . another interesting finding from the present study is the increased activity from the posterolateral ofc areas in beta , gamma , and high gamma bands . our finding is consistent with fmri findings of increased resting - state activity in ptsd ( yan et al . , 2013 ) . the ofc is closely connected to the limbic system , especially the amygdala , and is sometimes regarded as part of the expanded limbic system ( nauta , 1979 ) . while regions known to be part of the existing neurocircuitry model of ptsd ( i.e. , amygdala , vmpfc , and insular cortex ) have been studied extensively ( rauch et al . , 1998 , 2006 ; shin et al . , 2006 ) , the role of the posterolateral ofc in ptsd is unclear and should be examined further . based on our meg findings , posterolateral ofc activity increased with ptsd symptom severity , thus ofc and its interactions with the amygdala may be added to the existing neurocircuitry model of ptsd . this idea is supported by studies that show that ofc has direct anatomical projections to the amygdala and hippocampus via the uncinate fasciculus in humans ( bach et al . , 2011 ; talairach and tournoux , 1988 ) as well as in non - human primates ( carmichael and price , 1995 ) . it was also shown that such projections were abnormal in some psychiatric disorders such as conduct disorder ( passamonti et al . , 2012 ) , bipolar disorder ( benedetti et al . , 2011 ) , and schizophrenia ( jackowski et al . , 2012 ) . further studies are needed to confirm whether disrupted interactions between ofc - amygdala may be implicated in ptsd . individuals with ptsd showed extensive meg alpha - band hypoactivity from dlpfc , fp , anterior temporal lobes , precuneous cortex , and sensorimotor cortex . neuronal modeling studies showed that thalamo - cortical interactions are essential to the generation of alpha rhythms ( freyer et al . , 2011 ; hindriks and van putten , 2013 ; lopes da silva et al . , 1997 ) . combined eeg and fmri studies have also shown that increased alpha - band power in a brain area is associated with reduced functional connectivity with other brain areas , suggesting that alpha - band activity is associated with functional inhibition ( de munck et al . , 2009 ; scheeringa et al . , 2012 ) . the observed meg alpha - band hypoactivity may suggest a deficit in thalamo - cortical interactions , which possibly leads to reduced functional inhibition in the above cortical areas in ptsd . in general , a normal amount of alpha activity is preferred in the resting - state , and reduced alpha - band power has also been observed in individuals with alzheimer 's disease ( babiloni et al . , 2013 ; tartaglione et al . , our method plays an essential role in obtaining the source magnitude images for the neurocircuitry in ptsd ( fig .  1 , fig .  2 , fig . it was shown that fast - vestal can effectively create resting - state meg source images that are highly consistent with known neurophysiology findings ( huang et al . , 2014a ) . we have shown that for resting - state meg signal , the source magnitude images obtained using a beamformer technique ( a popular meg source analysis method ) are less consistent with neurophysiology findings ( huang et al . , 2014a ) . this is likely due to beamformer 's intrinsic limitation which assumes the neuronal sources are uncorrelated ( robinson and vrba , 1999 ; sekihara et al . , 2001 ; van veen et al . , 1997 ) , a questionable assumption when dealing with resting - state meg signals . in the present study , this is because we are in the process of finalizing the fast - vestal based voxel - wise meg connectivity method ( huang et al . although meg - based connectivity study is a hot topic in literature , with most published approaches used beamformer or minimum l2-norm based techniques to obtain the source time - courses ( brookes et al . it was known that source time - courses obtain by beamformer are distorted when multiple correlated neuronal sources contribute to the sensor - waveforms even at noiseless cases ( huang et al . , 2014a ) , and across - talk between source time - courses from minimum l2-norm approaches can also be a serious issue . however , even though many researchers were aware of the issues associated with distorted source time - courses , the impact on a variety of connectivity measures using the distorted source time - courses has not been examined thoroughly in resting - state data , at least to our knowledge . before we publish our method for fast - vestal based connectivity analysis , we believe that it would be beyond the scope of the present study to include meg connectivity results for the ptsd population . first , the spatial resolution and localization accuracy of meg are expected to be limited for amygdala , hippocampus , and vmpfc , which may explain some minor location discrepancies between our findings and those of previous fmri or pet studies . second , although we acquired resting - state meg signal in the eyes - closed condition , eye - movements and micro - eye - blinks may be confounding factors . although we pre - processed the meg data through both maxfilter and ica to remove the eye - movement and micro - eye - blinks , the impact of residual eye - activity - related artifacts may not be totally negligible . third , despite substantial efforts to ensure and monitor alertness during the eyes - closed condition ( see materials and methods ) , drowsiness may still have had an impact on the meg recording . fourth , since the active - duty and veteran ptsd patients are mostly males , the present study is dominated by male subjects , with just one woman in each of the two groups . despite these limitations , the present study showed that our meg source imaging technique revealed new abnormalities in the resting - state electromagnetic signals from ptsd neurocircuitry . abnormal resting - state electromagnetic signals in ptsd neurocircuitry can be effectively imaged by meg source imaging technique for different frequency bands . in high frequency bands ( i.e. , beta , gamma , and high gamma bands ) , ptsd was associated with 1 ) meg hyperactivity from amygdala , hippocampus , posterolateral ofc , dmpfc , and insular cortex ; and 2 ) meg hypoactivity from vmpfc , fp , and dlpfc . in alpha and low - frequency bands , ptsd was associated with extensive meg hypoactivity from dlpfc , fp , anterior temporal lobes , precuneous cortex , and sensorimotor cortex . lastly , ptsd symptom scores correlated positively with resting - state meg activity in left amygdala and posterolateral ofc and negatively with meg activity in vmpfc and precuneous . particularly , posterolateral ofc and precuneous may play important roles in the ptsd neurocircuitry model .
post - traumatic stress disorder ( ptsd ) is a leading cause of sustained impairment , distress , and poor quality of life in military personnel , veterans , and civilians . 
 indirect functional neuroimaging studies using pet or fmri with fear - related stimuli support a ptsd neurocircuitry model that includes amygdala , hippocampus , and ventromedial prefrontal cortex ( vmpfc ) . 
 however , it is not clear if this model can fully account for ptsd abnormalities detected directly by electromagnetic - based source imaging techniques in resting - state . 
 the present study examined resting - state magnetoencephalography ( meg ) signals in 25 active - duty service members and veterans with ptsd and 30 healthy volunteers . 
 in contrast to the healthy volunteers , individuals with ptsd showed : 1 ) hyperactivity from amygdala , hippocampus , posterolateral orbitofrontal cortex ( ofc ) , dorsomedial prefrontal cortex ( dmpfc ) , and insular cortex in high - frequency ( i.e. , beta , gamma , and high - gamma ) bands ; 2 ) hypoactivity from vmpfc , frontal pole ( fp ) , and dorsolateral prefrontal cortex ( dlpfc ) in high - frequency bands ; 3 ) extensive hypoactivity from dlpfc , fp , anterior temporal lobes , precuneous cortex , and sensorimotor cortex in alpha and low - frequency bands ; and 4 ) in individuals with ptsd , meg activity in the left amygdala and posterolateral ofc correlated positively with ptsd symptom scores , whereas meg activity in vmpfc and precuneous correlated negatively with symptom score . 
 the present study showed that meg source imaging technique revealed new abnormalities in the resting - state electromagnetic signals from the ptsd neurocircuitry . 
 particularly , posterolateral ofc and precuneous may play important roles in the ptsd neurocircuitry model .