Real-Time Motor Cortex Mapping for the Safe Resection of Glioma: An Intraoperative Resting-State fMRI Study.

BACKGROUND AND PURPOSE: Resting-state functional MR imaging has been used for motor mapping in presurgical planning but never used intraoperatively. This study aimed to investigate the feasibility of applying intraoperative resting-state functional MR imaging for the safe resection of gliomas using real-time motor cortex mapping during an operation. MATERIALS AND METHODS: Using interventional MR imaging, we conducted preoperative and intraoperative resting-state intrinsic functional connectivity analyses of the motor cortex in 30 patients with brain tumors. Factors that may influence intraoperative imaging quality, including anesthesia type (general or awake anesthesia) and tumor cavity (filled with normal saline or not), were studied to investigate image quality. Additionally, direct cortical stimulation was used to validate the accuracy of intraoperative resting-state fMRI in mapping the motor cortex. RESULTS: Preoperative and intraoperative resting-state fMRI scans were acquired for all patients. Fourteen patients who successfully completed both sufficient intraoperative resting-state fMRI and direct cortical stimulation were used for further analysis of sensitivity and specificity. Compared with those subjected to direct cortical stimulation, the sensitivity and specificity of intraoperative resting-state fMRI in localizing the motor area were 61.7% and 93.7%, respectively. The image quality of intraoperative resting-state fMRI was better when the tumor cavity was filled with normal saline (P = .049). However, no significant difference between the anesthesia types was observed (P = .102). CONCLUSIONS: This study demonstrates the feasibility of using intraoperative resting-state fMRI for real-time localization of functional areas during a neurologic operation. The findings suggest that using intraoperative resting-state fMRI can avoid the risk of intraoperative seizures due to direct cortical stimulation and may provide neurosurgeons with valuable information to facilitate the safe resection of gliomas.

Aberrant development of intrinsic brain activity in a rat model of caregiver maltreatment of offspring.

Caregiver maltreatment induces vulnerability to later-life psychopathology. Clinical and preclinical evidence suggest changes in prefrontal and limbic circuitry underlie this susceptibility. We examined this question using a rat model of maternal maltreatment and methods translated from humans, resting-state functional magnetic resonance imaging (R-fMRI). Rat pups were reared by mothers provided with insufficient or abundant bedding for nest building from postnatal (PN) days 8 to 12 and underwent behavioral assessments of affect-related behaviors (forced swim, sucrose preference and social interaction) in adolescence (PN45) and early adulthood (PN60). R-fMRI sessions were conducted under light anesthesia at both ages. Offspring reared with insufficient bedding (that is, maltreated) displayed enduring negative affective behaviors. Amygdala-prefrontal cortex (PFC) functional connectivity increased significantly from adolescence to adulthood in controls, but not in maltreated animals. We computed the fractional amplitude of low-frequency fluctuations (fALFF), an index of intrinsic brain activity, and found that fALFF in medial prefrontal cortex and anterior cingulate cortex (MPFC/ACC) increased significantly with age in controls but remained unchanged in maltreated animals during adolescence and adulthood. We used a seed-based analysis to explore changes in functional connectivity between this region and the whole brain. Compared with controls, maltreated animals demonstrated reduced functional connectivity between MPFC/ACC and left caudate/putamen across both ages. Functional connectivity between MPFC/ACC and right caudate/putamen showed a group by age interaction: decreased in controls but increased in maltreated animals. These data suggest that maltreatment induces vulnerability to psychopathology and is associated with differential developmental trajectories of prefrontal and subcortical circuits underlying affect regulation.

Reduced small world brain connectivity in probands with a family history of epilepsy.

BACKGROUND AND PURPOSE: The role of inheritance in ascertaining susceptibility to epilepsy is well established, although the pathogenetic mechanisms are still not very clear. Interviewing for a positive family history is a popular epidemiological tool in the understanding of this susceptibility. Our aim was to visualize and localize network abnormalities that could be associated with a positive family history in a group of patients with hot water epilepsy (HWE) using resting-state functional magnetic resonance imaging (rsfMRI). METHODS: Graph theory analysis of rsfMRI (clustering coefficient γ; path length λ; small worldness σ) in probands with a positive family history of epilepsy (FHE+, 25) were compared with probands without FHE (FHE-, 33). Whether a closer biological relationship was associated with a higher likelihood of network abnormalities was also ascertained. RESULTS: A positive family history of epilepsy had decreased γ, increased λ and decreased σ in bilateral temporofrontal regions compared to FHE- (false discovery rate corrected P ≤ 0.0062). These changes were more pronounced in probands having first degree relatives and siblings with epilepsy. Probands with multiple types of epilepsy in the family showed decreased σ in comparison to only HWE in the family. CONCLUSION: Graph theory analysis of the rsfMRI can be used to understand the neurobiology of diseases like genetic susceptibility in HWE. Reduced small worldness, proportional to the degree of relationship, is consistent with the current understanding that disease severity is higher in closer biological relations.

Repetitive transcranial magnetic stimulation induced modulations of resting state motor connectivity in writer's cramp.

BACKGROUND AND PURPOSE: Writer's cramp (WC) is a focal task-specific dystonia of the hand which is increasingly being accepted as a network disorder. Non-invasive cortical stimulation using repetitive transcranial magnetic stimulation (rTMS) has produced therapeutic benefits in some of these patients. This study aimed to visualize the motor network abnormalities in WC and also its rTMS induced modulations using resting state functional magnetic resonance imaging (rsfMRI). METHODS: Nineteen patients with right-sided WC and 20 matched healthy controls (HCs) were prospectively evaluated. All patients underwent a single session of rTMS and rsfMRI was acquired before (R1) and after (R2) rTMS. Seed-based functional connectivity analysis of several regions in the motor network was performed for HCs, R1 and R2 using SPM8 software. Thresholded (P < 0.05, false discovery rate corrected) group level mean correlation maps were used to derive significantly connected region of interest pairs. RESULTS: Writer's cramp showed a significant reduction in resting state functional connectivity in comparison with HCs involving the left cerebellum, thalamus, globus pallidus, putamen, bilateral supplementary motor area, right medial prefrontal lobe and right post central gyrus. After rTMS there was a significant increase in the contralateral resting state functional connectivity through the left thalamus-right globus pallidus-right thalamus-right prefrontal lobe network loop. CONCLUSIONS: It is concluded that WC is a network disorder with widespread dysfunction much larger than clinically evident and changes induced by rTMS probably act through subcortical and trans-hemispheric unaffected connections. Longitudinal studies with therapeutic rTMS will be required to ascertain whether such information could be used to select patients prior to rTMS therapy.

High-resolution fMRI using multislice partial k-space GR-EPI with cubic voxels.

The premises of this work are: 1) the limit of spatial resolution in fMRI is determined by anatomy of the microcirculation; 2) because of cortical gray matter tortuosity, fMRI experiments should (in principle) be carried out using cubic voxels; and 3) the noise in fMRI experiments is dominated by low-frequency BOLD fluctuations that are a consequence of spontaneous neuronal events and are pixel-wise dependent. A new model is proposed for fMRI contrast which predicts that the contrast-to-noise ratio (CNR) tends to be independent of voxel dimensions (in the absence of partial voluming of activated tissue), TE, and scanner bandwidth. These predictions have been tested at 3 T, and results support the model. Scatter plots of fMRI signal intensities and low-frequency fluctuations for activated pixels in a finger-tapping paradigm demonstrated a linear relationship between signal and noise that was independent of TE. The R(2) value was about 0.9 across eight subjects studied. The CNR tended to be constant across pixels within a subject but varied across subjects: CNR = 3.2 +/- 1.0. fMRI statistics at 20- and 40-ms TE values were indistinguishable, and TE values as short as 10 ms were used successfully. Robust fMRI data were obtained across all subjects using 1 x 1 x 1 mm(3) cubic voxels with 10 contiguous slices, although 1.5 x 1.5 x 1.5 mm(3) was found to be optimum. Magn Reson Med 46:114-125, 2001.

Use of jackknife resampling techniques to estimate the confidence intervals of fMRI parameters.

PURPOSE: The objective of this study was to determine the reliability and the confidence intervals of task-activated functional MRI (fMRI) parameters using a computer-intensive resampling technique. The jackknife, a commonly used method for resampling mathematical data, was used to calculate the confidence interval of fMRI parameters for a simple bilateral finger-tapping paradigm. METHOD: Four healthy test subjects (three men, one woman) were used to test the correlation coefficient and variability in the data. Each subject performed 4.5 cycles, each cycle having 20 s of bilateral finger tapping alternating with rest periods of equal time, producing 90 images. One additional scan of 10 cycles (200 images) was used to test the stability of the method itself. One thousand jackknifed resampled data sets of 85 elements each (from 90 original points) were generated, and the correlation coefficient was determined using an idealized "on/off" box-car reference waveform. RESULTS: Activation maps were generated that had the same confidence intervals at each pixel. These maps were more localized with less extraneous activated pixels than the maps generated with a fixed correlation coefficient threshold. There was no significant difference in the distribution of correlation coefficients between the 85, 90, and 95 element, jackknifed data sets; similar robustness was seen, as well. CONCLUSION: The jackknife resampling technique for data analysis produced reliable distributions and statistical parameters. The jackknife estimates were shown to be stable, even from a small initial sample size. This method may be used in lieu of test-retest analysis.

Assessment of auditory cortex activation with functional magnetic resonance imaging.

OBJECTIVE: The goal was to assess auditory cortex activation evoked by pure-tone stimulus with functional MRI. METHODS: Five healthy children, aged 7 to 10 years, were studied. Hearing evaluation was performed by pure-tone audiometry in a sound-treated room and in the MRI scanner with the scanner noise in the background. Subjects were asked to listen to pure tones (500, 1000, 2000, and 4000 Hz) at thresholds determined in the MRI scanner. Functional image processing was performed with a cross-correlation technique with a correlation coefficient of 0.5 (P < 0.0001). Auditory cortex activation was assessed by observing activated pixels in functional images. RESULTS: Functional images of auditory cortex activation were obtained in 3 children. All children showed activation in Heschl's gyrus, middle temporal gyrus, superior temporal gyrus, and planum temporale. The number of activated pixels in auditory cortexes ranged from 4 to 33. CONCLUSIONS: Functional images of auditory cortex activation evoked by pure-tone stimuli are obtained in healthy children with the functional MRI technique.

Effect of hemodilution on RBC velocity, supply rate, and hematocrit in the cerebral capillary network.

The effect of isovolemic hemodilution on the circulation of red blood cells (RBCs) in the cerebrocortical capillary network was studied by intravital videomicroscopy with use of a closed-cranial-window technique in the rat. Velocity and supply rate of RBCs were measured by tracking the movement and counting the number of fluorescently labeled cells. Arterial blood was withdrawn in increments of 2 ml and replaced by serum albumin. Arterial blood pressure was maintained constant with an infusion of methoxamine. Both velocity and supply rate of RBCs increased, by approximately equal amounts, as arterial hematocrit was reduced from 44 to 15%. The maximum increase in RBC velocity was 4.6 and in RBC supply rate was 5.2 times the baseline value. Calculated lineal density of RBC, an index of capillary hematocrit, did not change with hemodilution. The results suggest that RBC flow and oxygen supply in the cerebral capillary network are maintained during isovolemic hemodilution. The "optimal hematocrit" is as low as 15%.

Blind source separation of multiple signal sources of fMRI data sets using independent component analysis.

PURPOSE: The objective of this study was to separate multiple signal components present in functional MRI (fMRI) data sets. Blind source separation techniques were applied to the analysis of fMRI data to determine multiple physiologically relevant independent signal sources. METHOD: Computer simulations were performed to test the reliability and robustness of the independent component analysis (ICA). Four subjects (3 males and 1 female between 14 and 29 years old) were scanned under various stimulus conditions: (1) rest while breathing room air, (2) bilateral finger tapping while breathing room air, and (3) hypercapnia during bilateral finger tapping. RESULTS: Simulations performed on synthetic data sets demonstrated that not only could the algorithm reliably detect the shapes of each of the source signals, but it also preserved their relative amplitudes. The algorithm also performed robustly in the presence of noise. With use of fMRI time series data sets from bilateral finger tapping during hypercapnia, distinct physiologically relevant independent sources were reliably estimated. One independent component corresponded to the hypercapnic cerebrovascular response, and another independent component corresponded to cortical activation from bilateral finger tapping. In three of the four subjects, the underlying fluctuations in signal related to baseline respiratory rate were identified in the third independent component. Principal component analysis (PCA) could not separate these two independent physiological components. CONCLUSION: With use of ICA, signals originating from independent sources could be separated from a linear mixture of observed data. Limitations of PCA were also demonstrated.

Functional magnetic resonance imaging of auditory cortex in children.

OBJECTIVE: TO obtain images of auditory cortex activation in children by using functional magnetic resonance imaging (FMRI). METHODS: Seven healthy children (three girls and four boys), ages 6 to 10 years, were studied. Hearing evaluation was performed by puretone audiometry on the day of FMRI study. Brain imaging was performed on a commercial 1.5 T imager using a three-axis local gradient coil. During scanning the children were instructed to lie still and avoid any lip, eye, jaw, or other facial movements. Subjects were asked to listen to a standard text presented in on-off sequences. Functional images of the auditory cortex were acquired with FMRI technique. Functional imaging processing was done using cross-correlation techniques with a coefficient of 0.5 (P < .0001). RESULTS: Functional correlation images of the auditory cortex activation were obtained in six of seven children after image processing. All children showed activation in the superior temporal gyrus, Heschl's gyrus, planum temporale, frontal lobe, and parietal regions. There was no significant difference in the number and percentage of activated pixels on right and left auditory cortices. CONCLUSIONS: Functional images of auditory cortex activation were obtained in healthy children following binaural text presentation. Consistent activation was observed in primary and secondary auditory cortices with no hemispheric dominance. FMRI characteristics of the auditory cortex activation in healthy children should be established in order to study those with hearing impairment.

Acoustic echoplanar scanner noise and pure tone hearing thresholds: the effects of sequence repetition times and acoustic noise rates.

PURPOSE: Our goal was to determine the effects of acoustic echoplanar scanner noise on pure tone hearing thresholds in normal volunteers and to determine the influence of echoplanar sequence repetition time on threshold effects. METHOD: With use of a calibrated audiometer, pure tones ranging from 125 to 8,000 Hz were delivered monaurally to 10 normal-hearing volunteers in a quiet MR scanner suite and in the presence of acoustic scanner noise produced by three separate single shot blipped echoplanar pulse sequences varying only in repetition time (TR = 1,000, 2,000, or 3,000 ms), with all other parameters including the number of slices held constant. The magnitude of noise-induced threshold changes and the slopes of the threshold curves produced by each of the three echoplanar pulse sequences were then analyzed using multiple comparisons and a least significant difference method. The shapes of the threshold curves produced in each background state were best fit using a quadratic effect for frequency in a mixed effects linear model and compared using F test statistics. RESULTS: All of the volunteers demonstrated entirely normal hearing thresholds throughout the full range of tonal frequencies tested (< 25 dB) when no acoustic scanner noise was present in the scanner suite. Pure tone hearing thresholds significantly increased (p < 0.01) in the presence of acoustic scanner noise, with the magnitude of change inversely proportional to the repetition time and therefore the rate of periodic noise production by the echoplanar sequence used. The shape of the threshold curve in the presence of noise produced by the 1,000 ms TR sequence was not equivalent across the frequency spectrum tested but had a quadratic distribution with peak effects at 750-2,000 Hz. As the repetition time was increased and the periodic noise rate decreased, the magnitude of the noise-induced threshold changes significantly lessened (p < 0.01) and the quadratic distributions of the threshold curves changed significantly (p < 0.01), tending toward a more planar configuration. CONCLUSION: Background acoustic echoplanar scanner noise can significantly increase pure tone thresholds in the optimal frequency hearing range (125-8,000 Hz). However, the threshold effects are not equivalent across the frequency spectrum, and the magnitude of threshold changes is dependent on the rate at which periodic acoustic scanner noises are produced for a given sequence repetition time.

Cortical activation response to acoustic echo planar scanner noise.

PURPOSE: Our goal was to determine the distribution of auditory and language cortex activation in response to acoustic echo planar scanner noise with functional MRI (fMRI). METHOD: Acoustic scanner noise and spoken text, reproduced on high output cassette tape, were separately delivered at equivalent intensities to six normal hearing adult volunteers through earphones during fMRI data acquisition. In nine other subjects, taped scanner noise was delivered in five successive iterations of the task to assess the consistency of cortical activation to the noise stimulus. Gyri of the auditory and language system were divided into 10 different subregions for analysis of cortical activation. The number of activated pixels and proportion of volunteers activating each cortical subregion were determined using a cross-correlation analysis. RESULTS: Cortical activation to taped acoustic scanner noise was present within the transverse temporal gyrus (primary auditory cortex) in all subjects, but activation was highly variable between subjects in auditory association and language relevant cortex. Auditory association cortex activation was seen in the planum polari, planum temporali, and middle temporal gyrus/superior temporal sulcus regions in one-half to two-thirds of the volunteers. There was no significant difference in the distribution of cortical activation within individual subjects across five successive iterations of the scanner noise task. Listening to spoken text consistently activated primary and association auditory cortex bilaterally as well as language relevant cortex in some cases. The mean number of activated pixels was significantly greater for text listening than acoustic scanner noise in auditory association and language relevant cortical subregions (p < 0.01), although the distribution of activity was similar between the two tasks. CONCLUSION: This preliminary investigation suggests that the complex sounds produced by the echo planar pulse sequence can activate relatively large regions of auditory and language cortex bilaterally, with the extent of activation outside the primary auditory cortex being variable between subjects. However, the distribution of activation within individual subjects was relatively constant across several iterations of the scanner noise stimulus.

Spontaneous fluctuations in cerebral oxygen supply. An introduction.

Spontaneous, low frequency (4-12 cpm) fluctuations, independent of the cardiac and respiratory cycles, in human and animal brains were first recorded with the O2 polarographic technique in the late 1950s. They were seen in NADH and cytochrome oxidase and associated with spontaneous vasomotion pial and large cerebral arteries. Renewed interest in spontaneous fluctuations was generated by studies with laser-Doppler flowmetry (LDF), reflectance oximetry and functional MRI. Spontaneous fluctuations were consistently produced when cerebral perfusion was challenged by systemic or local manipulations; the fluctuation amplitude reached 30-40% of the mean. The most potent stimuli are hypotension, hyperventilation, cerebral artery occlusion and cerebral vasoconstriction elicited, for example, by a nitric oxide synthase inhibitor but not by indomethacin. The fluctuations are suspended by CO2 and halothane at concentrations that produce hyperemia. Recently, spontaneous fluctuations were recorded by LDF microprobes in areas as small as 130 microns and by video-microscopy in single capillaries. The fluctuations were absent in severe, focally ischemic brain territories. The dependence of spontaneous fluctuations on intravascular pressure argues for the importance of a myogenic mechanism, however, neuronal modulation may also play a role. Coherence of small vessel vasomotion may be required for the emergence of regional flow fluctuations. There is a need to elucidate the spatial and frequency domains in which fluctuations are present under normal physiological conditions and those in which they may reflect brain injury and pathologies of diagnostic or prognostic value.

Contour-based registration technique to differentiate between task-activated and head motion-induced signal variations in fMRI.

Data acquired using functional magnetic resonance imaging are often contaminated by head motion. As a result, optimal information regarding task-induced (or resting-state) signal changes cannot be extracted. Intensity-based registration methods, including intensity correlation or minimum intensity variance techniques, are widely used to register two or more images. It is shown here that intensity-based registration cannot accurately register two or more images in the presence of local intensity changes arising from functional magnetic resonance, fMRI, signals. In this paper, we present a contour-based technique that can be used not only for a more robust registration, but also to help differentiate between task-induced and motion-induced signal changes. Results obtained using both phantom and human brain images demonstrate advantages of this technique compared with a conventional intensity registration technique.

Effects of hypoxia and hypercapnia on capillary flow velocity in the rat cerebral cortex.

The velocity of red blood cells (RBC) in individual capillaries of the rat cerebral cortex was assessed using direct, intravital video microscopy under normal conditions and during systemic hypoxia or hypercapnia. The movement of RBC in capillaries within 50-microm depth of the parietal cortex was visualized with the aid of fluorescent labeling of RBC in a closed cranial window preparation in pentobarbital-anesthetized, artificially ventilated adult rats. Hypoxia was produced by lowering the concentration of oxygen in the inspired gas from 30 to 15% for 5 min. Hypercapnia was achieved by increasing the inspired CO2 concentration (FiCO2) from 0 to 5% and then to 10% for 5 min at each level. The mean arterial pressure was maintained constant during both maneuvers. Under control conditions, fast and heterogeneous RBC flow in multioriented, tortuous capillaries was observed. During hypoxia, RBC velocity increased from 0.61 +/- 0.06 to 0.82 +/- 0.10 mm/sec (35% change). During hypercapnia, RBC velocity increased from 0.73 +/- 0.05 to 1.07 +/- 0. 11 mm/sec (46% change) at 5% CO2 and to 1.19 +/- 0.11 mm/sec (63% change) at 10% CO2. Corresponding changes in regional blood flow as assessed by laser-Doppler flowmetry during hypercapnia were 69 +/- 7 and 128 +/- 21%, respectively. The RBC velocity increased in almost all capillaries during hypoxia and during moderate hypercapnia. However, a substantial number of capillaries showed no change or a small decrease in RBC velocity during severe hypercapnia. A significant negative correlation between the velocity change at 10% CO2 and the normocapnic resting velocity was found in a group of capillaries isolated by cluster analysis. These results suggest that the dominant component of cerebral hyperemic response to hypoxia and to moderate hypercapnia is an increase in capillary RBC flow velocity. A more complex change in the velocity distribution occurs during severe hypercapnia and results in increased homogeneity of RBC perfusion in the cerebrocortical capillary network.

Simultaneous assessment of flow and BOLD signals in resting-state functional connectivity maps.

We have recently demonstrated using functional magnetic resonance imaging the presence of synchronous low-frequency fluctuations of signal intensities from the resting human brain that have a high degree of temporal correlation (p < 0.0001) both within and across the sensorimotor cortex. A statistically significant overlap between the resting-state functional connectivity map and the task-activation map due to bilateral finger tapping was obtained. Similar results have been obtained in the auditory and visual cortex. Because the pulse sequence used for collecting data was sensitive to blood flow and blood oxygenation, these low-frequency fluctuations of signal intensity may have arisen from variations of both. The objective of this study was simultaneously to determine the contribution of the blood oxygenation level signal and the flow signal to physiological fluctuations in the resting brain using the flow-sensitive alternating inversion recovery pulse sequence. In all subjects, the functional connectivity maps obtained from BOLD had a greater coincidence with task-activation maps than the corresponding functional connectivity maps obtained from blood-flow signals at the same level of statistical significance. Results of this study suggest that while variations in blood flow might contribute to functional connectivity maps, BOLD signals play a dominant role in the mechanism that gives rise to functional connectivity in the resting human brain.

Synchronous oscillations in cerebrocortical capillary red blood cell velocity after nitric oxide synthase inhibition.

Low-frequency (4-12 cpm) spontaneous oscillations in cerebral blood flow are well known and their augmentation after nitric oxide synthase inhibition has recently been described. However, the presence of these oscillations in blood flow velocity in the capillary network of the brain has not been demonstrated. In this paper, low-frequency oscillations in red blood cell flow velocity in cortical capillaries using intravital video microscopy were studied before and after infusion of the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME). Fluorescein isothiocyanate-labeled red blood cells were injected intravenously and served as markers of capillary flow. Red cell velocity was measured by off-line image tracking. After infusion of L-NAME (30 mg/kg), red cell velocity decreased from an average of 1.0 +/- 0.1 mm/sec to 0.53 +/- 0.1 mm/sec. Simultaneously, low-frequency oscillations in velocity emerged as indicated by an 81 +/- 17% increase in standard deviation of the 4- to 8-cpm frequency components. There was a significant temporal correlation (r = 0.58, P < 0.01) in red cell velocity between neighboring capillaries after L-NAME. Principal component analysis suggested that the high temporal correlation was a consequence of low-frequency oscillations rather than phase. These results are consistent with a model in which low-frequency spontaneous oscillations in flow velocity are brought about by precapillary vasomotion. This study provides for the first time direct evidence for low-frequency synchronous oscillations of red cell flow velocity in the cerebral capillary network.