HomotopicLI: Rationale, characteristics, and implications of a new threshold-free lateralization index of functional magnetic resonance imaging.

The reliable preoperative estimation of brain hemispheric asymmetry may be achieved through multiple lateralization indices using functional magnetic resonance imaging. Adding to our previously developed AveLI, we devised a novel threshold-free lateralization index, HomotopicLI, which computes a basic formula, (Left - Right) / (Left + Right), using voxel values of pairs located symmetrically in relation to the midsagittal line as the terms Left and Right, and averages them within the regions-of-interest. The study aimed to evaluate HomotopicLI before clinical applications. Data were collected from 56 healthy participants who performed four language tasks. We compared seven index types, including HomotopicLI, AveLI, and BaseLI; BaseLI was calculated using the sums of voxel values as the terms. Contrary to our expectations, HomotopicLI performed similarly to AveLI but better than BaseLI in detecting right dominance. A detailed analysis of unilaterally activated voxels of the homotopic pairs revealed that unilateral activation occurred more frequently on the right than on the left when HomotopicLI indicated right dominance. The voxel values during right unilateral activation were smaller than those in the left, causing right dominances in the homotopic pairs by HomotopicLI. These unique features provide an advantage in detecting residual, compensative functions spreading weakly in the non-dominant hemisphere.

How Memory Switches Brain Responses of Patients with Post-traumatic Stress Disorder.

To characterize the brain responses to traumatic memories in post-traumatic stress disorder (PTSD), we conducted task-employed functional magnetic resonance imaging and, in the process, devised a simple but innovative approach-correlation computation between task conditions. A script-driven imagery task was used to compare the responses with a script of the patients' own traumatic memories and with that of tooth brushing as a daily activity and to evaluate how eye movement desensitization and reprocessing (EMDR), an established therapy for PTSD, resolved the alterations in patients. Nine patients with PTSD (seven females, aged 27-50 years) and nine age- and gender-matched healthy controls participated in this study. Six patients underwent the second scan under the same paradigm after EMDR. We discovered intense negative correlations between daily and traumatic memory conditions in broad areas, including the hippocampus; patients who had an intense suppression of activation during daily recognition showed an intense activation while remembering a traumatic memory, whereas patients who had a hyperarousal in daily recognition showed an intense suppression while remembering a traumatic memory as a form of "shut-down." Moreover, the magnitude of the discrepancy was reduced in patients who remitted after EMDR, which might predict an improved prognosis of PTSD.

Altered resting-state frontoparietal control network in children with attention-deficit/hyperactivity disorder.

The frontoparietal control network, anatomically and functionally interposed between the dorsal attention network and default mode network, underpins executive control functions. Individuals with attention-deficit/hyperactivity disorder (ADHD) commonly exhibit deficits in executive functions, which are mainly mediated by the frontoparietal control network. Involvement of the frontoparietal control network based on the anterior prefrontal cortex in neurobiological mechanisms of ADHD has yet to be tested. We used resting-state functional MRI and seed-based correlation analyses to investigate functional connectivity of the frontoparietal control network in a sample of 25 children with ADHD (7-14 years; mean 9.94 ± 1.77 years; 20 males), and 25 age-, sex-, and performance IQ-matched typically developing (TD) children. All participants had limited in-scanner head motion. Spearman's rank correlations were used to test the associations between altered patterns of functional connectivity with clinical symptoms and executive functions, measured by the Conners' Continuous Performance Test and Spatial Span in the Cambridge Neuropsychological Test Automated Battery. Compared with TD children, children with ADHD demonstrated weaker connectivity between the right anterior prefrontal cortex (PFC) and the right ventrolateral PFC, and between the left anterior PFC and the right inferior parietal lobule. Furthermore, this aberrant connectivity of the frontoparietal control network in ADHD was associated with symptoms of impulsivity and opposition-defiance, as well as impaired response inhibition and attentional control. The findings support potential integration of the disconnection model and the executive dysfunction model for ADHD. Atypical frontoparietal control network may play a pivotal role in the pathophysiology of ADHD.

Stable signatures of schizophrenia in the cortical-subcortical-cerebellar network using fMRI of verbal working memory.

A dysfunction in working memory (WM) is a core cognitive impairment in schizophrenia that involves the cortical-subcortical-cerebellar network. We propose that in addition to other often-referred markers, the signal reduction in the network during verbal working memory (VWM) is a stable and intrinsic indicator of illness. We presented a Sternberg VWM task to 46 patients with schizophrenia and 46 healthy controls matched on performance accuracy during functional magnetic resonance imaging (fMRI). Reduced activation was demonstrated in the thalamus, cerebellar vermis, pons and the triangular part of the inferior frontal gyrus (IFG) in the patient group. We also found a "failure of deactivation" in the default mode network (DMN) in patients as represented by a low versus high load VWM. In addition, a reduced left lateralization in the triangular and opercular parts of the IFG was observed in the patient group replicating previous "failure of lateralization" findings in schizophrenia. A comparison of long (10 to 19 years) and short (3 to 9 years) durations of illness (DoIs) demonstrated that the DoI was only associated with the activation changes in the middle frontal gyrus and lateral temporal cortex but not with the IFG-subcortico-cerebellar regions observed. These alterations were consistent with the cognitive dysmetria described in the cortical-subcortical-cerebellar network in schizophrenia. In conclusion, the combination of reduced activation in the cortical-subcortical-cerebellar network during VWM in particular, reduced deactivation in the DMN and reduced lateralization in the IFG is thought to be stable neuroimaging signatures of schizophrenia.

AveLI: a robust lateralization index in functional magnetic resonance imaging using unbiased threshold-free computation.

The laterality index (LI) is often applied in functional magnetic resonance imaging (fMRI) studies to determine functional hemispheric lateralization. A difficulty in using conventional LI methods lies in ensuring a legitimate computing procedure with a clear rationale. Another problem with LI is dealing with outliers and noise. We propose a method called AveLI that follows a simple and unbiased computational principle using all voxel t-values within regions of interest (ROIs). This method first computes subordinate LIs (sub-LIs) using each of the task-related positive voxel t-values in the ROIs as the threshold as follows: sub-LI=(Lt-Rt)/(Lt+Rt), where Lt and Rt are the sums of the t-values at and above the threshold in the left and right ROIs, respectively. The AveLI is the average of those sub-LIs and indicates how consistently lateralized the performance of the subject is across the full range of voxel t-value thresholds. Its intrinsic weighting of higher t-value voxels in a data-driven manner helps to reduce noise effects. The resistance against outliers is demonstrated using a simulation. We applied the AveLI as well as other "non-thresholding" and "thresholding" LI methods to two language tasks using participants with right- and left-hand preferences. The AveLI showed a moderate index value among 10 examined indices. The rank orders of the participants did not vary between indices. AveLI provides an index that is not only comprehensible but also highly resistant to outliers and to noise, and it has a high reproducibility between tasks and the ability to categorize functional lateralization.

Extensive stimulus repetition leads older adults to show delayed functional magnetic resonance imaging adaptation.

We investigated whether extensive repetition can diminish age-related differences between younger and older adults in functional magnetic resonance adaptation (fMR-A). Datasets were obtained from 26 younger and 24 older healthy adults presented with two scenes that repeated 20 times amongst other novel scenes during fMRI scanning. The average cortical responses to the first eight (Repetitions 1-7) and the last eight (Repetitions 12-19) presentations out of 20 were compared within each group. Younger adults showed similar levels of fMR-A in both repetition sets. Conversely, older adults did not show reliable fMR-A in Repetitions 1-7, but they did in Repetitions 12-19; subtracting the latter from the former revealed a significant effect within left inferior occipital, left lingual, and the posterior part of fusiform gyrus. We concluded that cortical responsiveness in older adults are compromised, but extensive repetition can lead older adults to show a delayed but closer level of fMR-A compared to younger adults.

Neural substrates of phonological selection for Japanese character Kanji based on fMRI investigations.

Japanese and Chinese both share the same ideographic/logographic character system. How these characters are processed, however, is inherently different for each language. We harnessed the unique property of homophone judgment in Japanese kanji to provide an analogous Chinese condition using event-related functional magnetic resonance imaging (fMRI) in 33 native Japanese speakers. We compared two types of kanji: (1) kanji that usually evokes only one pronunciation to Japanese speakers, which is representative of most Chinese characters (monophonic character); (2) kanji that evoked multiple pronunciation candidates, which is typical in Japanese kanji (heterophonic character). Results showed that character pairs with multiple sound possibilities increased activation in posterior regions of the left, middle and inferior frontal gyri (MFG and IFG), the bilateral anterior insulae, and the left anterior cingulate cortex as compared with those of kanji with only one sound. The activity seen in the MFG, dorsal IFG, and ventral IFG in the left posterior lateral prefrontal cortex, which was thought to correspond with language components of orthography, phonology, and semantics, respectively, was discussed in regards to their potentially important roles in information selection among competing sources of the components. A comparison with previous studies suggested that detailed analyses of activation in these language areas could explain differences between Japanese and Chinese, such as a greater involvement of the prefrontal language production regions for Japanese, whereas, for Chinese there is more phonological processing of inputs in the superior temporal gyrus.

Ontology for FMRI as a biomedical informatics method.

Ontological engineering is one of the most challenging topics in biomedical informatics because of its key role in integrating the heterogeneous database used by biomedical information services. Ontology can translate concepts and their real-world relationships into expressions that can be processed by computer programs or web services, providing a unique taxonomic frame to describe a pathway for extracting, processing, storing, and retrieving information. In developing clinical functional neuroimaging, which requires the integration of heterogeneous information derived from multimodal measurement of the brain, these features will be indispensable. Neuroimaging ontology is remarkable in that it requires detailed description of the hypothesis, the paradigm employed, and a scheme for data generation. Neuroimaging modalities, such as functional magnetic resonance imaging (fMRI), magnetoencephalography (MEG), electroencephalography (EEG), and near infrared spectroscopy (NIRS), share similar application purposes, imaging protocol, analyzing methods, and data structure; semantic gaps that remain among the modalities will be bridged as ontology develops. High-performance, global resource information database (GRID) computing and the applications organized as service-oriented computing (SOC) will support the heavy processing to integrate the heterogeneous neuroimaging system. We have been developing such a distributed intelligent neuroimaging system for real-time fMRI analysis, called BAXGRID, and a neuroimaging database. The fMRI ontology of this system will be integrated with established medical ontologies, such as the Unified Medical Language System (UMLS).

BAX: a toolbox for the dynamic analysis of functional MRI datasets.

We developed a toolbox called BAX (brain activation explorer) for the dynamic analysis of functional magnetic resonance imaging (fMRI) datasets using the general linear model. The toolbox provides a graphical user interface where several routines can be accessed to extract different sets of information from a given series of functional images. The dynamic analysis can be implemented using either an incremental approach or a sliding window approach. In particular, BAX can be used to construct dynamic activation maps that can be used to assess the contribution of newly added volumes in the final activation map, detect problematic segments in the dataset, or localize in time dynamic changes in brain activity. Consistency maps, which graphically represent the number of times voxels are consecutively detected as active in a given analysis, can also be constructed using either incremental or sliding window analysis. BAX runs under Matlab (MathWorks, Inc.) and requires some routines from SPM2 (Wellcome Department of Cognitive Neurology, London, UK) for its operation. It can be freely downloaded at http://www.medgrid.org/ website.

Subregions of human parietal cortex selectively encoding object orientation.

Computation of object orientation could be an independent process from those of other object features, but currently neither the location of human brain areas selectively coding orientation information nor an optimum experimental paradigm have yet been established. In this study, functional magnetic resonance imaging was used to investigate brain activation in the parietal cortices related to object orientation. Using an Arabic digit whose spatial attributes were carefully manipulated, we found parietal areas exclusively sensitive to object orientation, but not to general spatial attention. It seems that, by excluding confounds such as mental manipulation or working memory as well as inherent spatial information within the stimuli, functional segregation within the parietal lobe can be effectively probed.

Dynamic monitoring of brain activation under visual stimulation using fMRI--the advantage of real-time fMRI with sliding window GLM analysis.

An fMRI technique based on real-time analysis was applied to evaluate the advantages of dynamic monitoring of the t-statistics based on a general linear model. The temporal change of the t-statistics in V1 and V4 under four conditions of visual stimuli covering different visual fields with or without coloring was estimated using an incremental analysis and a sliding window analysis (SWA). The SWA not only visualized the dynamic change of the activation in response to the task conditions and switching, but also enabled us to evaluate the temporal correlation of the t-statistics among the four visual areas. It was suggested that the activity in the V4 was bilaterally organized, and the altering color stimuli gave stronger stimulation to the V1 than did the black and white stimuli. Although the activation map at each time point represents the brain activity during several task and rest blocks, a SWA will be useful to evaluate the transition of neuronal activation in response to several sequential task conditions. An incremental analysis will be useful to monitor the ongoing activation in real-time during the scan, since it gives a higher t-value according to the accumulation of volume data. These two methods will be complementary.

An FMRI study to investigate auditory attention: a model of the cocktail party phenomenon.

In human life, discrimination of a target voice from other voices or sounds is indispensable, and inability for such discrimination results in sensory aphasia. To investigate the neuronal basis of the attentional system for human voices, we evaluated brain activity during listening comprehension tasks using functional magnetic resonance imaging (fMRI) at 3T. Diotic listening comprehension tasks, in which a narration was superimposed by another given by the same speaker (SV experiment) or by a different speaker (DV experiment), were presented to normal volunteers. The story indicated in the baseline task blocks, in which only one narration was presented, was intensively followed during the superimposed task blocks. In each experiment, 6 task blocks, 3 blocks for each condition, and 7 rest blocks were alternatively repeated, and the contrast of the superimposed condition to the baseline condition in each session was obtained. In the DV experiment, compared with the control condition, activation in Wernicke's area (BA22) was increased. In the SV experiment, activation in the frontal association cortex (BA6, BA9/ 46, BA32, BA13/47) was additionally increased. These results suggested that difficulty in phonological processing to discriminate human voices calls for further semantic, syntactic, and prosodic processing, as well as augmented selective attention.

Activation of the precuneus is related to reduced reaction time in serial reaction time tasks.

Multiple brain areas are activated during serial reaction time (RT) tasks (SRTTs), but the part of the brain that facilitates reductions in RT remains unclear. The present study attempted to determine the brain region contributing most to improved RTs during explicit SRTTs. Subjects comprised 18 healthy volunteers who were instructed to press one of four buttons corresponding to visual stimuli as quickly as possible and with minimal errors during functional MRI. Stimuli were presented either in random order (control condition) or in a repeated six-item sequence (learning condition). Conventional analysis contrasting learning and control conditions revealed activation in the prefrontal-parietal area, which shifted to motor area. Subjects with high RT reduction showed more prominent activation in the precuneus than subjects with low RT reduction. Intra-subject correlation analysis revealed that time course of precuneus activation was unrelated to time-course of RT reduction. However, inter-subject correlation analysis revealed that RT changes correlate only with precuneus activation, meaning that subjects showing more prominent RT reduction revealed more prominent activation of the precuneus, which is known to play critical roles in controlling finger movements with reference to buffered memory.

An fMRI study of temporal sequencing of motor regulation guided by an auditory cue--a comparison with visual guidance.

The neuronal system to process and transfer auditory information to the higher motor areas was investigated using fMRI. Two different types of internal modulation of auditory pacing (1 Hz) were combined to design a 2x2 condition experiment, and the activation was compared with that under a visual guidance. The bilateral anterior portion of the BA22 (ant-BA22) and the left BA41/42 were more extensively activated by the combined modulation condition under the auditory cue than that under the visual cue. Among the four auditory conditions with or without the two types of internal modulation, the activation in the ant-BA22 was augmented only on the left side by the combined modulation condition. The left ant-BA22 may be especially involved in integrating the external auditory cue with internal modulation, while the activation on the right side did not depend on the complexity. The role of the left BA41/42 in motor regulation may be more specific to the processing of an auditory cue than that on the right side. These two areas in the left temporal lobe may be organized as a subsystem to handle the timing of complex movements under auditory cues, while the higher motor areas in the frontal lobe support both sensory modalities for the cue. This architecture may be considered as 'audio-motor control', which is similar to the visuo-motor control of the front-parietal network.

Temporal relationship between action and visual outcome modulates brain activation: an fMRI study.

Monitoring the visual outcome of our actions is critical to our visuo-motor behavior. To investigate the neural basis of monitoring visual change produced by self-movement, we examined the temporal relationship between manual depression of a button and visual feedback on activation of the brain. Six neurologically normal subjects participated in 3 experiments (synchronous, delayed, and visual [control]). Magnetic resonance (MR) images of their brains were acquired during the experiments using a scanner operating at 3T. In the synchronous experiment, subjects pressed a button at self-paced intervals and received synchronous visual stimuli in response. In the delayed experiment, visual stimuli were presented with a delay after subjects pressed a button at self-paced intervals. In the control experiment (visual experiment), subjects did not press the button, but viewed visual stimuli generated by a computer at random intervals. In the synchronous experiment, activation in the cerebellum and right parietal lobe was stronger than in the delayed experiment, whereas activation in the primary visual cortex was weaker than in the delayed and visual experiments. These results suggest that visual outcomes produced synchronously with action are processed in the cerebellum and the parietal area for the organization of optimal motor behavior, rather than in the primary visual area that is known to process the visual properties of external objects. The cerebellar signal related to visuo-motor contingency may modulate the cortical processing of visual input that is synchronous with action.

Implicit and explicit processing of kanji and kana words and non-words studied with fMRI.

Using functional magnetic resonance imaging (fMRI), we investigated the implicit language processing of kanji and kana words (i.e., hiragana transcriptions of normally written kanji words) and non-words. Twelve right-handed native Japanese speakers performed size judgments for character stimuli (implicit language task for linguistic stimuli), size judgments for scrambled-character stimuli (implicit language task for non-linguistic stimuli), and lexical decisions (explicit language task). The size judgments for scrambled-kanji stimuli and scrambled-kana stimuli produced activations on the bilateral lingual gyri (BA 18), the bilateral occipitotemporal regions (BA 19/37), and the bilateral superior and inferior parietal cortices (BA 7/40). Interestingly, besides these areas, activations of the left inferior frontal region (Broca's area, BA 44/45) and the left posterior inferior temporal cortex (PITC, BA 37), which have been considered as language areas, were additionally activated during size judgment for kanji character stimuli. Size judgment for kana character stimuli also activated Broca's area, the left PITC, and the left supramarginal gyrus (SMG, BA 40). The activations of these language areas were replicated in the lexical decisions for both kanji and kana. These findings suggest that language processing of both kanji and kana scripts is obligatory to literate Japanese subjects. Moreover, comparison between the scrambled kanji and the scrambled kana showed no activation in the language areas, while greater activation in the bilateral fusiform gyri (left-side predominant) was found in kanji vs. kana comparison during the size judgment and the lexical decision. Kana minus kanji activated the left SMG during the size judgment, and Broca's area and the left middle/superior temporal junction during the lexical decision. These results probably reflect that in implicit or explicit reading of kanji words and kana words (i.e., hiragana transcriptions of kanji words), although using largely overlapping cortical regions, there are still some differences. Kanji reading may involve more heavily visual orthographic retrieval and lexical-semantic system through the ventral route, while kana transcriptions of kanji words require phonological recoding to gain semantic access through the dorsal route.

An fMRI study of tool-use gestures: body part as object and pantomime.

A body part as object (BPO) gesture is one of the error patterns in apraxia. In the BPO gesture, people represent objects by their hands. To clarify the neuronal background of the BPO gesture, we compared the brain activation during the BPO gesture with that during ordinary pantomime in normal subjects using functional magnetic resonance imaging. Both the BPO gesture and the pantomime induced activation in the left parietal areas (Brodmann's area (BA) 7, 40), irrespective of the hand used. These areas might be activated by a common process of tool-related gestures. The BPO gesture also activated the right supramarginal gyrus (BA 40). This activation might reflect the characteristic process of BPO, the correlation of hands with tools by their forms and movements.

Application of independent component analysis to magnetic resonance imaging for enhancing the contrast of gray and white matter.

An application of independent component analysis (ICA) was attempted to develop a method of processing magnetic resonance (MR) images to extract physiologically independent components representing tissue relaxation times and achieve improved visualization of normal and pathologic structures. Anatomical T1-weighted, T2-weighted and proton density images were obtained from 10 normal subjects, 3 patients with brain tumors and 1 patient with multiple sclerosis. The data sets were analyzed using ICA based on the learning rule of Bell and Sejnowski after prewhitening operations. The three independent components obtained from the three original data sets corresponded to (1) short T1 components representing myelin of white matter and lipids, (2) relatively short T1 components representing gray matter and (3) long T2 components representing free water. The involvement of gray or white matter in brain tumor cases and the demyelination in the case of multiple sclerosis were enhanced and visualized in independent component images. ICA can potentially achieve separation of tissues with different relaxation characteristics and generate new contrast images of gray and white matter. With the proper choice of contrast for the original images, ICA may be useful not only for extracting subtle or hidden changes but also for preprocessing transformation before clustering and segmenting the structure of the human brain.

The effect of task block arrangement on the detectability of activation in fMRI.

The effect of task block arrangements on the detection of brain activation was investigated. Sessions of functional magnetic resonance imaging (fMRI) including the same number of two different task conditions but with different arrangements were compared. The two task conditions were, A) Ellipse-shaped black and white checkerboard flicker stimulation at 4.2 Hz covering the bilateral visual field, and B) the same flicker stimuli covering only the left visual field. In the rest blocks (0), the subjects looked at a fixation point. Four different task block arrangements were compared, 1) A0 (0A0A0A0) and B0 (0B0B0B0), 2) A0B0 (0A0B0A0B0A0B0), 3) AB0 (0AB0AB0AB0) and 4) AB (0ABABAB). Bilateral V1, V2, V3 and the left V5 were activated by condition A, and the right V1 and V2 by B. The activation in the left visual field by A0 was larger than in the other three conditions. In a differential analysis between conditions A and B, activation in the left V3 and V5 was declined by AB0 or AB. When rest blocks were located in the post-stimulus undershoot phase, the % signal change of the BOLD signal was emphasized, which caused augmented significance in the detection of the activity. It was indicated that the outcome of the activation map was influenced by the arrangement of task blocks, even though the same number of task blocks were repeated within the sessions. In fMRI studies, task conditions should be carefully compared within or across sessions considering the characteristics of hemodynamic response functions.

Finger movements lighten neural loads in the recognition of ideographic characters.

The role of finger writing movements in recognizing Japanese ideographic characters (Kanji) was investigated using functional magnetic resonance imaging at 3 T. A total of 12 healthy native Japanese-speaking volunteers were studied while counting the number of strokes in ideographic characters. In experiment 1, a representation of the pronunciation of an ideographic character was displayed using Japanese syllabic characters. Volunteers were required to count the strokes of the ideographic character corresponding to the displayed phonogram. This procedure included retrieval and generation of ideographic characters. In experiment 2, the ideographic character itself was displayed and the volunteers counted its strokes. This procedure focused on visuospatial imagery processes. Each experiment was conducted under two different motor conditions. One condition allowed the subject to use finger movements to count the strokes, while the other disallowed any finger movements. In both experiments, movement-allowed conditions duly activated the primary motor area. The phonogram-displayed and movement-disallowed condition induced an augmented activation in a part of the left premotor area, which was assumed to be Exner's area. This area might have been activated by a demand for sequential generation of character graphemes that corresponded to the phonogram displayed. The ideographic-character-displayed and movement-disallowed condition activated the dorsal occipitoparietal areas and the primary visual area, which might be involved in the visuospatial mental imagery processes. These results suggest that execution of finger movements during stroke counting of ideographic characters lightens the neural loads for grapheme generation on Exner's area and for the visuospatial imagery processes on the dorsal pathway.