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Behavioural Neurology 20 ( 2008) 127– 140 127 DOI 10.3233/ BEN- 2008- 0223 IOS Press Clinical application of standardized cognitive assessment using fMRI. I. Matrix reasoning Mark D. Allena, b,∗ and Alina K. Fonga aPsychology Department, Brigham Young University, Provo, UT, USA bNeuroscience Center, Brigham Young University, Provo, UT, USA Abstract. Functional MRI is increasingly recognized for its potential as a powerful new tool in clinical neuropsychology. This is likely due to the fact that, with some degree of innovation, it is possible to convert practically any familiar cognitive test into one that can be performed in the MRI scanning environment. However, like any assessment approach, meaningful interpretation of fMRI data for the purpose of patient evaluation crucially requires normative data derived from a sample of unimpaired persons, against which individual patients may be compared. Currently, no such normative data are available for any fMRI- based cognitive testing protocol. In this paper, we report the first of a series of fMRI- compatible cognitive assessment protocols, a matrix reasoning test ( f- MRT), for which normative samples of functional activation have been collected from unimpaired control subjects and structured in a manner that makes individual patient evaluation possible in terms of familiar z- score distributions. Practical application of the f- MRT is demonstrated via a contrastive case- study of two individuals with cognitive impairment in which fMRI data identifies subtleties in patient deficits otherwise missed by conventional measures of performance. Keywords: fMRI, matrix reasoning, cognitive assessment, normative data 1. Introduction Over the last decade and a half, functional magnet-ic resonance imaging ( fMRI) has become, by far, the dominant research tool for studying the neural sub-strates of cognitive processes, both in normal subjects as well as in those with cognitive/ brain impairments. It is not surprising then, that great interest should arise in potential clinical applications of fMRI as a diag-nostic and assessment tool for neurologists, neuropsy-chiatrists, neuropsychologists, and any other clinicians who routinely evaluate brain functioning in individual patients. Indeed, recent policy developments by pro-fessional governing organizations such as Division 40 of the American Psychological Association [ 24] and the American Medical Association Current Procedu-ral Terminology Editorial Panel [ 5,11] clearly indicate ∗ Corresponding author: Mark D. Allen, Department of Psychol-ogy, 1022 SWKT, Brigham Young University, Provo, UT 84602, USA. Tel.: + 1 801 422 6481; Fax: + 1 801 422 0602; E- mail: m allen@ byu. edu. that these organizations anticipate increased demand for fMRI in clinical settings in the near future. There are, however, several factors that currently limit the full utility fMRI as a diagnostic and assess-ment tool. These limitations, which primarily involve issues of validity and reliability, are articulated espe-cially well in a recent paper by Brown [ 6]. One of the more significant problems that Brown identifies, with respect to the validity of clinical fMRI, is the absence of large- scale normative data sets derived from repre-sentative samples of individuals without brain impair-ment, which would allow quantitative evaluations of patient brain activation patterns for any given cogni-tive process, with respect to the population from which the patient comes. Without well structured normative data- bases that accurately characterize normal brain ac-tivation patterns, it is currently not possible to provide contextualized, quantitative assessments of individual patient outcomes, expressed in terms of statistical de-viation from what would be expected in the absence of pathology. ISSN 0953- 4180/ 08/$ 17.00 2008 – IOS Press and the authors. All rights reserved 128 M. D. Allen and A. K. Fong / Cognitive assessment using fMRI: Matrix reasoning In this study, we describe a test protocol based on the classic Matrix Reasoning Test ( MRT), designed specif-ically for use in the fMRI scanning environment. This MRT adaptation, along with an adaptation of a stan-dard verbal fluency test reported in a companion paper ( Allen and Fong, 2008), represent two of a series of six fMRI protocols we have developed with the potential for clinical application. Other protocols in this series include adaptations of such familiar tests as the Trail Making Test- B [ 29], Face Memory Test [ 30], Verbal Memory Test [ 8], and Picture Naming Test [ 14]. In order to maximize the interpretability and practical ap-plication of the normative data obtained from our fMRI assessment protocols, with respect to comparable nor-mative data sets derived from conventional cognitive tests, we modeled our scanning protocols as closely as possible after the most commonly used neuropsycho-logical tests in contemporary assessment batteries [ 17, 21,35]. The motivation to keep our fMRI protocols closely structured to commonly used versions of these familiar neuropsychological tests follows a statement given in Hart et al. [ 11], regarding the governance of procedures and billing codes for clinical fMRI: At present, no standardized cognitive/ neuropsy-chologic testing packages have been certified by any duly charged governing body in terms of appro-priate stimuli or tasks. Testing guidelines in terms of choice of stimuli, tasks, and performance param-eters should thus presently conform in general to standard guidelines accepted for neurobehavioral and/ or neuropsychologic testing. Nevertheless, aside from some notable excep-tions [ 22,23,27,32,38], few neuroimaging studies have been designed specifically to mimic neuropsychologi-cal exams. There are three objectives of this paper. First we describe the development our fMRI adaptation of the MRT, which we have labeled the f- MRT protocol. This includes a description of the methods by which we gen-erated our test stimuli, as well as an empirical compari-son between performanceon our stimuli and those from a comparable conventional version of the test – name-ly, the Raven's Colored Progressive Matrices ( CPM). These concurrent validity measures include data from independent samples of both neurologically impaired and neurologically unimpaired subjects. Second, we present functional activation data from 32 control sub-jects without brain impairment who were scanned using the protocol. Finally, we introduce a method for assess-ing the reliability of activation patterns across subjects, which in turn provides the basis for a map of normative activation patterns for each exam. Specifically, each normative brain map represents a distribution of activa-tion values within functionally- defined brain regions of interest ( ROI), which allows one to evaluate individual patient result profiles, as expressed in z- scores, for any ROI or set of ROIs under investigation. An example of this ROI- based normative activation map, for the MRT data, will be presented here. Following the experimental portion of this study, we will present a practical application of the f- MRT, where we describe and contrast fMRI testing outcomes of two patients suffering traumatic brain injury. The primary objective of that section will be to demonstrate the ability of the f- MRT to distinguish between subtypes of neurological impairments associated with otherwise indistinguishable performance on behavioral measures alone. Concerning our first objective, there are many inher-ent challenges in converting a conventional " paper and pencil" test, such as the MRT, into a protocol that can be used to acquire valid and interpretable fMRI data. These challenges arise primarily from the physical and temporal limitations imposed by the MRI scanning en-vironment. For example, during scan acquisition, sub-jects' heads must remain entirely immobilized, such that it is generally not possible to obtain overt vocal responses during scanning, except under certain lim-ited circumstances ( see for example [ 1,3,4,9,10,13]). Likewise, all other body movements must be kept to an absolute minimum, such that subject responses are largely limited to hand and finger actions ( e. g., button presses). Another major challenge concerns the tem-poral constraints of the fMRI method. The use of a typ-ical MRI scanning facility is time- based and expensive. This, along with other factors such as subject fatigue and boredom necessitates, in most cases, much shorter test durations for fMRI protocols than for the respec-tive conventional tests they are modeled after. Other temporal constraints are more complex. For example, the fMRI technique critically relies on the detection of blood oxygen level dependent ( BOLD) changes in the brain, which are governed by intricate physiological processes with narrowly constrained temporal param-eters [ 20]. Therefore, it is usually necessary to place stricter control over exactly when and for how long a subject engages in a given cognitive activity or re-sponse behavior, compared to the restrictions found in comparable conventional tests. Because of these and other constraints, developing an fMRI- compatible protocol, such as theMRT adapta- M. D. Allen and A. K. Fong / Cognitive assessment using fMRI: Matrix reasoning 129 tion described here, requires a unique set of methods for presenting stimuli and obtaining subject responses in a manner which, to the extent possible, retains enough crucial similarities with each corresponding conven-tional test, to allowmeaningful comparisons to be made between fMRI activation patterns and performance pat-terns on conventional tests. In this way, our protocols might qualify as appropriate " testing packages" as de-fined by Hart et al. [ 11]. In order to verify the as-sumption that we have accurately modeled a tradition MRT, however, we performed convergent validity tests ( reported below) in which subjects were administered both the standard MRT test ( the CPM) and the f- MRT, with both tests administered outside of the scanning environment. Raven's Progressive Matrix ( RPM) is widely regard-ed as a classic test of non- verbal reasoning in the visual modality [ 2,28]. The task employed in the RPM, re-ferred generically as matrix reasoning, has been adapt-ed for use in many prevalent assessments, including variants of the original RPM ( i. e., the Colored and Advanced Progressive Matrices tests), as well as the Weschler Adult Intelligence Scale ( WAIS) and its vari-ants. It is commonly used to assess visually- based ab-stract problem- solving ability, while putatively placing little or no demands on verbal, motor, and complex visual processing skills [ 33]. The matrix reasoning task requires subjects to analyze visual pattern changes that occur along multiple dimensions within an array of stimulus objects. Subjects must ascertain the nature of each pattern change along each dimension indepen-dently, and then integrate this knowledge to determine the correct solution. Thus, the matrix test relies heavi-ly on visuospatial working memory, goal/ sub- goal pro-cessing, inductive reasoning, and deductive reasoning. The first fMRI study to directly test neural activity associated with solving matrix reasoning problems [ 22] found activation predominantly in bilateral inferior and middle frontal gyri, as well as bilaterally throughout the dorsal visual processing stream ( inferior/ middle occip-ital cortex and inferior/ superior parietal cortex). More recent studies [ 7,15] using somewhat improved tech-nology and methods ( e. g., more coverage of the dorsal brain) replicated this basic finding, with additional acti-vations found in medial frontal cortex, including dorsal anterior cingulate and supplementary motor cortex, as well as greater extents of dorsolateral prefrontal cor-tex. Finally, a very recent study by Melrose et al. [ 19] identified reliable activation of the basal ganglia dur-ing performance of this task. Although the studies re-ported above vary somewhat in design, they each em-ployed stimuli and protocols with the specific attempt to model familiar neuropsychological exams – namely theWAIS- III matrix reasoning subtest, and the original RPM. Given the similarities between our objectives and design approach, the results from these studies allow reasonable predictions about the activation patterns we expect to observe in this experiment, thus providing some means for assessing the validity of our protocol at the neural systems level. 2. Methods 2.1. Participants Thirty- two participants ( 16 male, 16 female) be-tween 20 and 39 years old ( Mean= 25.04; S. D= 4.23) volunteered to serve as control subjects for this study. Participants received no compensation, but were told that they would have the opportunity to see structural and functional images of their brains after the study. Hand dominance was assessed using the Edinburgh Handedness Inventory [ 25]. All but two subjects ( one male, one female) were determined to be dominant-ly right- handed. Mean L. Q. scores on the Edinburgh handedness scale – where scores above + 48 suggest strong right handedness – were + 71.8 ( Decile R. 3), sd = 35.0 for females; and + 69.1 ( Decile R. 3), sd = 31.5 for males; with no significant difference between sex-es ( t = 1.36, p > 0.1). All subjects were Caucasian, except for one Hispanic woman and one Asian/ Pacific Islander male, and spoke English as their first language. All participants were determined to have no history of neurological impairments ( assessed by a screening questionnaire), nor history of significant psychological pathology, and reported no use of psychotropic medi-cations. High resolution 3D SPGR and T2 axial FLAIR MRI scans revealed no detectible brain abnormalities in any control subjects, as determined by a qualified neuroradiologist. In addition to the overall good neu-ropsychological health of our control participants, they were also determined to be high functioning in cogni-tive ability. All subjects had completed at least one year of college education and were in good academic stand-ing at a university with high admission/ continuance standards. All participants consented to release pre-admission records ofACT ( or SAT) scores. Analysis of mean scores ( with SAT converted to ACT equivalents) revealed overall high performance, with a mean of 30 ( sd = 4.30) for females, and 29 ( sd = 2.16) for males, with no significant difference between sexes ( t = 1.38, p > 0.1). 130 M. D. Allen and A. K. Fong / Cognitive assessment using fMRI: Matrix reasoning Fig. 1. Sample item from the f- MRT matrix reasoning test. 2.2. Materials For this study, we created a set of 24 test stimulus items, conceptually modeled after problems found on the Raven's Progressive Matrices test, as well as items from the matrix reasoning subtest of the WAIS- III. It should be noted, however, that all items were unique-ly devised by the authors of this study – no direct re-productions or replications of items from any existing copyrighted exams were used. These items, along with 24 alternate stimuli, and 4 practice items, are referred collectively as the f- MRT. Each stimulus consists of a 3 × 3 matrix of complex visual figures, with one figure missing ( see Fig. 1). For each matrix problem, participants were given the simple instruction to " indicate what the missing figure should be," and to then select it from among the four choice alternatives presented on the right side of the matrix. For example, given the problem in Fig. 1, the participant must discover that the linear orientation of internal boxes varies as a function of rows, whereas the position of the filled- in box varies as a function of columns. Thus, the correct choice is " 2," where the orientation of boxes is directed upward from left to right, consistent with the other figures in the bottom row, and the filled- in box occupies the rightmost posi-tion, consistent with the other figures in third column. Following most standard applications of matrices tests, our participants were told to place more importance on response accuracy than on response speed. All partic-ipants were given 4 practice trials. After each prac-tice trial, the participant was asked to explain her/ his reasoning for solving the problem. If the participant made an incorrect choice, the experimenter revealed the correct choice and the reasoning behind selecting that choice. One important consideration in the creation of our f- MRT stimuli concerns problem difficulty. In order to obtain a reliable fMRI signal from a single subject asso-ciated with a given cognitive task, it is necessary to take repeated measurements of signal change across several epochs in which the subject repeatedly performs that cognitive task. An optimal measurement, therefore, re-quires that the subject engage cognitive mechanisms in a manner that is as consistent as possible across repe-titions of the task. This demand for consistency across task repetitions, however, leads to some difficulty in modeling familiarMRT protocols in the fMRI environ-ment. Most conventional versions of theMRT ( e. g., the RPM), include a range of difficulty across test items, where problems become increasingly more difficult as the test progresses. A straightforward adaptation of such a test, therefore, would lead to unacceptable lev-els of fMRI signal variability across task repetitions for reliable statistical modeling within a single subject. The challenge, then, was to create an MRT protocol which would retain the most fundamental psychomet-ric properties of the protocols practitioners are familiar with, while at the same time employing optimal fM-RI design techniques. The strategy we chose was to use items of moderate difficulty, that is, matrix prob-lems modeled after those found in the medium range of " progressive" style MRTs, such as the RPM and the WAIS- III. To be more specific, we estimate our stim-uli to be about as difficult as items near the ends of sections A and B of the standard RPM. Alternatively, M. D. Allen and A. K. Fong / Cognitive assessment using fMRI: Matrix reasoning 131 one might compare the f- MRT difficulty level to that of the Raven's Colored Progressive Matrices test ( CPM), given that the difficulty of the CPM is equivalent to sections A and B of the standard RPM. Because the f- MRT, by design, does not employ a " progressive" pattern of item difficulty, we cannot claim that it fully models the CPM, or any other sin-gle matrix test, in its entirety. Nevertheless, we might reasonably expect considerable correlations in perfor-mance between the f- MRT and the CPM. The reason for this is simply that subjects are more likely to make errors on the more difficult items of the CPM – that is, on those most similar to items on the f- MRT. 2.3. Evaluation of concurrent validity: The f- MRT and Raven's Colored Progressive Matrices In order to assess correlations in performance be-tween the f- MRT and the CPM, we collected addition-al data from a sample of 69 individuals without neu-rological impairment, as well as 17 individuals diag-nosed with neurological/ cognitive impairments. The 69 subjects without impairment were matched demo-graphically to the participants in the fMRI study, in terms of age, sex, and education level. The 17 patients with neurological impairments included 6 women and 11 men with an age range of 22- 85 years, who were referred for clinical fMRI scans. This sample includ-ed 1 individual diagnosed with vascular dementia, 4 with probable Alzheimer's Disease, and 12 with cogni-tive impairments following traumatic brain injury. All participants completed both the 36- item CPM and the 24- item f- MRT, where the f- MRT was converted into a " paper- and- pencil" format such that it could be admin-istered exactly as the CPM is. Both tests were given in a single session with test- order counterbalanced across participants. 2.3.1. Unimpaired subjects Performance scores for this group of 69 subjects were very high on both tests. The mean percent correct for the CPM was 97.37 ( sd = 3.48; range = 86– 100), which is in nearly perfect agreement with the normative data reported by Yuedall et al. [ 37] for normal subjects in this age range. The mean percent correct for the f- MRT was 98.36 ( sd = 2.98; range = 88– 100). Cor-relation analysis revealed a coefficient of + 0.90, sug-gesting that the f- MRT and CPM show strong concur-rent/ convergent validity in unimpaired populations. 2.3.2. Neurologically impaired subjects Performance scores for this group of 17 subjects showed substantially more variability. The mean per-cent correct for the CPM was 86.11 ( sd = 15.74; range = 47– 100). The mean percent correct for the f- MRT was 87.25 ( sd = 14.62; range = 50– 100). Corre-lation analysis revealed a coefficient of + 0.88, sug-gesting that the f- MRT and CPM show strong concur-rent/ convergent validity in a sample of patients with a variety of neurological/ cognitive impairments. 2.4. fMRI testing procedures All test stimuli were presented via MRI- compatible LCD goggles. Participants were instructed to make their responses by pressing one of four buttons on a fiber- optic response pad, held in both hands, using the index and middle fingers of each hand. At the beginning of each session, a " please wait prompt" appeared for 8 seconds to allow for T1 relaxation effects, followed by a 2- second " Ready?" prompt, after which the first test stimulus appeared. With each button- press response, the participant's accuracy and latency were recorded and the computer display was advanced to the next task epoch. Subjects were given the opportunity to solve as many of the 24 problems as possible during a functional scanning session of 4 minutes. Pilot trials revealed a consistent response time range of 1– 4 seconds for most items. Each test epoch, consisting of one test item, alternated with an 11- second " rest" epoch, in which subjects were instructed to count covertly from 1 to 10. This simple counting task is recommended as an optimal minimal- demand cognitive activity for " rest" epochs in fMRI experiments [ 34]. Thus, the duration of each test epoch varied, depending on subject response time to a given test item, whereas rest epochs were fixed at 11 seconds. 3. Data analysis 3.1. Image acquisition Functional images were acquired with a 1.5- T GE scanner at 23 contiguous axial locations with a slice thickness of 5 mm, using an EPIBOLD sequence with the critical parameters TR = 2000; TE = 40 ms. Conventional pre- processing and statistical analyses were performed using MRIcro and SPM2 ( http:// www. fil. ion. ucl. ac. uk) software packages, re-spectively. Preprocessing procedures included ac- 132 M. D. Allen and A. K. Fong / Cognitive assessment using fMRI: Matrix reasoning quisition time realignment, using sinc interpolation, followed by motion correction with EPI distortion unwarping. No head movement exceeded 1 mm translation or 1 ◦ rotation displacement. After mo-tion/ distortion correction, all functional volumes were spatially normalized and resampled using the Montre-al Neurological Institute ( MNI) templates implement-ed in SPM2, and spatially smoothed with an 8 mm FWHM Gaussian kernel, in order to increase signal- to-noise ratio and to reduce the effects of moderate inter-subject variability in brain anatomy. A high- resolution 3D SPGR whole- head volume was also collected from each subject and examined by a neuroradiologist for any structural anomalies that might disqualify the par-ticipant as a " normal" control subject. Each subject's SPGR image was then coregistered and normalized to their mean functional image in order to perform subject-specific ROI analyses that take into account individual variability in cortical landmark organization. 3.2. Conventional fMRI analyses 3.2.1. Subject- level analysis A time- series ANCOVA implemented in SPM2 was used to test each voxel, for each subject, against the null- hypothesis that changes in BOLD signal in that voxel, over the duration of the experiment, did not sig-nificantly correlate with the temporal sequencing of the cognitive task of interest. A boxcar waveform con-volved with a synthetic hemodynamic response func-tion ( HRF) with a 4 sec lag- to- peak was used to mod-el task- related activation. The data were high- passed-filtered in time, using a set of discrete cosine basis func-tions with a cut- off period of 128 seconds, and condi-tioned for temporal autocorrelations using AR1 correc-tion. For each participant, t- values for the contrast test condition versus control condition, as well as the sim-ple contrast test condition ( against an implicit baseline) were computed for each voxel, using the parameter es-timates of the ANCOVA. The resulting 3- dimensional contrast map from each subject was saved for further subject- level ROI analysis as well as for random effects ( RFX) group- level analysis. 3.2.2. Group- level analysis Activation at the group level was analyzed using the RFX approach recommended by Penny et al. [ 26], in which the value of the sum of the contrast weights for each voxel from each subject's ANCOVA was entered as a single data point in a second- level t- statistic com-putation, with the mean value for each voxel across subjects modeled as the effect term and the variance be-tween subjects modeled as the error term. Significant activation peaks at the group- level are reported with a critical FWE corrected p- value of < 0.001, and a voxel cluster extent threshold of 8. 3.3. ROI analysis In addition to the RFX group- level analysis, we per-formed ROI- based analyses for each control partici-pant. There were two reasons for this: First, as stated above, a primary objective of this study is to develop a method for assessing the reliability of activation pat-terns across subjects, in order to provide quantitative estimates of deviation for any individual patient against a normative sample. For our approach, these analy-ses were carried out in terms of functionally motivated ROIs. Second, the RFX model is sensitive only to ac-tivation that reliably occurs across subjects within in a relatively tight spatial proximity. Therefore, for some brain regions, such as dorsolateral prefrontal cortex, the RFX model might not be sensitive to some locally idiosyncratic, yet globally systematic patterns of acti-vation. This may be due to the relatively larger size of these functional regions, as well as the complexity of the processes they support. For example, large func-tional regions in the dorsolateral prefrontal cortex in particular have been shown to display broad divergence of activation peaks across subjects, as well as variable foci within even single subjects over repetitions of the same task [ 18]. Our procedure for establishing functional ROI des-ignations follows the automated anatomical labeling ( AAL) parcellation scheme described by Tzourio- Mazoyer et al. [ 36]. Although the AAL program it-self ( e. g., as implemented in SPM2) is designed to op-erate within the space of MNI- normalized brains, its anatomical specifications for region boundary identifi-cation are explicit and comprehensive enough that they can be applied to individual ( non- normalized) brains with reasonable precision. For our purposes, however, it was necessary to make a few supplemental designa-tions within the standard AAL scheme. These modi-fications were motivated primarily from empirical ob-servations, in terms of reliable activation patterns iden-tified throughout our data sets, but were also justified on a priori grounds, in terms of functional sub- regions that have been reliably identified by neurophysiological studies. Accordingly, we designated the following minor sup-plements and modifications to the AAL ROI cortical parcellation scheme: M. D. Allen and A. K. Fong / Cognitive assessment using fMRI: Matrix reasoning 133 1. A division between the superior and inferior por-tions of the precentral gyrus. 2. A merging of the posterior portions of the superi-or and middle frontal gyri into a single region cor-responding to Brodmann's area 6, often labeled premotor cortex [ 31]. 3. Designation of the frontal operculum, as the op-ercular portions of inferior frontal cortex and an-terior insula. 4. Designation of the frontal pole, as the portions of middle and superior frontal gyri anterior to pars triangularis, or approximately anterior to the MNI y- axis plane coordinate y=+ 40. After ROI parcellation of each subject's anatomical image, individual functional activation maps ( with a single t- value assigned to each voxel) were overlain for analysis of activation peak distributions on a subject-by- subject basis. Prior to analysis, each t- map was smoothed with a 1.5 mm FWHM Gaussian spatial fil-ter in order to condition extreme outlier t- value spikes within peak clusters. Each ROI was then inspected for the presence of cluster peaks. If an independent peak was found, the maximum ( smoothed) t- score was ex-tracted and saved as a data point for the group analysis of that ROI. If the maximum value within an ROI be-longed to a cluster with a centroid in an adjacent ROI ( i. e., the highest intensity voxel fell at the border of an adjacent ROI), the ROI was determined to not have a peak. When more than one peak was identified in an ROI, the locations of the peaks were catalogued and, if consistently found across subjects, used to motive further ROI divisions ( e. g., list- item 1 above). Following the above guidelines and procedures for extracting t- values from each ROI within each subject, means and standard deviations of extracted scores were computed across subjects and used to derive a normal-ized distribution of z- scores for each ROI. 4. Results 4.1. Task performance on the f- MRT The average response accuracy was 98% ( range 92– 100%). The mean reaction time for all participants across all trials was 3509 ms ( SD = 1208 ms). 4.2. Group- level BOLD activation Significant activation at the group level ( see Fig. 2) was highly consistent with patterns found in similar studies [ 7,15,19,27]. Results based on the contrast test-control differed only slightly from the simple contrast test ( versus implicit baseline). Given our interest in whole brain activation associated with all perceptual and cognitive components of the MRT task we mod-eled, we report the slightly more comprehensive pat-tern found for the simple contrast test. See Table 1a for a complete summary. Consistent with the dominant visuospatial nature of this task, strong clusters of acti-vation were found throughout the ventral and dorsal vi-sual processing streams, extending from fusiform cor-tex, through inferior and middle occipital cortex, reach-ing the parietal lobe with foci in intraparietal sulcus. Strong bilateral precentral gyrus/ premotor activation is also present and is most readily attributed to manual motor response preparation, but is also consistent with studies demonstrating activation in these areas for tasks involving abstract spatial processing [ 16,31]. Clear ac-tivationwas present in frontal areas involved with prob-lem solving, such as medial SMA/ dorsal anterior cin-gulate, posterior areas of dorsolateral prefrontal cortex, and inferior frontal cortex. As predicted by sensitivity limitations of the RFX approach, though, dorsolateral prefrontal activation was not as robust in other areas strongly associated with problem solving, such as su-perior/ middle frontal gyri and the frontal pole. Howev-er, the ROI analyses reported below clearly confirmed expected activation in these areas. 4.3. ROI analysis For all significant regions identified by theRFXmod-el, independent activation peaks were confirmed in cor-responding subject- specific ROIs, with very few ex-ceptions at the t- value corresponding to the probabil-ity threshold p < 0.001, uncorrected ( t > 3.45), and with no exceptions at the t- value corresponding to the threshold p < 0.01, uncorrected ( t > 2.49). As for individual activation peaks found in ROIs that did not reach significance on the RFX model, the following was observed: There were a few spurious ROI peaks, which occurred infrequently ( 1 additional peak found in 2 subjects), which were not consistent across sub-jects. However, there were two regions in which sig-nificant peaks were found consistently across all sub-jects at the thresholdp < 0.001, uncorrected ( t> 3.45). These were bilateral superior/ middle frontal gyrus, and the frontal pole ( see Table 1b). 134 M. D. Allen and A. K. Fong / Cognitive assessment using fMRI: Matrix reasoning Fig. 2. Distribution of significant RFX- modeled group- level activation for the f- MRT matrix reasoning test. Surface- projection rendered on smoothed MNI brain template. 5. Summary and discussion of experimental results: Two methods of analysis In this section, we described and tested methods for collecting fMRI data using a protocol that approxi-mates traditional matrix reasoning tests as performed in conventional neuropsychological settings. The re-sults from this experiment were highly consistent with results from previous studies that employed similar, though not identical, MRT protocols. Additionally, we performed individual ROI analyses on each control subject, using an augmentedAAL parcellation scheme. This analysis revealed two important details: First, ac-tivation peaks were confirmed on a subject- by- subject basis for each significant region identified by the group-level RFX analysis, with nearly perfect consistency across subjects. Second, for the relatively large dor-solateral prefrontal and frontal pole regions, the ROI analyses revealed consistently large peaks in each sub-ject. Because the precise location of these peaks var-ied across subjects by a few millimeters, however, this regional- level consistencywas not revealed by the RFX analysis. The second objective of our ROI analysis was to de-rive a distribution of sample t- values for each region activated in control subjects while performing the f- MRT. These regional distributions, in turn, allow one to perform quantitative assessments of individual sub-jects/ patients who are administered this fMRI- adapted MRT protocol. Altogether, our analyses identify 11 critical ROIs for the f- MRT, including 9 regions identi-fied by RFX and ROI analyses, as well as 2 additional frontal regions identified by ROI analysis alone. These regions are presented in Table 2, along with the means and standard deviations computed from the maximal ( filter- conditioned) t- scores extracted from each of the 32 participants. The data summary presented in Table 2 is most in-formative for two reasons. First, it allows one to assess the relative intensity of activation elicited in each ROI during average performance of the MRT task. This, in turn might suggest the relative contribution of each area in terms of successful task performance. Conclu-sions of this sort, of course, must be drawn with some caution, given that some cortical regions are inherently prone to higherBOLD signal detection, all things being equal. A second source of information concerns the variance of peak activations across individuals, and its application for clinical assessment. The variance with-in each ROI, as a numerical expression of the " normal" M. D. Allen and A. K. Fong / Cognitive assessment using fMRI: Matrix reasoning 135 Table 1a Group- level random effects model activation foci ( p < 0.001, FWE corrected) for the f- MRT matrix reasoning test Region ( AAL) MNI ( x, y, z) t- score Fusiform/ Inferior occipital cortex Right Left 35, − 72, − 16 − 28, − 84, − 16 15.74 7.53 Middle occipital gyrus Right Left 31, − 89, 3 − 28, − 93, 2 13.73 10.62 Superior parietal lobule/ intraparietal sulcus Right Left 24, − 72, 52 − 36, − 60, 48 12.93 12.00 Medial supplementary motor area/ Dorsal anterior cingulate gyrus 1, 16, 45 11.79 Thalamus Right Left 8, − 21, 12 − 10, − 23, 13 9.92 11.26 Precentral gyrus/ Premotor area∗ Superior Right Left Inferior Right Left 27, − 9, 61 − 27, − 9, 59 46, − 2, 39 − 50, 2, 34 9.09 8.38 8.93 10.94 Anterior insula/ frontal operculum Right Left 37, 22, 8 − 32, 26, 3 9.11 9.06 Basal ganglia ( caudate) Right Left 14, 12, 10 − 10, 10, 11 8.17 8.89 Inferior frontal gyrus Right Left 47, 28, 22 − 47, 38, 13 7.40 8.93 ∗ Premotor area = Portions of superior and middle frontal gyri corresponding to BA 6. Table 1b Subject- level analysis of the f- MRT. Additional activa-tion foci present in all 32 control participants identified by ROI analysis Region ( AAL) Average t- score ( SD) Bilateral superior/ middle frontal gyrus∗ 8.42 ( 2.40) Bilateral frontal pole∗∗ 5.73 ( 2.00) ∗ Excludes portions corresponding to BA 6. ∗∗ Portions of superior and middle frontal gyri anterior to y=+ 40 ( MNI). range of expected peak values, provides the statistical basis for evaluating activation patterns from individual subject/ patients, with respect to group norms. A prac-tical approach for applying this procedure is described in the next section. 6. Clinical application of the ROI analysis The procedure for assessing a single patient's func-tional activation on the f- MRT ( or any of the other fMRI- adapted neuropsychological protocols we have developed) with respect to our normative sample is fair-ly straightforward. Following the same methods ap-plied to the control subjects, each patient's structural brain scan is first parcellated according to our augment-ed AAL scheme, and coregistered with his/ her mean functional image. Next, maximal t- scores are extracted from each ROI of the patient's spatially filtered acti-vation map, according to the same parameters set for the control subjects. Using the means and standard de- 136 M. D. Allen and A. K. Fong / Cognitive assessment using fMRI: Matrix reasoning Table 2 Means and standard deviations of extracted maximum t- values for each critical ROI associated with the Matrix Reasoning Test for a sample of 32 control subjects Cortical regions Fusiform Middle Superior mSMA Thalamus Precentral Anterior Superior/ Basal Inferior Frontal inferior occipital parietal dorsal gyrus insula middle ganglia frontal pole occipital gyrus lobule/ anterior frontal gyrus cortex ( IPS) cingulate gyrus Mean 10.02 9.78 10.67 8.82 4.84 9.54 5.82 8.42 5.35 7.29 5.73 StDev 3.24 3.92 3.55 3.09 1.71 3.17 1.81 2.40 1.58 1.94 2.00 IPS = Intraparietal Sulcus; mSMA = Medial Supplementary Motor Area. viations from the control sample, a patient's maximal t- value can then be expressed as a z- score within each ROI. This application highlights one of the ways in which fMRI assessments might greatly enhance knowledge about a patient's deficit with respect to a given cogni-tive task. For example, following the standard paper and pencil application of a matrix reasoning test, the clinician learns only whether a patient solves matrix problems correctly or not. With functional imaging, on the other hand, the clinician may learn further de-tails about the functionality of the independent neural mechanisms that contribute to a patient's overall level of performance, as typically expressed in terms of a single value, score, label, or index ( e. g., a z- score). Since its development, we have analyzed over 100 patients with complaints of cognitive impairment using the f- MRT and its companion protocols. We present here sample data from two patients suffering moderate cognitive impairments following traumatic brain injury. Although these two patients share many commonali-ties, both in terms of overall cognitive functioning, as well as performance specifically on matrix reasoning tests, their f- MRT analyses show divergent profiles. 6.1. Patient descriptions Descriptive summaries of the two patients of interest, referred to as P01 and P02, are given in Table 3. Both patients are female college students in their twenties who were involved in motor vehicle accidents. Both pa-tients reported symptoms of persistent post- concussive syndrome, including difficulties with attention, verbal memory, verbal fluency, mood regulation, and moti-vation. Neuroradiological analyses were performed at the time of neuropsychological/ fMRI assessment. In-spection of MRI brain images, including axial T1, axial FLAIR, and axial T2 FSE sequences, revealed no ab-normalities. Comprehensive neuropsychological bat-teries administered at the time of fMRI scanning indi-cated global cognitive performance in the low- normal range for each patient's age, gender, and level of educa-tion ( RBANS scores in Table 3 are representative in this regard). Of particular interest, both patients showed notable impairments on matrix reasoning tests – name-ly the CPM and the matrix reasoning subtest of the WAIS- III – with scores on both tests falling in the range of 1.5– 2.5 standard deviations below normal. 6.2. Patient f- MRT analysis Both patients were administered the f- MRT within two weeks of the time standard neuroimaging and neu-ropsychological assessments were administered. As indicated in Table 3, accuracy and reaction time per-formance by P01 and P02 on the f- MRT was consistent with performance on conventional tests, with scores in the range of − 0.61 and − 1.93 standard deviations below means for the control group. 6.2.1. ROI analysis: Comparison of P01 and P02 The greatest value of the f- MRT assessment is that it provides information about patient functioning that goes beyond simple measures of test performance. ROI analyses of f- MRT data from P01 and P02 provide a case- in- point. Outcomes of the ROI analyses for P01 and P02 are given in Figs 3 and 4, respectively. It should be recalled that the values in these figures do not merely represent levels of functional activation for each ROI, but rather represent degree of statistical deviation from normal activation within each region. Inspection of these figures reveals clear distinctions between P01 and P02. For example, the analysis for P01 in Fig. 3 implicates a disruption primarily of dorso-lateral pre- frontal structures, where t- values fall around 2 standard deviations belowthe mean, as well as medial prefrontal cortex, where values fall more than 1 stan-dard deviation below the mean. It appears then, that for P01, structures involved in the executive operations associated with the MRT task, including the dorsal an-terior cingulate, appear selectively compromised. M. D. Allen and A. K. Fong / Cognitive assessment using fMRI: Matrix reasoning 137 Table 3 Demographic information and selection of neurobehavioral characteristics of sample patients P01 and P02. At the time of testing, both patients were concurrently administered conventional neuropsychological tests and the f- MRT P01 P02 Sex F F Age 26 22 Years of education 16 14 Time since injury ( months) 24 10 Glasgow coma scale 14 Not reported Loss of consciousness ( minutes) < 30 < 5 Post traumatic amnesia ( hours) Anterograde 12 8 Retrograde 24 None RBANS total scale score ( percentile) 89 ( 23) 94 ( 34) Matrix reasoning subtest WAIS- III Raw score ( age percentile) 10/ 24 ( 7) 9/ 24 ( 6) RCPM raw score (* z- score) 32/ 36 (− 2.32) 33/ 36 (− 1.52) f- MRT performance ( z- score) Accuracy 92% (− 1.92) 96% (− 0.61) Mean reaction time ( ms) 4807 (− 1.07) 5842 (− 1.93) Notes: RBANS = Repeatable Battery for the Assessment of Neuropsy-chological Status; WAIS = Wechler Adult Intelligence Scale; RCPM = Ravens Coloured Progressive Matrices; ∗ Based on Yeudall et al. [ 37]. Region Fusiform/ Inferior Occipital Cortex Middle Occipital Gyrus Superior Parietal Lobule/ ( IPS) mSMA/ Dorsal Anterior Cingulate Thalamus Pre-central Gyrus Anterior Insula Superior/ Middle Frontal Gyrus Basal Ganglia Inferior Frontal Gyrus Frontal Pole Group Mean 10.02 9.78 10.67 8.82 4.84 9.54 5.82 8.42 5.35 7.29 5.73 Group StDev 3.24 3.92 3.55 3.09 1.71 3.17 1.81 2.40 1.58 1.94 2.00 Patient t value 11.63 12.10 11.65 5.05 5.20 10.90 5.50 3.41 5.95 4.09 1.67 Patient z- score 0.50 0.59 0.28 - 1.23 0.21 0.43 - 0.18 - 2.10 0.38 - 1.65 - 2.03 IPS = Intraparietal Sulcus; mSMA = Medial Supplementary Motor Area Fig. 3. Sample report of selected patient outcome ( P01) on the ROI analysis of the f- MRT. Tick marks along vertical columns indicate patient z- scores (− 3 to + 3) for each brain region. Note: value levels do not simply represent relative activation in each region. Rather, they represent degree of statistical deviation from normal for each region. In contrast to this, P02 shows a different pattern of activation deficits, where abnormalities are restricted primarily to parietal cortex and basal ganglia, where z- scores fall more than two standard deviations below the mean. This suggests that for P02, disruptions to mechanisms of spatial processing, and perhapsworking memory processing capacity, provide the most likely explanation for her performance impairments on the MRT. The contrastive outcomes for P01 and P02, then, il-lustrate that fMRI analysis offers a means for identi-fying differing patterns of disruption to the neurocog- 138 M. D. Allen and A. K. Fong / Cognitive assessment using fMRI: Matrix reasoning Region Fusiform/ Inferior Occipital Cortex Middle Occipital Gyrus Superior Parietal Lobule/ ( IPS) mSMA/ Dorsal Anterior Cingulate Thalamus Pre-central Gyrus Anterior Insula Superior/ Middle Frontal Gyrus Basal Ganglia Inferior Frontal Gyrus Frontal Pole Group Mean 10.02 9.78 10.67 8.82 4.84 9.54 5.82 8.42 5.35 7.29 5.73 Group StDev 3.24 3.92 3.55 3.09 1.71 3.17 1.81 2.40 1.58 1.94 2.00 Patient t value 9.71 10.56 3.48 7.98 5.35 10.02 6.06 9.89 1.66 7.60 5.49 Patient z- score - 0.09 0.20 - 2.02 - 0.27 0.30 0.15 0.13 0.61 - 2.33 0.16 - 0.12 IPS = Intraparietal Sulcus; mSMA = Medial Supplementary Motor Area Fig. 4. Sample report of selected patient outcome ( P02) on the ROI analysis of the f- MRT. Tick marks along vertical columns indicate patient z- scores (− 3 to + 3) for each brain region. nitive systems that underlie a particular cognitive task across patients who otherwise show equal performance on behavioral measures alone. 7. Summary and conclusion In this study we addressed the emerging need to pro-vide neuropsychological assessments adapted for use with fMRI technology. We have presented here an adaptation of the Matrix Reasoning Test, the f- MRT, and shown that in a sample population of normal sub-jects, activation patterns are consistent both with pre-vious fMRI studies using similar protocols, and activa-tion is consistent with cognitive mechanisms hypothe-sized to be critical for successful performance on the MRT from a neural systems point of view. As such, we suggest that the data presented here represent a major step toward the full utility of fMRI as a diagnostic and assessment tool, specifically in that we provide a proto-col that is structured in a way that allows performance and activation patterns to be compared in a meaningful way to performance on conventionalMRT assessments familiar to most clinicians ( e. g., as illustrated by the sample reports in Figs 3 and 4). Another significant aspect of our current effort, though, is that we present a method for collecting and archiving activation patterns from normal subjects, such that the reliability of strength and locations of ac-tivation peaks can be evaluated on a region- by- region basis across subjects. This, in turn, allows one to de-termine a range of expected " normal" activation values for each region, and thus provides a normative scale for evaluating individual patient outcomes. Using this approach, we have demonstrated at least one case in which fMRI analysis revealed critical distinctions be-tween two patients with highly similar performance abilities. It may not be surprising to find such distinc-tions for a complex task such as the MRT, where suc-cessful performance is hypothesized to rely on multiple cognitive sub- systems. While the goal of the current study has been to model a familiar version of the MRT, one might obtain even greater analytic specificity using fMRI, by examining the independent cognitive compo-nents that make up a complex cognitive task like the MRT in relative isolation, as described, for example, in the event- related fMRI approach to theWisconsin card sorting task by Monchi et al. [ 22]. References [ 1] S. Abrahams, L. Goldstein, A. Simmons, M. Brammer, S. Williams, V. Giampietro, C. Andrew and N. Leigh, Functional magnetic resonance imaging of verbal fluency and confronta-tion naming using compressed image acquisition to permit overt responses, Human Brain Mapping 20 ( 2003), 29– 40. M. D. Allen and A. K. Fong / Cognitive assessment using fMRI: Matrix reasoning 139 [ 2] D. Alderton and G. E. Larson, Dimensionality of Raven's Ad-vanced Progressive Matrices Items, Educational and Psycho-logical Measurement 50 ( 1990), 887– 900. [ 3] D. M. Barch, C. S. Carter, T. S. Braver, F. W. Sabb, D. C. Noll and J. D. Cohen, Overt verbal responding during fMRI scanning: Empirical investigations of problems and potential solutions, Neuroimage 10 ( 1999), 642– 657. [ 4] S. Basho, E. Palmer, M. Rubio, B. Wulfeck and R.- A. Muller, Effects of generation mode in fMRI adaptations of semantic fluency: Paced production and overt speech, Neuropsycholo-gia 45 ( 2007), 1697– 1706. [ 5] J. A. Bobholz, S. M. Rao, A. J. Saykin and N. Pliskin, Clinical use of functional magnetic resonance imaging: Reflections on the new CPT codes, Neuropsychology Review 17 ( 2007), 189– 191. [ 6] G. Brown, Functional magnetic resonance imaging in clinical practice: Look before you leap, Neuropsychology Review 17 ( 2007), 103– 106. [ 7] K. Christoff, V. Prabhakaran, J. Dorfman, Z. Zhao, J. Kroger, K. Holyoak and J. Gabrieli, Rostrolateral prefrontal cortex involvement in relational integration during reasoning, Neu-roImage 14 ( 2001), 1136– 1149. [ 8] D. C. Delis, J. Kramer, E. Kaplan and B. A. Ober, Califor-nia Verbal Learning Test ( CVLT) Manual, San Antonio, TX: Psychological Corporation, 1987. [ 9] C. H. Y. Fu, K. Morgan, J. Suckling, S. C. Williams, C. Andrew, G. N. Vythelingum and P. K. McGuire, A functional magnetic resonance imaging study of overt letter verbal fluency using a clustered acquisition sequence: Greater anterior cingulate activation with increased task demand, NeuroImage 17 ( 2002), 871– 879. [ 10] C. H. Y. Fu, A. McIntosh, J. Kim, W. Chau, E. Bullmore, S. Williams, G. Honey and P. K. McGuire, Modulation of effec-tive connectivity by cognitive demand in phonological verbal fluency, NeuroImage 30 ( 2006), 266– 271. [ 11] J. Hart, S. M. Rao and M. Nuwer, Clinical functional magnetic resonance imaging, Cognitive and Behavioral Neurology 20 ( 2007), 141– 144. [ 12] S. Huettel, A. Song and G. McCarthy, Functional Magnetic Resonance Imaging, Sunderland, MA: Sinauer, 2004. [ 13] I. Kan and S. Thompson- Schill, Effect of name agreement on prefrontal activity during overt and covert picture naming, Cognitive, Affective, & Behavioral Neurscience 4 ( 2004), 43– 57. [ 14] E. Kaplan, H. Goodglass and S. Weintraub, The Boston Nam-ing Test. Experimental Edition, Philadelphia: Lea & Febiger, 1983. [ 15] J. Kroger, F. Sabb, C. Fales, S. Bookheimer, M. Cohen and K. Holyoak, Recruitment of anterior dorsolateral prefrontal cortex in human reasoning: A parametric study of relational complexity, Cerebral Cortex 12 ( 2002), 477– 485. [ 16] C. Lamm, C. Windischberger, E. Moser and H. Bauer, The functional role of dorso- lateral premotor cortex during mental rotation: An event- related fMRI study separating cognitive processing steps using a novel task paradigm, Neuroimage 36 ( 2007), 1374– 1386. [ 17] M. D. Lezak, Neuropsychological Assessment, Fourth edition, New York: Oxford University Press, 2004. [ 18] D. J. McGonigle, A. M. Howseman, B. S. Athwal, K. J. Friston, R. S. Fackowiak and A. P. Holmes, Variability in fMRI: An ex-amination of intersession differences, NeuroImage 11 ( 2000), 708– 734. [ 19] R. Melrose, R. M. Poulin and C. E. Stern, An fMRI Investi-gation of the role of the basal ganglia in reasoning, Brain Research 1142 ( 2007), 146– 158. [ 20] M. R. Metea and E. A. Newman, Glial Cells Dilate and Con-strict Blood Vessels: A Mechanism of Neurovascular Cou-pling, Journal of Neuroscience 26 ( 2006), 2862– 2870. [ 21] M. Mitrushina, K. Boone, J. Razani and L. D'Elia, Hand-book of Normative Data for Neuropsychological Assessment, Second edition, New York: Oxford University Press, 2005. [ 22] O. Monchi, M. Petrides, V. Petre, K. Worsley and A. Dagher, Wisconsin card sorting revisited: Distinct neural circuits par-ticipating in different stages of the dask identified by event-related functional magnetic resonance imaging, Journal of Neuroscience 21 ( 2001), 7733– 7741. [ 23] C. Moritz, S. Johnson, K. McMillan, V. Haughton and E. Meyerland, Functional MRI neuroanatomic correlates of the Hooper Visual Organization Test, Journal of the International Neuropsychological Society 10 ( 2004), 939– 947. [ 24] Official Position of the Division of Clinical Neuropsycholo-gy ( APA Division 40) on the Role of Neuropsychologists in Clinical Use of fMRI: Approved by the Division 40 Executive Committee July 28, 2004. The Clinical Neuropsychologist 18 ( 2004), 349– 351. [ 25] R. C. Oldfield, The assessment and analysis of handedness: The Edinburgh Inventory, Neuropsychologia 9 ( 1971), 97– 113. [ 26] W. D. Penny, A. P. Holmes and K. J. Friston, Random effects analysis, In: Human Brain Function, ( 2nd ed.), R. S. J. Frack-owiak, K. J. Friston, C. Frith, R. Dolan, K. J. Friston, C. J. Price, S. Zeki, Z. Ashburner and W. D. Penny, eds, Academic Press, 2003. [ 27] V. Prabhakaran, J. A. L. Smith, J. E. Desmond, G. H. Glover and J. D. E. Gabrieli, Neural substrates of fluid reasoning: An fMRI study of neocortical activation during performance of the Raven's Progressive Matrices Test, Cognitive Psychology 33 ( 1997), 43– 63. [ 28] J. Raven, Standardization of progressive matrices, British Journal of Medical Psychology 19 ( 1938), 137– 150. [ 29] R. M. Reitan and D. Wolfson, The Halstead- Reitan Neuropsy-chological Test Battery, Tucson, AZ: Neuropsychology Press, 1985. [ 30] C. R. Reynolds and E. D. Bigler, Test of Memory and Learning, Austin, TX: Pro- Ed, 1994. [ 31] W. Richter, R. Somorjai, R. Summers, M. Jarmasz, R. S. Menon, J. S. Gati, A. P. Georgopoulos, C. Tegeler, K. Ugurbil and S. G. Kim, Motor area activation during mental rotation studied by time- resolved single- trial fMRI, Journal of Cogni-tive Neuroscience 122 ( 2000), 310– 320. [ 32] R. Schlosser, M. Hutchinson, S. Joseffer, H. Rusinek, A. Saari-maki, J. Stevenson, S. L. Dewey and J. D. Brodie, Function-al magnetic resonance imaging of human brain activity in a verbal fluency task, Journal of Neurology, Neurosurgery & Psychiatry 64 ( 1998), 492– 498. [ 33] O. Spreen and E. Strauss, A Compendium of Neuropsycho-logical Tests: Administration, Norms, and Commentary, ( 2nd ed.), New York: Oxford University Press, 1998. [ 34] C. Stark and L. Squire, When zero is not zero: The problem of ambiguous baseline conditions in fMRI, Proceedings of the National Academy of Science, USA 98 ( 2001), 12760– 12766. [ 35] E. Strauss, E. Sherman and O. Spreen, A Compendium of Neu-ropsychological Tests: Administration, Norms, and Commen-tary ( 3rd ed.), New York: Oxford University Press, 2006. [ 36] N. Tzourio- Mazoyer, B. Landeau, D. Papathanassiou, F. Criv-ello, O. Etard, N. Delcroix, B. Mazoyer and M. Joliot, Auto- 140 M. D. Allen and A. K. Fong / Cognitive assessment using fMRI: Matrix reasoning mated anatomical labeling of activation in SPM using a macro-scopic anatomical parcellation of the MNI MRI single- subject brain, Neuroimage 15 ( 2002), 273– 289. [ 37] L. T. Yeudall, D. Fromm, J. R. Reddon and W. O. Stefanyuk, Normative data stratified by age and sex for 12 neuropsy-chological tests, Journal of Clinical Psychology 42 ( 1986), 920– 946. [ 38] K. Zakzanis, R. Mraz and S. Graham, An fMRI study of the Trail Making Test, Neuropsychologia 43 ( 2005), 1878– 1886.
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Table of Contents
'When Montana and I Were Young': Margaret Bells
Memoir of a Northern Montana Childhood edited by Mary Clearman Blew page 2 American Pathways: An Exploration of Trails and the American Imagination by Elliott West page 20 'Well I Have Lived in Montana Almost a Week and Like It Fine': Letters From the Davis Homestead, 1910-1926 by Seena B. Kohl page 32 Creating a Mythic Past: Spanish Architecture in Montana by Hipolito Rafael Chacon page 46 Read this article online! Looking Back The Editors Remember page 60 The Montana Traveler Crossing a Landscape of Sorrow: The Nez Perce (Nee-Me-Poo) National Historic Trail by Dan Gard page 65 Read this article online! Montana Reviews page 68
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Does Undercorrection of Myopia Retard Myopia Progression Among Kindergarten Children?
This study has been withdrawn prior to enrollment.
(Stringent eligibility criterion caused difficulties in recruiting patients.)
KK Women's and Children's Hospital
Information provided by:
KK Women's and Children's Hospital
ClinicalTrials.gov Identifier:
First received: July 3, 2006
Last updated: October 3, 2011
Last verified: October 2011
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The purpose of this study is to find out if undercorrection of myopia slow down the progression of myopia in kindergarten children.
Condition | Intervention | Phase |
Refractive Error - Myopia |
Drug: cyclopentolate |
Phase 1 |
Study Type: | Interventional |
Study Design: | Allocation: Randomized Intervention Model: Factorial Assignment Masking: Double-Blind |
Official Title: | Does Undercorrection of Myopia Retard Myopia Progression Among Kindergarten |
Resource links provided by NLM:
MedlinePlus related topics:
Refractive Errors
Drug Information available for:
Cyclopentolate hydrochloride
U.S. FDA Resources
Further study details as provided by KK Women's and Children's Hospital:
Ages Eligible for Study: | 5 Years to 6 Years |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | Yes |
Inclusion Criteria:
- Children of chinese descent aged 5 - 6yrs
- Refractive error of -1.00 to -3.00Ds
- Less than 1.50 astigmatism in each eye. (No oblique axis)
- Visual acuity is 6/6 or better in both eyes.
- No binocular problems, no anisometropia >1.50D
- Will be staying in S'pore for at least 2 years.
Exclusion Criteria:
Contacts and Locations
More Information
No publications provided
Additional relevant MeSH terms:
ClinicalTrials.gov processed this record on March 10, 2014
No publications provided
ClinicalTrials.gov Identifier: | NCT00348166 History of Changes |
Other Study ID Numbers: | RAU/085/2005 |
Study First Received: | July 3, 2006 |
Last Updated: | October 3, 2011 |
Health Authority: | Singapore: Domain Specific Review Boards |
Additional relevant MeSH terms:
Myopia Refractive Errors Eye Diseases Cyclopentolate Mydriatics Autonomic Agents Peripheral Nervous System Agents Physiological Effects of Drugs |
Pharmacologic Actions Parasympatholytics Muscarinic Antagonists Cholinergic Antagonists Cholinergic Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action |
ClinicalTrials.gov processed this record on March 10, 2014


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Graphics Card- AMD Radeon HD 6800 Series x2Operating System- Windows 7 Premium , Intel i7-3960X CPU @ 3.30GHz , 3301 Mhz, 6 Cores
Issue Details- In order to get any type of Bf3 and MoH : warfighter I need to disable CrossFire and then Gameplay is not issue free with random in game DC's and freezes.
Its only when playing Origin games. All titles thru Steam (cod, l4d etc) are all guns blazing.
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Jerry Remy to miss another week
Posted by Peter Abraham, Globe Staff
June 18, 2013 09:37 AM
NESN announced that Jerry Remy will miss the Red Sox games this week. Remy has been out since May 28 because of illness.
Remy wrote on Twitter on May 28 that he was suffering from allergies and would be out for three games. That was followed with an update on June 5 saying he had pneumonia.
There have been no updates on the condition of the broadcaster since.
Remy was treated for lung cancer in 2008 and missed much of the 2009 season recovering. In April, Remy said he was treated for cancer again during spring training.
Jim Rice (Game 1) and Peter Gammons (Game 2) will join Don Orsillo for today's doubleheader. Tom Caron will work with Orsillo on Wednesday.
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News, analysis and commentary from the following Boston Globe and Boston.com writers:
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- Chad Finn, Boston.com/Globe sports reporter
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Tour testimonials
We have had so many wonderful and talented guests on our tours. Some are designers or yarn dyers, some have podcasts, many are bloggers and all are wonderful knitters. Here are some reviews from them. We are so blown away by these wonderful words that as a thank you we have put up links to their sites and blogs and we hope you'll check them out (this is our initiative only… so no arm twisting went on).
The Knitting Iceland tour met all my expectations, and more (and my expectations were high). Beautiful scenery, lovely yarns, interesting classes, the wonderful city of Reykjavik, and 15 or so fantastic new friends! Truly an unforgettable week.
Karen Baumer, San Francisco CA – Karen's designs
My two Knitting Iceland experiences have been amazing. Ragga has boundless energy and enthusiasm for her country and knitting. The food and accommodation were excellent! I would highly recommend a Knitting Iceland holiday and would love to go on another soon!
Sherry James, North Yorkshire, England – Sherry's hand dyed yarn
To say that my Knitting Iceland adventure was one of the best vacations of MY LIFE, is an understatement.
It's been many years since I've been able to take a proper vacation (my partner is paraplegic and it's hard to be away from home for long periods), but this year, I was able to sign up for the Knit to the Music retreat and I couldn't be happier with the experience. First off, the whole sign up and purchase was easy peasy. It's nice to pay for the whole thing at once with the travel agency. Along the way I made changes to the lodging a couple of times and I never had any trouble reaching Ragga or Lina, the travel agent. Next, the classes were being taught by the lovely Franklin Habit, and they were all something I was interested in learning (photography, lace), but the piece de resistance was the Mini Lopapeysa class with Knitting Iceland owner & producer, Ragga Eiriksdottir. This last workshop was a super fun way to learn all the steps to create this classic Icelandic garment.
Our accommodations were clean & cheerful (we opted for the Backpackers Hostel). If you want less hustle and bustle, I'd suggest the lovely Sunna Guesthouse. When I return (and boy howdy will I return!) I'll be staying at Sunna. The sightseeing options led skillfully by Ragga were simply dazzling: dramatic countryside, gorgeous horses & sheep, rejuvenating hot springs, exploding geysirs, breath-taking waterfalls, & oh-my-goodness LOPI for days. It doesn't get much better than this for fiber lovers. The shops, the food, the lopapeysas & the super duper charming people of Iceland (all of whom are mutli-lingual with English very widespread) made this trip an A++++ extravaganza. But wait, there's more!
For this particular retreat, our price included wristbands for the legendary Iceland Airwaves music festival. I'm pretty jaded with the live music scene (I used to regularly attend CMJ, South by Southwest & Winter Music Conference for work and for play) but Iceland Airwaves really know how to spoil the music lover. There were literally hundreds of performers doing multiple shows at multiple venues (some of them free and open to the non-paying public). There was a healthy mixture of folk, indie rock, dance, pop, experimental & even classical. My personal highlight was seeing the legendary Bjork, but also Owen Pallett & the incredible Icelandic Symphony. My only regret is not losing more sleep to see more music.
I cannot recommend Knitting Iceland more highly and, I personally cannot wait to return for my next Icelandic Adventure!!!
Most sincerely,
WonderMike (aka Michael Wade) – Mike's podcast
This is a part from a longer blog post from Marjorie Liu who spent 2 days with Ragga in 2011: "…we reached the home of a wonderful woman named Helga, who owns the spread highlighted in those pictures from yesterday. What an incredible experience. I can't even begin to describe it. I'm not going to try. If you come to Iceland, you need to find out for yourselves.
Ragga took me on some other adventures, and introduced me to some truly warm, kind people: artists, entrepreneurs, farmers, designers, and visionaries. I will never forget this experience. Should you ever visit Iceland — and you're interested in textiles, farming, knitting, design — I recommend that you contact her and Knitting Iceland. Ragga is dynamite.
Marjorie M Liu, Indiana, USA – Marjorie's website
My husband, David, and I met Ragga when we were in Iceland for a short vacation. With very little notice, she was able to throw together a great afternoon tour especially tailored to our interests.
Knowing that David is a knitwear designer, she arranged for us to meet a couple of top Icelandic designers before taking us to see the Ístex spinning mill and, of course, the Álafoss store for some serious stash enhancement. She also took us to a local yarn shop where I made my most treasured find of the trip – a thick tome of traditional Icelandic textile patterns. My only regret is that I didn't bring home even more wool. We will definitely be going back!
Mel Vassey, NH, USA – Mel's blog


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Rain late tomorrow night Details >
Mar 09, 2014; 9:17 PM ET Short-Range Weather forecast overview for the Southeast United States
Springlike warmth will pour from the Plains to the East over the next few days before another winter storm unfolds at midweek.
Short-Range Weather forecast overview for the Southeast United States
See the weather conditions anticipated for some of the top vacation destinations for spring breakers.
A storm responsible for ice in the South Central states Tuesday will continue to bring snow, sleet and freezing rain to North Carolina and Virginia Friday.
Extended Weather forecast overview for the Southeast United States
Spring will tease the Midwest and East briefly Friday into Saturday and again early next week, thanks to a couple of pushes of milder air.
Drenching, locally severe thunderstorms will cross the Florida Peninsula Thursday threatening outdoor activities, including MLB spring training games.
The long-lasting and relentless winter season has broken seasonal maintenance expenditure records across much of the U.S.
Read Story >Think Mount Vesuvius was a one-off event? Think again. Though the odds of their erupting may be slim, plenty of powerful volcanoes lie just outside cities around the world.
Read Story >


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Tuff Coat ™ II Kevlar ® work gloves have no seams to fail
You'll get outstanding puncture resistance with these gloves. They combine the high tensile strength of DuPont ™ fiber with the resiliency of a natural rubber. Dipped rubber is textured for good grip. Gloves conform to the natural shape of the hand for a comfortable fit. Uncoated-back design ventilates for cool wear. Kevlar ® work gloves offer excellent dexterity. Gloves meet ANSI level 2 for cut resistance. One pair. Imported. Atlas KV300. Specify Men's size: S (7), M (8), L (9) or XL (10) from the selection box above. See drop down for sizes currently available.
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Great for gardening when pulling Thistle
By CMP
from PA
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Comments about Atlas Glove Atlas Tuff-Coat II Rubber-coated Kevlar Gloves:
Love these gloves. They are great when doing any kind of gardening work. I have a great deal of thisles and the thorns don't pentrate when pulling. Have been using these for years.
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i would buy this product again
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from seabrook, TX.
Comments about Atlas Tuff-Coat II Rubber-coated Kevlar Gloves:
I use this product as a commercial diver. It is a durable product and lasts in the environment I use it in. I only wish that the fingers had a better fit for longer fingers. Great product.


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Read below the list of predictions that did NOT come true:
Why should we believe someone who has been wrong again and again and again....1. OUR CITIES WILL DIE OF THIRST
TIM Flannery, an expert in bones, has made a fortune from books and lectures warning that we face global warming doom. He scared us so well that we last year made him Australian of the Year.
In March, Flannery said: The water problem is so severe for Adelaide that it may run out of water by early 2009.
In fact, Adelaides reservoirs are now 75 per cent full, just weeks from 2009.
In June last year, Flannery warned Brisbanes water supplies are so low they need desalinated water urgently, possibly in as little as 18 months.
In fact, 18 months later, its dams are 46 per cent full after Brisbanes wettest spring in 27 years.
In 2005, Flannery predicted Sydneys dams could be dry in just two years.
In fact, three years later its dams are 63 per cent full, not least because June last year was its wettest since 1951.
In 2004, Flannery said global warming would cause such droughts that there is a fair chance Perth will be the 21st centurys first ghost metropolis.
In fact, Perth now has the lowest water restrictions of any state capital, thanks to its desalination plant and dams that are 40 per cent full after the citys wettest November in 17 years.
Lesson: This truly is a land of drought and flooding rains. Distrust a professional panic merchant who predicts the first but ignores the second.
PROFESSOR Ove Hoegh-Guldberg, of Queensland University, is Australias most quoted reef expert.
Hes advised business, green and government groups, and won our rich Eureka Prize for scares about the Great Barrier Reef. Hes chaired a $20 million global warming study of the World Bank.
In 1999, Hoegh-Guldberg warned that the Great Barrier Reef was under pressure from global warming, and much of it had turned white.
In fact, he later admitted the reef had made a surprising recovery.
In 2006, he warned high temperatures meant between 30 and 40 per cent of coral on Queenslands great Barrier Reef could die within a month.
In fact, he later admitted this bleaching had a minimal impact.
In 2007, he warned that temperature changes of the kind caused by global warming were again bleaching the reef.
In fact, the Global Coral Reef Monitoring Network last week said there had been no big damage to the reef caused by climate change in the four years since its last report, and veteran diver Ben Cropp said this week that in 50 years hed seen none at all.
Lesson: Reefs adapt, like so much of nature. Learn again that scares make big headlines and bigger careers.
IN April this year, the papers were full of warnings the Arctic ice could all melt.
Were actually projecting this year that the North Pole may be free of ice for the first time, claimed Dr David Barber, of Manitoba University, ignoring the many earlier times the Pole has been ice free.
Its hard to see how the system may bounce back (this year), fretted Dr Ignatius Rigor, of Washington Universitys polar science centre.
Tim Flannery also warned this may be the Arctics first ice-free year, and the ABC and Age got reporter Marian Wilkinson to go stare at the ice and wail: Here you can see climate change happening before your eyes.
In fact, the Arctics ice cover this year was almost 10 per cent above last years great low, and has refrozen rapidly since. Meanwhile, sea ice in the Southern Hemisphere has been increasing. Been told either cool fact?
Yet Barber is again in the news this month, predicting an ice-free Arctic now in six years. Did anyone ask him how he got his last prediction wrong?
Lesson: The media prefers hot scares to cool truths. And it rarely holds its pet scaremongers to account.
AL Gore sold his scary global warming film, An Inconvenient Truth, shown in almost every school in the country, with a poster of a terrible hurricane.
Former US president Bill Clinton later gloated: It is now generally recognised that while Al Gore and I were ridiculed, we were right about global warming. . . Its going to lead to more hurricanes.
In fact, there is still no proof of a link between any warming and hurricanes.
Australia is actually getting fewer cyclones, and last month researchers at Florida State University concluded that the 2007 and 2008 hurricane seasons had the least tropical activity in the Northern Hemisphere in 30 years.
Lesson: Beware of politicians riding the warming bandwagon.
ROSS Garnaut, a professor of economics, is the guru behind the Rudd Governments global warming policies.
He this year defended the ugly curved steel roof hed planned at the rear of his city property, telling angry locals he was protecting himself from climate change: Severe and more frequent hailstones will be a feature of this change, he said.
In fact, even the Intergovernmental Panel on Climate Change admits decreases in hail frequency are simulated for Melbourne. . .
Lesson: Beware also of government advisers on that warming wagon.
A BAD ski season three years ago - right after a great one - had The Age and other alarmists blaming global warming. The CSIRO, once our top science body, fanned the fear by claiming resorts such as Mt Hotham and Mt Buller could lose a quarter of their snow by 2020.
In fact, this year was another boom one for skiing, with Mt Hotham and Mt Buller covered in snow five weeks before the season started.
Whats more, a study this year in the Hydrological Sciences Journal checked six climate models, including one used by the CSIRO.
It found they couldnt even predict the regional climate wed had already: Local model projections cannot be credible . . .
It also confirmed the finding of a study last year in the International Journal of Climatology that the 22 most cited global warming models could not accurately explain the (global) climate from the recent past.
As for predicting the future. . .
Lesson: The CSIROs scary predictions are near worthless.
THE CSIRO last year claimed Perth was particularly vulnerable and had a 90 per cent chance of getting less rain and higher temperatures.
There are not many other parts of the world where the IPCC has made a prediction that a drop in rainfall is highly likely, it said.
In fact, Perth has just had its coldest and wettest November since 1991.
Lesson: As I said, dont trust the CSIROs model or its warnings.
THE seas will rise up to 100m by 2100, claims ABC Science Show host Robyn Williams. Six metres, suggests Al Gore. So lets take in climate refugees from low-lying Tuvalu, says federal Labor. And ban coastal development, says the Brumby Government.
In fact, while the seas have slowly risen since the last ice age, before man got gassy, theyve stopped rising for the last two, according to data from the Jason-1 satellite.
There is no evidence for accelerated sea-level rises, the Royal Netherlands Meteorological Institute declared last month.
Lesson: Trust the data, not the politicians.
The British Met Office is home to the Hadley Centre, one of the top centres of the man-made global warming faith.
In April it predicted: The coming summer is expected to be a typical British summer.
In fact, in August it admitted: (This) summer . . . has been one of the wettest on record across the UK.
In September it predicted: The coming winter (is) likely to be milder than average.
In fact, winter has been so cold that London had its first October snow in 74 yearsand on the very day Parliament voted to fight global warming.
Lesson: If the Met cant predict the weather three months out, what can it know of the climate 100 years hence?
SPEAKING of the Met, it has so far predicted 2001, 2002, 2004, 2005 and 2007 would be the worlds hottest or second-hottest year on record, but nine of the past 10 years it predicted temperatures too high.
In fact, the Met this month conceded 2008 would be the coldest year this century.
That makes 1998 still the hottest year on record since the Medieval Warm Period some 1000 years ago. Indeed, temperatures have slowly fallen since around 2002.
As Roger Pielke Sr, Professor Emeritus of Colorado State Universitys Department of Atmospheric Science, declared this month: Global warming has stopped for the last few years.


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SC-HC55 Compact Stereo System with iPod® Dock
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Want to gift wine like a master this holiday season? Charles Curtis, master of wine and former head of wine for Christie's, joins Lunch Break with three fine wines at three affordable price points for everyone on your list. Photo: Getty Images.
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Hypogonadism can begin during fetal development, before puberty or during adulthood. Signs and symptoms depend on when the condition develops.
If the body doesn't produce enough testosterone during fetal development, the result may be impaired growth of the external sex organs. Depending on when hypogonadism develops and how much testosterone is present, a child who is genetically male may be born with:
Male hypogonadism may delay puberty or cause incomplete or lack of normal development. It can cause:
In adult males, hypogonadism may alter certain masculine physical characteristics and impair normal reproductive function. Signs and symptoms may include:
Hypogonadism can also cause mental and emotional changes. As testosterone decreases, some men may experience symptoms similar to those of menopause in women. These may include:
See a doctor if you have any symptoms of male hypogonadism. Establishing the cause of hypogonadism is an important first step to getting appropriate treatment.
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Please inform louise c baker that she is an ahole. This young lady has surely paid for her foolishless & seems to be trying to get her life together, but the self righteous schmucks like ms. Baker will NEVER let her forget her past! Some people just need to feel superior and sit in judgement. Have u never made mistakes?


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- Master twenty-four hour cool in this gorgeous printed dress - ideal paired with your favourite heeled boots for day - take your cues from the catwalk and embellish with statement jewels to radiate of-the-moment chic. Model is 5'10 /178cm, a standard UK 8 and is wearing a size XS. This item runs true to size.
- Multicoloured floral printed sheath dress featuring contrasting black jersey full length sleeves, a scoop neck and a detachable lining. DKNY dress simply pulls on.
92% silk, 8% elastane. Sleeves 95% viscose, 5% elastane. Detachable lining 100% polyester. Dry clean only. -
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The Milwaukee Police Department record custodian of State of Wisconsin accident reports.
Traffic accident reports filed by the Milwaukee Police Department are generally available 10 business days after the accident date. Requests for accident reports can be made by contacting the Wisconsin Department of Transportation at:
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Phone: (608) 266-8753 Fax: (608) 261-8201
Additional information concerning accidents and accident reports can be found on the Wisconsin Department of Transportation website.
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Apple is one of the most prominent companies in the world, and arguably, it's the most visible technology brand in the world.
It's hard to believe that little more than a decade ago, Apple was potentially on the brink of disaster. While many people were involved in turning Apple around, one man, Steve Jobs, provided the vision that led the company to new heights.
But the Steve Jobs era at Apple is officially over. Yesterday, the visionary leader of the world's richest technology company resigned from his post as CEO.
Read more...
by Patricio Robles 25 August 2011 08:49am 1 comment
Apple's WWDC events are always big news, and yesterday was no exception.
Steve Jobs himself took to the stage as the company unveiled its first official look at iOS 5, which is now available in beta to iOS Developer Program members.
by Patricio Robles 07 June 2011 14:32pm 3 comments
When you combine the world's most popular mobile and tablet computing devices with an advertising model that Steve Jobs himself was said to have called "revolutionary", you might expect overnight success.
But that hasn't exactly been the case for Apple and its iAd offering. Although it is far from a failure, it hasn't exactly upended the mobile advertising space -- yet at least.
by Patricio Robles 22 December 2010 14:50pm 4 comments
The battle to bring the internet to the small screen is heating up. And the fight to control when and how the internet is brought to the small screen is heating up too.
After finding Google TV blocked by a number of television networks, a Google product manager for Google TV recently stated that the company hasn't done a good enough job communicating what the product is to content owners. And it doesn't seem to be improving in that effort.
by Patricio Robles 12 November 2010 15:13pm 7 comments
For advertisers looking for the holy grail in mobile, the iPhone is one of the most attractive targets. And with iAd, Apple is aiming for nothing less than the perfect mobile ad.
But sometimes perfect is the enemy of good, and if rumors that have been circulating are to be believed, Apple's quest for the perfect mobile ad is driving advertisers crazy. It's also driving them away from the advertising solution that's supposed to help them.
by Patricio Robles 04 October 2010 09:11am 3 comments
Apple's press conference last Friday was a notable event for the company. Not simply because Steve Jobs took the stage, but because the purpose of the press conference was to address problems being reported with an existing product, the iPhone 4.
It was unfamiliar territory for Apple and Steve Jobs. Jobs, of course, is used to introducing new products, not dealing with an existing one that is the subject of customer complaints, class action lawsuits and a media firestorm.
by Patricio Robles 19 July 2010 09:04am 0 comments
When Apple made it clear that apps created with Adobe's Flash Packager for iPhone would not be permitted in the App Store, Steve Jobs had an explanation: "We know from painful experience that letting a third party layer of software come between the platform and the developer ultimately results in sub-standard apps and hinders the enhancement and progress of the platform." Many, myself included, found Jobs' explanation to be somewhat disingenuous. Tools that facilitate cross-platform development aren't necessarily responsible for bad code and poor software; bad development practices and poorly-skilled developers almost always are.
by Patricio Robles 13 July 2010 13:20pm 0 comments
Imagine: you're getting crummy reception on your brand new smart phone when you hold it a particular way. You fire off an email to the CEO of the manufacturer. To your surprise, you get a response back: "Just avoid holding it in that way."
Soon, you learn that you're not the only one having problems. But you also discover that the company, rather than admit to a problem, has allegedly instructed its customer service representatives to use "positioning statements" to ensure consumers that everything is fine.
by Patricio Robles 30 June 2010 10:29am 2 comments
Earlier this week, Apple made an announcement that produced many headlines: in the 80 days following the debut of the iPad, the company has sold 3m tablets. For those of us who wondered if the iPad would sell, the answer is clearly a resounding "Yes!"
Not surprisingly, Apple's early success with the iPad has given a new form of ammunition to those who believe that the PC's best days are behind it. Even Steve Jobs stated earlier this month, "PCs are going to be like trucks. They're still going to be around, they're still going to have a lot of value, but they're going to be used by one out of X people."
by Patricio Robles 24 June 2010 15:05pm 1 comment
In April, Apple CEO Steve Jobs explained in detail why consumers aren't going to see Flash support on the iPhone and iPad. Long story short: Adobe Flash "is no longer necessary." Although Apple's lack of support for Flash is often cited as an iPhone/iPad drawback, Flash certainly isn't going to win a whole lot of popularity contests either. But the question remains: is there a place for Flash in the mobile market?
We may soon have an answer.
by Patricio Robles 23 June 2010 12:14pm 3 comments