Peter T. Fox

Correspondence of the brain's functional architecture during activation and rest.

Neural connections, providing the substrate for functional networks, exist whether or not they are functionally active at any given moment. However, it is not known to what extent brain regions are continuously interacting when the brain is “at rest.” In this work, we identify the major explicit activation networks by carrying out an image-based activation network analysis of thousands of separate activation maps derived from the BrainMap database of functional imaging studies, involving nearly 30,000 human subjects. Independently, we extract the major covarying networks in the resting brain, as imaged with functional magnetic resonance imaging in 36 subjects at rest. The sets of major brain networks, and their decompositions into subnetworks, show close correspondence between the independent analyses of resting and activation brain dynamics. We conclude that the full repertoire of functional networks utilized by the brain in action is continuously and dynamically “active” even when at “rest.”

Positron emission tomographic studies of the processing of singe words

PET images of blood flow change that were averaged across individuals were used to identify brain areas related to lexical (single-word) processing, A small number of discrete areas were activated during several task conditions including: modality-specific (auditory or visual) areas activated by passive word input, primary motor and premotor areas during speech output, and yet further areas during tasks making semantic or intentional demands.

Cingulate function in depression: A potential predictor of treatment response

THE relationship between pretreatment regional cerebral glucose metabolism and eventual antidepressant drug response was measured using positron emission tomography (PET) in hospitalized patients with unipolar depression. Rostral anterior cingulate metabolism uniquely differentiated eventual treatment responders from non-responders. Hypometabolism characterized non-responders when compared with controls, in contrast to responders who were hypermetabolic. Metabolism in no other region discriminated the two groups, nor did associated demographic, clinical or behavioral measures, including motor speed, cognitive performance, depression severity or illness chronicity. Cingulate hypermetabolism may represent an important adaptive response to depression and failure of this response may underlie poor outcome. A critical role for rostral cingulate area 24a/b in the limbic-cortical network involved in abnormal mood states is proposed.

Coordinate‐based activation likelihood estimation meta‐analysis of neuroimaging data: A random‐effects approach based on empirical estimates of spatial uncertainty

A widely used technique for coordinate‐based meta‐analyses of neuroimaging data is activation likelihood estimation (ALE). ALE assesses the overlap between foci based on modeling them as probability distributions centered at the respective coordinates. In this Human Brain Project/Neuroinformatics research, the authors present a revised ALE algorithm addressing drawbacks associated with former implementations. The first change pertains to the size of the probability distributions, which had to be specified by the used. To provide a more principled solution, the authors analyzed fMRI data of 21 subjects, each normalized into MNI space using nine different approaches. This analysis provided quantitative estimates of between‐subject and between‐template variability for 16 functionally defined regions, which were then used to explicitly model the spatial uncertainty associated with each reported coordinate. Secondly, instead of testing for an above‐chance clustering between foci, the revised algorithm assesses above‐chance clustering between experiments. The spatial relationship between foci in a given experiment is now assumed to be fixed and ALE results are assessed against a null‐distribution of random spatial association between experiments. Critically, this modification entails a change from fixed‐ to random‐effects inference in ALE analysis allowing generalization of the results to the entire population of studies analyzed. By comparative analysis of real and simulated data, the authors showed that the revised ALE‐algorithm overcomes conceptual problems of former meta‐analyses and increases the specificity of the ensuing results without loosing the sensitivity of the original approach. It may thus provide a methodologically improved tool for coordinate‐based meta‐analyses on functional imaging data. Hum Brain Mapp 2009.

Bias between MNI and talairach coordinates analyzed using the ICBM-152 brain template

MNI coordinates determined using SPM2 and FSL/FLIRT with the ICBM‐152 template were compared to Talairach coordinates determined using a landmark‐based Talairach registration method (TAL). Analysis revealed a clear‐cut bias in reference frames (origin, orientation) and scaling (brain size). Accordingly, ICBM‐152 fitted brains were consistently larger, oriented more nose down, and translated slightly down relative to TAL fitted brains. Whole brain analysis of MNI/Talairach coordinate disparity revealed an ellipsoidal pattern with disparity ranging from zero at a point deep within the left hemisphere to greater than 1‐cm for some anterior brain areas. MNI/Talairach coordinate disparity was generally less for brains fitted using FSL. The mni2tal transform generally reduced MNI/Talairach coordinate disparity for inferior brain areas but increased disparity for anterior, posterior, and superior areas. Coordinate disparity patterns differed for brain templates (MNI‐305, ICBM‐152) using the same fitting method (FSL/FLIRT) and for different fitting methods (SPM2, FSL/FLIRT) using the same template (ICBM‐152). An MNI‐to‐Talairach (MTT) transform to correct for bias between MNI and Talairach coordinates was formulated using a best‐fit analysis in one hundred high‐resolution 3‐D MR brain images. MTT transforms optimized for SPM2 and FSL were shown to reduced group mean MNI/Talairach coordinate disparity from a 5‐13 mm to 1‐2 mm for both deep and superficial brain sites. MTT transforms provide a validated means to convert MNI coordinates to Talairach compatible coordinates for studies using either SPM2 or FSL/FLIRT with the ICBM‐152 template. Hum Brain Mapp 2007.

A link between the systems: functional differentiation and integration within the human insula revealed by meta-analysis

Whether we feel sympathy for another, listen to our heartbeat, experience pain or negotiate, the insular cortex is thought to integrate perceptions, emotions, thoughts, and plans into one subjective image of “our world”. The insula has hence been ascribed an integrative role, linking information from diverse functional systems. Nevertheless, various anatomical and functional studies in humans and non-human primates also indicate a functional differentiation of this region. In order to investigate this functional differentiation as well as the mechanisms of the functional integration in the insula, we performed activation-likelihood-estimation (ALE) meta-analyses of 1,768 functional neuroimaging experiments. The analysis revealed four functionally distinct regions on the human insula, which map to the social-emotional, the sensorimotor, the olfacto-gustatory, and the cognitive network of the brain. Sensorimotor tasks activated the mid-posterior and social-emotional tasks the anterior-ventral insula. In the central insula activation by olfacto-gustatory stimuli was found, and cognitive tasks elicited activation in the anterior-dorsal region. A conjunction analysis across these domains revealed that aside from basic somatosensory and motor processes all tested functions overlapped on the anterior-dorsal insula. This overlap might constitute a correlate for a functional integration between different functional systems and thus reflect a link between them necessary to integrate different qualities into a coherent experience of the world and setting the context for thoughts and actions.

ALE meta-analysis: Controlling the false discovery rate and performing statistical contrasts

Activation likelihood estimation (ALE) has greatly advanced voxel‐based meta‐analysis research in the field of functional neuroimaging. We present two improvements to the ALE method. First, we evaluate the feasibility of two techniques for correcting for multiple comparisons: the single threshold test and a procedure that controls the false discovery rate (FDR). To test these techniques, foci from four different topics within the literature were analyzed: overt speech in stuttering subjects, the color‐word Stroop task, picture‐naming tasks, and painful stimulation. In addition, the performance of each thresholding method was tested on randomly generated foci. We found that the FDR method more effectively controls the rate of false positives in meta‐analyses of small or large numbers of foci. Second, we propose a technique for making statistical comparisons of ALE meta‐analyses and investigate its efficacy on different groups of foci divided by task or response type and random groups of similarly obtained foci. We then give an example of how comparisons of this sort may lead to advanced designs in future meta‐analytic research. Hum Brain Mapp 25:155–164, 2005.

Cerebellum implicated in sensory acquisition and discrimination rather than motor control.

Recent evidence that the cerebellum is involved in perception and cognition challenges the prevailing view that its primary function is fine motor control. A new alternative hypothesis is that the lateral cerebellum is not activated by the control of movement per se, but is strongly engaged during the acquisition and discrimination of sensory information. Magnetic resonance imaging of the lateral cerebellar output (dentate) nucleus during passive and active sensory tasks confirmed this hypothesis. These findings suggest that the lateral cerebellum may be active during motor, perceptual, and cognitive performances specifically because of the requirement to process sensory data.

Automated labeling of the human brain: a preliminary report on the development and evaluation of a forward-transform method.

A forward‐transform method for retrieving brain labels from the 1988 Talairach Atlas using x‐y‐z coordinates is presented. A hierarchical volume‐occupancy labeling scheme was created to simplify the organization of atlas labels using volume and subvolumetric components. Segmentation rules were developed to define boundaries that were not given explicitly in the atlas. The labeling scheme and segmentation rules guided the segmentation and labeling of 160 contiguous regions within the atlas. A unique three‐dimensional (3‐D) database label server called the Talairach Daemon (http://ric.uthscsa.edu/projects) was developed for serving labels keyed to the Talairach coordinate system. Given an x‐y‐z Talairach coordinate, a corresponding hierarchical listing of labels is returned by the server. The accuracy and precision of the forward‐transform labeling method is now under evaluation. Hum. Brain Mapping 5:238–242, 1997.

A stereotactic method of anatomical localization for positron emission tomography.

Surgicalxtant methods for anatomical localization within a physiological image are inadequate for precise regional correlations between anatomy and physiology. We have developed a method for determining the location of any region of interest within a positron emission tomographic (PET) image by transformation of the tomographic location coordinates into coordinates within a stereotactic atlas of the human brain. The specific anatomical assumptions of this approach were identified and validated within groups of normal subjects by means of measurements made from lateral skull radiographs and nuclear magnetic resonance proton images. A high degree of accuracy and reproducibility was demonstrated when this technique was applied to groups of normal subjects by determining the anatomical location of two physiologically defined PET areas: the cavernous sinus and visually responsive cortex. This method is simple to implement and highly objective. Generalization of the localization procedure for use with structural tomography is readily accomplished.