Peter E. Turkeltaub

Meta-Analysis of the Functional Neuroanatomy of Single-Word Reading: Method and Validation

Intersubject variability and subtle differences in experimental design can lead to variable results in studies of cognitive processes such as reading. To accurately identify the neural processes associated with cognition and sensorimotor processing, meta-analytic methods capable of identifying areas of consistent activation among studies are useful. This paper describes a novel approach for combining published neuroimaging results from multiple studies, designed to maximize the quantification of interstudy concordance while minimizing the subjective aspects of meta-analysis. In this method, a localization probability distribution was modeled for each activation focus obtained from 11 PET studies of reading single words aloud, and the union of these distributions was taken to yield an activation likelihood estimate map for the brain. Significance was assessed via permutation analysis of randomly generated sets of foci. Regions of significant concordance were identified in bilateral motor and superior temporal cortices, pre-SMA, left fusiform gyrus, and the cerebellum. These meta-analytic results were validated by comparison with new fMRI data on aloud word reading in normal adult subjects. Excellent correspondence between the two statistical maps was observed, with fMRI maxima lying close to all meta-analysis peaks and statistical values at the peaks identified by the two techniques correlating strongly. This close correspondence between PET meta-analysis and fMRI results also demonstrates the validity of using fMRI for the study of language tasks involving overt speech responses. Advantages of this automated meta-analysis technique include quantification of the level of concordance at all brain locations and the provision for use of a threshold for statistical significance of concordance.

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.

Development of neural mechanisms for reading

The complexities of pediatric brain imaging have precluded studies that trace the neural development of cognitive skills acquired during childhood. Using a task that isolates reading-related brain activity and minimizes confounding performance effects, we carried out a cross-sectional functional magnetic resonance imaging (fMRI) study using subjects whose ages ranged from 6 to 22 years. We found that learning to read is associated with two patterns of change in brain activity: increased activity in left-hemisphere middle temporal and inferior frontal gyri and decreased activity in right inferotemporal cortical areas. Activity in the left-posterior superior temporal sulcus of the youngest readers was associated with the maturation of their phonological processing abilities. These findings inform current reading models and provide strong support for Ortons 1925 theory of reading development.

Minimizing Within-Experiment and Within-Group Effects in Activation Likelihood Estimation Meta-Analyses

Activation Likelihood Estimation (ALE) is an objective, quantitative technique for coordinate‐based meta‐analysis (CBMA) of neuroimaging results that has been validated for a variety of uses. Stepwise modifications have improved ALEs theoretical and statistical rigor since its introduction. Here, we evaluate two avenues to further optimize ALE. First, we demonstrate that the maximum contribution of an experiment makes to an ALE map is related to the number of foci it reports and their proximity. We present a modified ALE algorithm that eliminates these within‐experiment effects. However, we show that these effects only account for 2–3% of cumulative ALE values, and removing them has little impact on thresholded ALE maps. Next, we present an alternate organizational approach to datasets that prevents subject groups with multiple experiments in a dataset from influencing ALE values more than others. This modification decreases cumulative ALE values by 7–9%, changes the relative magnitude of some clusters, and reduces cluster extents. Overall, differences between results of the standard approach and these new methods were small. This finding validates previous ALE reports against concerns that they were driven by within‐experiment or within‐group effects. We suggest that the modified ALE algorithm is theoretically advantageous compared with the current algorithm, and that the alternate organization of datasets is the most conservative approach for typical ALE analyses and other CBMA methods. Combining the two modifications minimizes both within‐experiment and within‐group effects, optimizing the degree to which ALE values represent concordance of findings across independent reports. Hum Brain Mapp, 2012.

The image of time: A voxel-wise meta-analysis

Although there has been an explosion of interest in the neural correlates of time perception during the past decade, substantial disagreement persists regarding the structures that are relevant to interval timing. We addressed this important issue by conducting a comprehensive, voxel-wise meta-analysis using the activation likelihood estimation algorithm; this procedure models each stereotactic coordinate as a 3D Gaussian distribution, then tests the likelihood of activation across all voxels in the brain (Turkeltaub et al., 2002). We included 446 sets of activation foci across 41 studies of timing that report whole-brain analyses. We divided the data set along two dimensions: stimulus duration (sub- vs. supra-second) and nature of response (motor vs. perceptual). Our meta-analyses revealed dissociable neural networks for the processing of duration with motor or perceptual components. Sub-second timing tasks showed a higher propensity to recruit sub-cortical networks, such as the basal ganglia and cerebellum, whereas supra-second timing tasks were more likely to activate cortical structures, such as the SMA and prefrontal cortex. We also detected a differential pattern of activation likelihood in basal ganglia structures, depending on the interval and task design. Finally, a conjunction analysis revealed the SMA and right inferior frontal gyrus as the only structures with significant voxels across all timing conditions. These results suggest that the processing of temporal information is mediated by a distributed network that can be differentially engaged depending on the task requirements.

Safety of Transcranial Direct Current Stimulation: Evidence Based Update 2016.

This review updates and consolidates evidence on the safety of transcranial Direct Current Stimulation (tDCS). Safety is here operationally defined by, and limited to, the absence of evidence for a Serious Adverse Effect, the criteria for which are rigorously defined. This review adopts an evidence-based approach, based on an aggregation of experience from human trials, taking care not to confuse speculation on potential hazards or lack of data to refute such speculation with evidence for risk. Safety data from animal tests for tissue damage are reviewed with systematic consideration of translation to humans. Arbitrary safety considerations are avoided. Computational models are used to relate dose to brain exposure in humans and animals. We review relevant dose-response curves and dose metrics (e.g. current, duration, current density, charge, charge density) for meaningful safety standards. Special consideration is given to theoretically vulnerable populations including children and the elderly, subjects with mood disorders, epilepsy, stroke, implants, and home users. Evidence from relevant animal models indicates that brain injury by Direct Current Stimulation (DCS) occurs at predicted brain current densities (6.3-13 A/m(2)) that are over an order of magnitude above those produced by conventional tDCS. To date, the use of conventional tDCS protocols in human trials (≤40 min, ≤4 milliamperes, ≤7.2 Coulombs) has not produced any reports of a Serious Adverse Effect or irreversible injury across over 33,200 sessions and 1000 subjects with repeated sessions. This includes a wide variety of subjects, including persons from potentially vulnerable populations.

A Meta‐analysis of Functional Neuroimaging Studies of Dyslexia

Reading and phonological processing deficits have been the primary focus of neuroimaging studies addressing the neurologic basis of developmental dyslexia, but to date there has been no objective assessment of the consistency of these findings. To address this issue, spatial coordinates reported in the literature were submitted to two parallel activation likelihood estimate (ALE) meta‐analyses. First, a meta‐analysis including 96 foci from nine publications identified regions where typical readers are likely to show greater activation than dyslexics: two left extrastriate areas within BA 37, precuneus, inferior parietal cortex, superior temporal gyrus, thalamus, and left inferior frontal gyrus. Right hemisphere ALE foci representing hypoactivity in dyslexia were found in the fusiform, postcentral, and superior temporal gyri. To identify regions in which dyslexic subjects reliably show greater activation than controls, 75 foci from six papers were entered into a second meta‐analysis. Here ALE results revealed hyperactivity associated with dyslexia in right thalamus and anterior insula. These findings suggest that during the performance of a variety of reading tasks, normal readers activate left‐sided brain areas more than dyslexic readers do, whereas dyslexia is associated with greater right‐sided brain activity. The most robust result was in left extrastriate cortex, where hypoactivity associated with dyslexia was found. However, the ALE maps provided no support for cerebellar dysfunction, nor for hyperactivity in left frontal cortex in dyslexia, suggesting that these findings, unlike those described above, are likely to be more varied in terms of their reproducibility or spatial location.

Localization of Sublexical Speech Perception Components

Models of speech perception are in general agreement with respect to the major cortical regions involved, but lack precision with regard to localization and lateralization of processing units. To refine these models we conducted two Activation Likelihood Estimation (ALE) meta-analyses of the neuroimaging literature on sublexical speech perception. Based on foci reported in 23 fMRI experiments, we identified significant activation likelihoods in left and right superior temporal cortex and the left posterior middle frontal gyrus. Sub-analyses examining phonetic and phonological processes revealed only left mid-posterior superior temporal sulcus activation likelihood. A lateralization analysis demonstrated temporal lobe left lateralization in terms of magnitude, extent, and consistency of activity. Experiments requiring explicit attention to phonology drove this lateralization. An ALE analysis of eight fMRI studies on categorical phoneme perception revealed significant activation likelihood in the left supramarginal gyrus and angular gyrus. These results are consistent with a speech processing network in which the bilateral superior temporal cortices perform acoustic analysis of speech and non-speech auditory stimuli, the left mid-posterior superior temporal sulcus performs phonetic and phonological analysis, and the left inferior parietal lobule is involved in detection of differences between phoneme categories. These results modify current speech perception models in three ways: (1) specifying the most likely locations of dorsal stream processing units, (2) clarifying that phonetic and phonological superior temporal sulcus processing is left lateralized and localized to the mid-posterior portion, and (3) suggesting that both the supramarginal gyrus and angular gyrus may be involved in phoneme discrimination.

The BrainMap strategy for standardization, sharing, and meta-analysis of neuroimaging data.

BackgroundNeuroimaging researchers have developed rigorous community data and metadata standards that encourage meta-analysis as a method for establishing robust and meaningful convergence of knowledge of human brain structure and function. Capitalizing on these standards, the BrainMap project offers databases, software applications, and other associated tools for supporting and promoting quantitative coordinate-based meta-analysis of the structural and functional neuroimaging literature.FindingsIn this report, we describe recent technical updates to the project and provide an educational description for performing meta-analyses in the BrainMap environment.ConclusionsThe BrainMap project will continue to evolve in response to the meta-analytic needs of biomedical researchers in the structural and functional neuroimaging communities. Future work on the BrainMap project regarding software and hardware advances are also discussed.

Differences in the experience of active and sham transcranial direct current stimulation

BACKGROUND A limited number of studies have shown that modulation of cortical excitability using transcranial direct current stimulation (tDCS) is safe and tolerable. Few have directly evaluated whether sham and active stimulation are indistinguishable. OBJECTIVE We aimed to demonstrate tDCS safety and tolerability in a large cohort, and to compare the occurrence and severity of side effects between sham and active stimulation sessions. METHODS One hundred thirty-one healthy subjects undergoing 277 tDCS sessions rated on a 1 to 5 scale the perception of side effects during and after stimulation. Proportions of active and sham sessions associated with side effects were compared using Fisher exact test, and distributions of severity ratings were compared using the Kruskal-Wallis test. RESULTS No serious adverse effects occurred. Side effects most commonly reported were tingling (76%), itching (68%), burning (54%), and pain (25%). Side effect severity was mild, with fewer than 2% of responses indicating a severity > 3 on all questions except tingling (15%), itching (20%), burning (7%), pain (5%), and fatigue (3%) during stimulation. Rates of sensory side effects were statistically significantly higher in active stimulation sessions compared with sham sessions. No other stimulation parameters had a statistically significant impact on side effect occurrence. CONCLUSIONS TDCS is a safe well-tolerated technique with no evidence of risk for serious adverse effects. Sensory side effects are common, but the severity is typically low. Because sensory side effects are more frequent and more severe in active compared with sham tDCS, the current method of sham stimulation may not be an adequate control condition for some studies.