Loss, gain and choice difficulty in gambling patients: Neural and behavioural processes.

Impaired decision-making is often displayed by individuals suffering from gambling disorder (GD). Since there are a variety of different phenomena influencing decision-making, we focused in this study on the effects of GD on neural and behavioural processes related to loss aversion and choice difficulty. Behavioural responses as well as brain images of 23 patients with GD and 20 controls were recorded while they completed a mixed gambles task, where they had to decide to either accept or reject gambles with different amounts of potential gain and loss. We found no behavioural loss aversion in either group and no group differences regarding loss and gain-related choice behaviour, but there was a weaker relation between choice difficulty and decision time in patients with GD. Similarly, we observed no group differences in processing of losses or gains, but choice difficulty was weaker associated with brain activity in the right anterior insula and anterior cingulate cortex in patients with GD. Our results showed for the first time the effects of GD on neural processes related to choice difficulty. In addition, our findings on choice difficulty give new insights on the psychopathology of GD and on neural processes related to impaired decision-making in GD.

Ageing as risk factor for tinnitus and its complex interplay with hearing loss-evidence from online and NHANES data.

BACKGROUND: Tinnitus affects 10 to 15% of the population, but its underlying causes are not yet fully understood. Hearing loss has been established as the most important risk factor. Ageing is also known to accompany increased prevalence; however, the risk is normally seen in context with (age-related) hearing loss. Whether ageing per se is a risk factor has not yet been established. We specifically focused on the effect of ageing and the relationship between age, hearing loss, and tinnitus. METHODS: We used two samples for our analyses. The first, exploratory analyses comprised 2249 Austrian individuals. The second included data from 16,008 people, drawn from a publicly available dataset (NHANES). We used logistic regressions to investigate the effect of age on tinnitus. RESULTS: In both samples, ageing per se was found to be a significant predictor of tinnitus. In the more decisive NHANES sample, there was an additional interaction effect between age and hearing loss. Odds ratio analyses show that per unit increase of hearing loss, the odds of reporting tinnitus is higher in older people (1.06 vs 1.03). CONCLUSIONS: Expanding previous findings of hearing loss as the main risk factor for tinnitus, we established ageing as a risk factor in its own right. Underlying mechanisms remain unclear, and this work calls for urgent research efforts to link biological ageing processes, hearing loss, and tinnitus. We therefore suggest a novel working hypothesis that integrates these aspects from an ageing brain viewpoint.

Recognition and perception of emotions in juvenile myoclonic epilepsy.

OBJECTIVE: Perception and recognition of emotions are fundamental prerequisites of human life. Patients with juvenile myoclonic epilepsy (JME) may have emotional and behavioral impairments that might influence socially desirable interactions. We aimed to investigate perception and recognition of emotions in patients with JME by means of neuropsychological tests and functional magnetic resonance imaging (fMRI). METHODS: Sixty-five patients with JME (median age = 27 years, interquartile range [IQR] = 23-34) were prospectively recruited at the Department of Neurology, Christian Doppler University Hospital, Paracelsus Medical University, Salzburg, Austria. Patients were compared to 68 healthy controls (median age = 24 years, IQR = 21-31), matched for sex, age, and education. All study participants underwent the Networks of Emotion Processing test battery (NEmo), an fMRI paradigm of "dynamic fearful faces," a structured interview for psychiatric and personality disorders, and comprehensive neuropsychological testing. RESULTS: JME patients versus healthy controls demonstrated significant deficits in emotion recognition in facial and verbal tasks of all emotions, especially fear. fMRI revealed decreased amygdala activation in JME patients as compared to healthy controls. Patients were at a higher risk of experiencing psychiatric disorders as compared to healthy controls. Cognitive evaluation revealed impaired attentional and executive functioning, namely psychomotor speed, tonic alertness, divided attention, mental flexibility, and inhibition of automated reactions. Duration of epilepsy correlated negatively with parallel prosodic and facial emotion recognition in NEmo. Deficits in emotion recognition were not associated with psychiatric comorbidities, impaired attention and executive functions, types of seizures, and treatment. SIGNIFICANCE: This prospective study demonstrated that as compared to healthy subjects, patients with JME had significant deficits in recognition and perception of emotions as shown by neuropsychological tests and fMRI. The results of this study may have importance for psychological/psychotherapeutic interventions in the management of patients with JME.

Cloze enough? Hemodynamic effects of predictive processing during natural reading.

Evidence accrues that readers form multiple hypotheses about upcoming words. The present study investigated the hemodynamic effects of predictive processing during natural reading by means of combining fMRI and eye movement recordings. In particular, we investigated the neural and behavioral correlates of precision-weighted prediction errors, which are thought to be indicative of subsequent belief updating. Participants silently read sentences in which we manipulated the cloze probability and the semantic congruency of the final word that served as an index for precision and prediction error respectively. With respect to the neural correlates, our findings indicate an enhanced activation within the left inferior frontal and middle temporal gyrus suggesting an effect of precision on prediction update in higher (lexico-)semantic levels. Despite being evident at the neural level, we did not observe any evidence that this mechanism resulted in disproportionate reading times on participants' eye movements. The results speak against discrete predictions, but favor the notion that multiple words are activated in parallel during reading.

Basal forebrain volume reliably predicts the cortical spread of Alzheimer's degeneration.

Alzheimer's disease neurodegeneration is thought to spread across anatomically and functionally connected brain regions. However, the precise sequence of spread remains ambiguous. The prevailing model used to guide in vivo human neuroimaging and non-human animal research assumes that Alzheimer's degeneration starts in the entorhinal cortices, before spreading to the temporoparietal cortex. Challenging this model, we previously provided evidence that in vivo markers of neurodegeneration within the nucleus basalis of Meynert (NbM), a subregion of the basal forebrain heavily populated by cortically projecting cholinergic neurons, precedes and predicts entorhinal degeneration. There have been few systematic attempts at directly comparing staging models using in vivo longitudinal biomarker data, and none to our knowledge testing if comparative evidence generalizes across independent samples. Here we addressed the sequence of pathological staging in Alzheimer's disease using two independent samples of the Alzheimer's Disease Neuroimaging Initiative (n1 = 284; n2 = 553) with harmonized CSF assays of amyloid-ß and hyperphosphorylated tau (pTau), and longitudinal structural MRI data over 2 years. We derived measures of grey matter degeneration in a priori NbM and the entorhinal cortical regions of interest. To examine the spreading of degeneration, we used a predictive modelling strategy that tests whether baseline grey matter volume in a seed region accounts for longitudinal change in a target region. We demonstrated that predictive spread favoured the NbM→entorhinal over the entorhinal→NbM model. This evidence generalized across the independent samples. We also showed that CSF concentrations of pTau/amyloid-ß moderated the observed predictive relationship, consistent with evidence in rodent models of an underlying trans-synaptic mechanism of pathophysiological spread. The moderating effect of CSF was robust to additional factors, including clinical diagnosis. We then applied our predictive modelling strategy to an exploratory whole-brain voxel-wise analysis to examine the spatial specificity of the NbM→entorhinal model. We found that smaller baseline NbM volumes predicted greater degeneration in localized regions of the entorhinal and perirhinal cortices. By contrast, smaller baseline entorhinal volumes predicted degeneration in the medial temporal cortex, recapitulating a prior influential staging model. Our findings suggest that degeneration of the basal forebrain cholinergic projection system is a robust and reliable upstream event of entorhinal and neocortical degeneration, calling into question a prevailing view of Alzheimer's disease pathogenesis.

Effective Connectivity of the Hippocampus Can Differentiate Patients with Schizophrenia from Healthy Controls: A Spectral DCM Approach.

We applied spectral dynamic causal modelling (Friston et al. in Neuroimage 94:396-407. https://doi.org/10.1016/j.neuroimage.2013.12.009 , 2014) to analyze the effective connectivity differences between the nodes of three resting state networks (i.e. default mode network, salience network and dorsal attention network) in a dataset of 31 male healthy controls (HC) and 25 male patients with a diagnosis of schizophrenia (SZ). Patients showed increased directed connectivity from the left hippocampus (LHC) to the: dorsal anterior cingulate cortex (DACC), right anterior insula (RAI), left frontal eye fields and the bilateral inferior parietal sulcus (LIPS & RIPS), as well as increased connectivity from the right hippocampus (RHC) to the: bilateral anterior insula (LAI & RAI), right frontal eye fields and RIPS. In SZ, negative symptoms predicted the connectivity strengths from the LHC to: the DACC, the left inferior parietal sulcus (LIPAR) and the RHC, while positive symptoms predicted the connectivity strengths from the LHC to the LIPAR and from the RHC to the LHC. These results reinforce the crucial role of hippocampus dysconnectivity in SZ pathology and its potential as a biomarker of disease severity.

Multi-level assessment of obsessive-compulsive disorder (OCD) reveals relations between neural and neurochemical levels.

BACKGROUND: While considerable progress has been made in exploring the psychological, the neural, and the neurochemical dimensions of OCD separately, their interplay is still an open question, especially their changes during psychotherapy. METHODS: Seventeen patients were assessed at these three levels by psychological questionnaires, fMRI, and venipuncture before and after inpatient psychotherapy. Seventeen controls were scanned at comparable time intervals. First, pre/post treatment changes were investigated for all three levels separately: symptom severity, whole-brain and regional activity, and the concentrations of cortisol, serotonin, dopamine, brain-derived neurotrophic factor (BDNF), and immunological parameters (IL-6, IL-10, TNFα). Second, stepwise linear modeling was used to find relations between the variables of the levels. RESULTS: The obsessive-compulsive, depressive, and overall symptom severity was significantly reduced after psychotherapy. At the neural level, the activity in the anterior cingulate cortex (ACC), in frontal regions, in the precuneus, and in the putamen had significantly decreased. No significant changes were found on the neurochemical level. When connecting the levels, a highly significant model was found that explains the decrease in neural activity of the putamen by increases of the concentrations of cortisol, IL-6, and dopamine. CONCLUSION: Multivariate approaches offer insight on the influences that the different levels of the psychiatric disorder OCD have on each other. More research and adapted models are needed.

Measuring visual perspective taking in the brain with avatars and arrows: Which question are we asking?

There is an ongoing debate about the involvement of Theory of Mind (ToM) processes in Visual Perspective Taking (VPT). In an fMRI study (Schurz et al., 2015), we borrowed the positive features from a novel VPT task - which is widely used in behavioral research - to study previously overlooked experimental factors in neuroimaging studies. However, as Catmur et al. (2016) rightly argue in a comment on our work, our data do not speak strongly to questions discussed in the original behavioral studies, in particular the issue of implicit mentalizing. We appreciate the clarification of these interpretational limitations of our study, but would like to point out the differences between questions emerging from behavioral and neuroimaging research on VPT. Different from what Catmur et al. (2016) discuss, our study was not intended as a test of implicit mentalizing. In fact, the terms "automatic" and "implicit mentalizing" were never mentioned in our manuscript. Our study addressed a methodological gap between ToM and VPT research, which we identified in two previous meta-analyses on the topics (Schurz et al., 2013, 2014). With this difference in mind we show that the critical points levelled by Catmur et al. (2016) cease to apply.

Words in Context: The Effects of Length, Frequency, and Predictability on Brain Responses During Natural Reading.

Word length, frequency, and predictability count among the most influential variables during reading. Their effects are well-documented in eye movement studies, but pertinent evidence from neuroimaging primarily stem from single-word presentations. We investigated the effects of these variables during reading of whole sentences with simultaneous eye-tracking and functional magnetic resonance imaging (fixation-related fMRI). Increasing word length was associated with increasing activation in occipital areas linked to visual analysis. Additionally, length elicited a U-shaped modulation (i.e., least activation for medium-length words) within a brain stem region presumably linked to eye movement control. These effects, however, were diminished when accounting for multiple fixation cases. Increasing frequency was associated with decreasing activation within left inferior frontal, superior parietal, and occipito-temporal regions. The function of the latter region-hosting the putative visual word form area-was originally considered as limited to sublexical processing. An exploratory analysis revealed that increasing predictability was associated with decreasing activation within middle temporal and inferior frontal regions previously implicated in memory access and unification. The findings are discussed with regard to their correspondence with findings from single-word presentations and with regard to neurocognitive models of visual word recognition, semantic processing, and eye movement control during reading.

Left ventral occipitotemporal activation during orthographic and semantic processing of auditory words.

The present fMRI study investigated the hypothesis that activation of the left ventral occipitotemporal cortex (vOT) in response to auditory words can be attributed to lexical orthographic rather than lexico-semantic processing. To this end, we presented auditory words in both an orthographic ("three or four letter word?") and a semantic ("living or nonliving?") task. In addition, a auditory control condition presented tones in a pitch evaluation task. The results showed that the left vOT exhibited higher activation for orthographic relative to semantic processing of auditory words with a peak in the posterior part of vOT. Comparisons to the auditory control condition revealed that orthographic processing of auditory words elicited activation in a large vOT cluster. In contrast, activation for semantic processing was only weak and restricted to the middle part vOT. We interpret our findings as speaking for orthographic processing in left vOT. In particular, we suggest that activation in left middle vOT can be attributed to accessing orthographic whole-word representations. While activation of such representations was experimentally ascertained in the orthographic task, it might have also occurred automatically in the semantic task. Activation in the more posterior vOT region, on the other hand, may reflect the generation of explicit images of word-specific letter sequences required by the orthographic but not the semantic task. In addition, based on cross-modal suppression, the finding of marked deactivations in response to the auditory tones is taken to reflect the visual nature of representations and processes in left vOT.

Dyslexic brain activation abnormalities in deep and shallow orthographies: A meta-analysis of 28 functional neuroimaging studies.

We used coordinate-based meta-analysis to objectively quantify commonalities and differences of dyslexic functional brain abnormalities between alphabetic languages differing in orthographic depth. Specifically, we compared foci of under- and overactivation in dyslexic readers relative to nonimpaired readers reported in 14 studies in deep orthographies (DO: English) and in 14 studies in shallow orthographies (SO: Dutch, German, Italian, Swedish). The separate meta-analyses of the two sets of studies showed universal reading-related dyslexic underactivation in the left occipitotemporal cortex (including the visual word form area (VWFA)). The direct statistical comparison revealed higher convergence of underactivation for DO compared with SO in bilateral inferior parietal regions, but this abnormality disappeared when foci resulting from stronger dyslexic task-negative activation (i.e., deactivation relative to baseline) were excluded. Higher convergence of underactivation for DO compared with SO was further identified in the left inferior frontal gyrus (IFG) pars triangularis, left precuneus, and right superior temporal gyrus, together with higher convergence of overactivation in the left anterior insula. Higher convergence of underactivation for SO compared with DO was found in the left fusiform gyrus, left temporoparietal cortex, left IFG pars orbitalis, and left frontal operculum, together with higher convergence of overactivation in the left precentral gyrus. Taken together, the findings support the notion of a biological unity of dyslexia, with additional orthography-specific abnormalities and presumably different compensatory mechanisms. The results are discussed in relation to current functional neuroanatomical models of developmental dyslexia. Hum Brain Mapp 37:2676-2699, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Between- and within-site variability of fMRI localizations.

This study provides first data about the spatial variability of fMRI sensorimotor localizations when investigating the same subjects at different fMRI sites. Results are comparable to a previous patient study. We found a median between-site variability of about 6 mm independent of task (motor or sensory) and experimental standardization (high or low). An intraclass correlation coefficient analysis using data quality measures indicated a major influence of the fMRI site on variability. In accordance with this, within-site localization variability was considerably lower (about 3 mm). We conclude that the fMRI site is a considerable confound for localization of brain activity. However, when performed by experienced clinical fMRI experts, brain pathology does not seem to have a relevant impact on the reliability of fMRI localizations. Hum Brain Mapp 37:2151-2160, 2016. © 2016 Wiley Periodicals, Inc.

Visual Experience Shapes Orthographic Representations in the Visual Word Form Area.

Current neurocognitive research suggests that the efficiency of visual word recognition rests on abstract memory representations of written letters and words stored in the visual word form area (VWFA) in the left ventral occipitotemporal cortex. These representations are assumed to be invariant to visual characteristics such as font and case. In the present functional MRI study, we tested this assumption by presenting written words and varying the case format of the initial letter of German nouns (which are always capitalized) as well as German adjectives and adverbs (both usually in lowercase). As evident from a Word Type × Case Format interaction, activation in the VWFA was greater to words presented in unfamiliar case formats relative to familiar case formats. Our results suggest that neural representations of written words in the VWFA are not fully abstract and still contain information about the visual format in which words are most frequently perceived.

Intrinsic functional connectivity differentiates minimally conscious from unresponsive patients.

Despite advances in resting state functional magnetic resonance imaging investigations, clinicians remain with the challenge of how to implement this paradigm on an individualized basis. Here, we assessed the clinical relevance of resting state functional magnetic resonance imaging acquisitions in patients with disorders of consciousness by means of a systems-level approach. Three clinical centres collected data from 73 patients in minimally conscious state, vegetative state/unresponsive wakefulness syndrome and coma. The main analysis was performed on the data set coming from one centre (Liège) including 51 patients (26 minimally conscious state, 19 vegetative state/unresponsive wakefulness syndrome, six coma; 15 females; mean age 49 ± 18 years, range 11-87; 16 traumatic, 32 non-traumatic of which 13 anoxic, three mixed; 35 patients assessed >1 month post-insult) for whom the clinical diagnosis with the Coma Recovery Scale-Revised was congruent with positron emission tomography scanning. Group-level functional connectivity was investigated for the default mode, frontoparietal, salience, auditory, sensorimotor and visual networks using a multiple-seed correlation approach. Between-group inferential statistics and machine learning were used to identify each network's capacity to discriminate between patients in minimally conscious state and vegetative state/unresponsive wakefulness syndrome. Data collected from 22 patients scanned in two other centres (Salzburg: 10 minimally conscious state, five vegetative state/unresponsive wakefulness syndrome; New York: five minimally conscious state, one vegetative state/unresponsive wakefulness syndrome, one emerged from minimally conscious state) were used to validate the classification with the selected features. Coma Recovery Scale-Revised total scores correlated with key regions of each network reflecting their involvement in consciousness-related processes. All networks had a high discriminative capacity (>80%) for separating patients in a minimally conscious state and vegetative state/unresponsive wakefulness syndrome. Among them, the auditory network was ranked the most highly. The regions of the auditory network which were more functionally connected in patients in minimally conscious state compared to vegetative state/unresponsive wakefulness syndrome encompassed bilateral auditory and visual cortices. Connectivity values in these three regions discriminated congruently 20 of 22 independently assessed patients. Our findings point to the significance of preserved abilities for multisensory integration and top-down processing in minimal consciousness seemingly supported by auditory-visual crossmodal connectivity, and promote the clinical utility of the resting paradigm for single-patient diagnostics.

Resting-State and Task-Based Functional Brain Connectivity in Developmental Dyslexia.

Reading requires the interaction between multiple cognitive processes situated in distant brain areas. This makes the study of functional brain connectivity highly relevant for understanding developmental dyslexia. We used seed-voxel correlation mapping to analyse connectivity in a left-hemispheric network for task-based and resting-state fMRI data. Our main finding was reduced connectivity in dyslexic readers between left posterior temporal areas (fusiform, inferior temporal, middle temporal, superior temporal) and the left inferior frontal gyrus. Reduced connectivity in these networks was consistently present for 2 reading-related tasks and for the resting state, showing a permanent disruption which is also present in the absence of explicit task demands and potential group differences in performance. Furthermore, we found that connectivity between multiple reading-related areas and areas of the default mode network, in particular the precuneus, was stronger in dyslexic compared with nonimpaired readers.

Clarifying the role of theory of mind areas during visual perspective taking: Issues of spontaneity and domain-specificity.

Visual perspective taking is a fundamental feature of the human social brain. Previous research has mainly focused on explicit visual perspective taking and contrasted brain activation for other- versus self-perspective judgements. This produced a conceptual gap to theory of mind studies, where researchers mainly compared activation for taking another's mental perspective to non-mental control conditions. We compared brain activation for visual perspective taking to activation for non-mental control conditions where the avatar was replaced by directional (arrow, lamp) or non-directional (brick-wall) objects. We found domain-specific activation linked to the avatar's visual perspective in right TPJ, ventral mPFC and ventral precuneus. Interestingly, we found that these areas are spontaneously processing information linked to the other's perspective during self-perspective judgements. Based on a review of the visual perspective taking literature, we discuss how these findings can explain some of the inconsistent/negative results found in previous studies comparing other- versus self-perspective judgements.

Impaired consciousness is linked to changes in effective connectivity of the posterior cingulate cortex within the default mode network.

The intrinsic connectivity of the default mode network has been associated with the level of consciousness in patients with severe brain injury. Especially medial parietal regions are considered to be highly involved in impaired consciousness. To better understand what aspect of this intrinsic architecture is linked to consciousness, we applied spectral dynamic causal modeling to assess effective connectivity within the default mode network in patients with disorders of consciousness. We included 12 controls, 12 patients in minimally conscious state and 13 in vegetative state in this study. For each subject, we first defined the four key regions of the default mode network employing a subject-specific independent component analysis approach. The resulting regions were then included as nodes in a spectral dynamic causal modeling analysis in order to assess how the causal interactions across these regions as well as the characteristics of neuronal fluctuations change with the level of consciousness. The resulting pattern of interaction in controls identified the posterior cingulate cortex as the main driven hub with positive afferent but negative efferent connections. In patients, this pattern appears to be disrupted. Moreover, the vegetative state patients exhibit significantly reduced self-inhibition and increased oscillations in the posterior cingulate cortex compared to minimally conscious state and controls. Finally, the degree of self-inhibition and strength of oscillation in this region is correlated with the level of consciousness. These findings indicate that the equilibrium between excitatory connectivity towards posterior cingulate cortex and its feedback projections is a key aspect of the relationship between alterations in consciousness after severe brain injury and the intrinsic functional architecture of the default mode network. This impairment might be principally due to the disruption of the mechanisms underlying self-inhibition and neuronal oscillations in the posterior cingulate cortex.

Accessing orthographic representations from speech: the role of left ventral occipitotemporal cortex in spelling.

The present fMRI study used a spelling task to investigate the hypothesis that the left ventral occipitotemporal cortex (vOT) hosts neuronal representations of whole written words. Such an orthographic word lexicon is posited by cognitive dual-route theories of reading and spelling. In the scanner, participants performed a spelling task in which they had to indicate if a visually presented letter is present in the written form of an auditorily presented word. The main experimental manipulation distinguished between an orthographic word spelling condition in which correct spelling decisions had to be based on orthographic whole-word representations, a word spelling condition in which reliance on orthographic whole-word representations was optional and a phonological pseudoword spelling condition in which no reliance on such representations was possible. To evaluate spelling-specific activations the spelling conditions were contrasted with control conditions that also presented auditory words and pseudowords, but participants had to indicate if a visually presented letter corresponded to the gender of the speaker. We identified a left vOT cluster activated for the critical orthographic word spelling condition relative to both the control condition and the phonological pseudoword spelling condition. Our results suggest that activation of left vOT during spelling can be attributed to the retrieval of orthographic whole-word representations and, thus, support the position that the left vOT potentially represents the neuronal equivalent of the cognitive orthographic word lexicon.

Reading in the brain of children and adults: a meta-analysis of 40 functional magnetic resonance imaging studies.

We used quantitative, coordinate-based meta-analysis to objectively synthesize age-related commonalities and differences in brain activation patterns reported in 40 functional magnetic resonance imaging (fMRI) studies of reading in children and adults. Twenty fMRI studies with adults (age means: 23-34 years) were matched to 20 studies with children (age means: 7-12 years). The separate meta-analyses of these two sets showed a pattern of reading-related brain activation common to children and adults in left ventral occipito-temporal (OT), inferior frontal, and posterior parietal regions. The direct statistical comparison between the two meta-analytic maps of children and adults revealed higher convergence in studies with children in left superior temporal and bilateral supplementary motor regions. In contrast, higher convergence in studies with adults was identified in bilateral posterior OT/cerebellar and left dorsal precentral regions. The results are discussed in relation to current neuroanatomical models of reading and tentative functional interpretations of reading-related activation clusters in children and adults are provided.

Fixation-related FMRI analysis in the domain of reading research: using self-paced eye movements as markers for hemodynamic brain responses during visual letter string processing.

The present study investigated the feasibility of using self-paced eye movements during reading (measured by an eye tracker) as markers for calculating hemodynamic brain responses measured by functional magnetic resonance imaging (fMRI). Specifically, we were interested in whether the fixation-related fMRI analysis approach was sensitive enough to detect activation differences between reading material (words and pseudowords) and nonreading material (line and unfamiliar Hebrew strings). Reliable reading-related activation was identified in left hemisphere superior temporal, middle temporal, and occipito-temporal regions including the visual word form area (VWFA). The results of the present study are encouraging insofar as fixation-related analysis could be used in future fMRI studies to clarify some of the inconsistent findings in the literature regarding the VWFA. Our study is the first step in investigating specific visual word recognition processes during self-paced natural sentence reading via simultaneous eye tracking and fMRI, thus aiming at an ecologically valid measurement of reading processes. We provided the proof of concept and methodological framework for the analysis of fixation-related fMRI activation in the domain of reading research.