Ketamine induces multiple individually distinct whole-brain functional connectivity signatures.

Background: Ketamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine's molecular mechanisms connect to its neural and behavioral effects. Methods: We conducted a single-blind placebo-controlled study, with participants blinded to their treatment condition. 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr). We quantified resting-state functional connectivity via data-driven global brain connectivity and related it to individual ketamine-induced symptom variation and cortical gene expression targets. Results: We found that: (i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; (ii) ketamine's data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, while the mean effect did not; and (iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level. Conclusions: These results highlight the importance of considering individual behavioral and neural variation in response to ketamine. They also have implications for the development of individually precise pharmacological biomarkers for treatment selection in psychiatry. Funding: This study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1-190420) (FXV, KHP); Swiss Neuromatrix Foundation (Grant No. 2016-0111) (FXV, KHP); Swiss National Science Foundation under the framework of Neuron Cofund (Grant No. 01EW1908) (KHP); Usona Institute (2015 - 2056) (FXV). Clinical trial number: NCT03842800.

Ketamine is a widely used anesthetic as well as a popular illegal recreational drug. Recently, it has also gained attention as a potential treatment for depression, particularly in cases that don't respond to conventional therapies. However, individuals can vary in their response to ketamine. For example, the drug can alter some people's perception, such as seeing objects as larger or small than they are, while other individuals are unaffected. Although a single dose of ketamine was shown to improve depression symptoms in approximately 65% of patients, the treatment does not work for a significant portion of patients. Understanding why ketamine does not work for everyone could help to identify which patients would benefit most from the treatment. Previous studies investigating ketamine as a treatment for depression have typically included a group of individuals given ketamine and a group given a placebo drug. Assuming people respond similarly to ketamine, the responses in each group were averaged and compared to one another. However, this averaging of results may have masked any individual differences in response to ketamine. As a result, Moujaes et al. set out to investigate whether individuals show differences in brain activity and behavior in response to ketamine. Moujaes et al. monitored the brain activity and behavior of 40 healthy individuals that were first given a placebo drug and then ketamine. The results showed that brain activity and behavior varied significantly between individuals after ketamine administration. Genetic analysis revealed that different gene expression patterns paired with differences in ketamine response in individuals ­ an effect that was hidden when the results were averaged. Ketamine also caused greater differences in brain activity and behavior between individuals than other drugs, such as psychedelics, suggesting ketamine generates a particularly complex response in people. In the future, extending these findings in healthy individuals to those with depression will be crucial for determining whether differences in response to ketamine align with how effective ketamine treatment is for an individual.

What is it like to do a visuo-spatial working memory task: A qualitative phenomenological study of the visual span task.

Working memory is typically measured with specifically designed psychological tasks. When evaluating the validity of working memory tasks, we commonly focus on the reliability of the outcome measurements. Only rarely do we focus on how participants experience these tasks. Accounting for lived experience of working memory task may help us better understand variability in working memory performance and conscious experience in general. We replicated recently established protocols for the phenomenological investigation of working memory using the visual span task. We collected subjective reports from eighteen healthy participants (10 women) aged 21 to 35 years. We observed that working memory can be phenomenologically characterized at three different time scales: background feelings, strategies, and tactics. On the level of tactics, we identified transmodality (i.e., how one modality of lived experience can be transformed into another one) as the central phenomenological dynamic at play during working memory task performance.

Static and dynamic fMRI-derived functional connectomes represent largely similar information.

Functional connectivity (FC) of blood oxygen level-dependent (BOLD) fMRI time series can be estimated using methods that differ in sensitivity to the temporal order of time points (static vs. dynamic) and the number of regions considered in estimating a single edge (bivariate vs. multivariate). Previous research suggests that dynamic FC explains variability in FC fluctuations and behavior beyond static FC. Our aim was to systematically compare methods on both dimensions. We compared five FC methods: Pearson's/full correlation (static, bivariate), lagged correlation (dynamic, bivariate), partial correlation (static, multivariate), and multivariate AR model with and without self-connections (dynamic, multivariate). We compared these methods by (i) assessing similarities between FC matrices, (ii) by comparing node centrality measures, and (iii) by comparing the patterns of brain-behavior associations. Although FC estimates did not differ as a function of sensitivity to temporal order, we observed differences between the multivariate and bivariate FC methods. The dynamic FC estimates were highly correlated with the static FC estimates, especially when comparing group-level FC matrices. Similarly, there were high correlations between the patterns of brain-behavior associations obtained using the dynamic and static FC methods. We conclude that the dynamic FC estimates represent information largely similar to that of the static FC.

Human brain state dynamics reflect individual neuro-phenotypes.

Neural activity and behavior manifest state and trait dynamics, as well as variation within and between individuals. However, the mapping of state-trait neural variation to behavior is not well understood. To address this gap, we quantify moment-to-moment changes in brain-wide co-activation patterns derived from resting-state functional magnetic resonance imaging. In healthy young adults, we identify reproducible spatio-temporal features of co-activation patterns at the single subject level. We demonstrate that a joint analysis of state-trait neural variations and feature reduction reveal general motifs of individual differences, encompassing state-specific and general neural features that exhibit day-to-day variability. The principal neural variations co-vary with the principal variations of behavioral phenotypes, highlighting cognitive function, emotion regulation, alcohol and substance use. Person-specific probability of occupying a particular co-activation pattern is reproducible and associated with neural and behavioral features. This combined analysis of state-trait variations holds promise for developing reproducible neuroimaging markers of individual life functional outcome.

Dense attention network identifies EEG abnormalities during working memory performance of patients with schizophrenia.

Introduction: Patients with schizophrenia typically exhibit deficits in working memory (WM) associated with abnormalities in brain activity. Alterations in the encoding, maintenance and retrieval phases of sequential WM tasks are well established. However, due to the heterogeneity of symptoms and complexity of its neurophysiological underpinnings, differential diagnosis remains a challenge. We conducted an electroencephalographic (EEG) study during a visual WM task in fifteen schizophrenia patients and fifteen healthy controls. We hypothesized that EEG abnormalities during the task could be identified, and patients successfully classified by an interpretable machine learning algorithm. Methods: We tested a custom dense attention network (DAN) machine learning model to discriminate patients from control subjects and compared its performance with simpler and more commonly used machine learning models. Additionally, we analyzed behavioral performance, event-related EEG potentials, and time-frequency representations of the evoked responses to further characterize abnormalities in patients during WM. Results: The DAN model was significantly accurate in discriminating patients from healthy controls, ACC = 0.69, SD = 0.05. There were no significant differences between groups, conditions, or their interaction in behavioral performance or event-related potentials. However, patients showed significantly lower alpha suppression in the task preparation, memory encoding, maintenance, and retrieval phases F(1,28) = 5.93, p = 0.022, η2 = 0.149. Further analysis revealed that the two highest peaks in the attention value vector of the DAN model overlapped in time with the preparation and memory retrieval phases, as well as with two of the four significant time-frequency ROIs. Discussion: These results highlight the potential utility of interpretable machine learning algorithms as an aid in diagnosis of schizophrenia and other psychiatric disorders presenting oscillatory abnormalities.

Individual differences in spatial working memory strategies differentially reflected in the engagement of control and default brain networks.

Spatial locations can be encoded and maintained in working memory using high-precision, fine-grained representations that are cognitively demanding, or coarse and less demanding categorical representations. In this study, we employed an individual differences approach to identify brain activity correlates of the use of fine-grained and categorical representations in spatial working memory. We combined data from six fMRI studies, resulting in a sample of 153 (77 women, 25 ± 6 years) healthy participants performing a spatial working memory task. Our results showed that individual differences in the use of spatial representations in working memory were associated with distinct patterns of brain activation, with fine-grained representations requiring greater engagement of attentional and control brain systems, while categorical representations were associated with decreased inhibition of the default network. These findings may indicate a greater need for ongoing maintenance and protection against interference for fine-grained compared to categorical representations.

The Diversity of Strategies Used in Working Memory for Colors, Orientations, and Positions: A Quantitative Approach to a First-Person Inquiry.

The study of individual experience during the performance of a psychological task using a phenomenological approach is a relatively new area of research. The aim of this paper was to combine first- and third-person approaches to investigate whether the strategies individuals use during a working memory task are associated with specific task conditions, whether the strategies combine to form stable patterns, and whether the use of specific strategies is related to task accuracy. Thirty-one participants took part in an experiment in which they were instructed to remember colors, orientations, or positions of stimuli presented in a change detection task. After every 7th-15th trial, participants took part in an in-depth phenomenological interview in which they described their experiences during the trial that immediately preceded the interview. Qualitative analysis revealed a set of 18 strategies that participants used while performing the task, which we divided into active and passive strategies of encoding, maintenance, and retrieval. Quantitative analysis revealed that while many strategies were used in all task conditions, some strategies and their combinations may be better suited to the specific task demands, while others are more general in nature. The results also suggest a distinction between strategies for encoding object identity and spatial features. Finally, our results did not provide robust evidence for a relationship between specific strategies and task accuracy.

Corrigendum: autohrf-an R package for generating data-informed event models for general linear modeling of task-based fMRI data.

[This corrects the article DOI: 10.3389/fnimg.2022.983324.].

QuNex-An integrative platform for reproducible neuroimaging analytics.

Introduction: Neuroimaging technology has experienced explosive growth and transformed the study of neural mechanisms across health and disease. However, given the diversity of sophisticated tools for handling neuroimaging data, the field faces challenges in method integration, particularly across multiple modalities and species. Specifically, researchers often have to rely on siloed approaches which limit reproducibility, with idiosyncratic data organization and limited software interoperability. Methods: To address these challenges, we have developed Quantitative Neuroimaging Environment & Toolbox (QuNex), a platform for consistent end-to-end processing and analytics. QuNex provides several novel functionalities for neuroimaging analyses, including a "turnkey" command for the reproducible deployment of custom workflows, from onboarding raw data to generating analytic features. Results: The platform enables interoperable integration of multi-modal, community-developed neuroimaging software through an extension framework with a software development kit (SDK) for seamless integration of community tools. Critically, it supports high-throughput, parallel processing in high-performance compute environments, either locally or in the cloud. Notably, QuNex has successfully processed over 10,000 scans across neuroimaging consortia, including multiple clinical datasets. Moreover, QuNex enables integration of human and non-human workflows via a cohesive translational platform. Discussion: Collectively, this effort stands to significantly impact neuroimaging method integration across acquisition approaches, pipelines, datasets, computational environments, and species. Building on this platform will enable more rapid, scalable, and reproducible impact of neuroimaging technology across health and disease.

Static and dynamic functional connectomes represent largely similar information.

Functional connectivity (FC) of blood-oxygen-level-dependent (BOLD) fMRI time series can be estimated using methods that differ in sensitivity to the temporal order of time points (static vs. dynamic) and the number of regions considered in estimating a single edge (bivariate vs. multivariate). Previous research suggests that dynamic FC explains variability in FC fluctuations and behavior beyond static FC. Our aim was to systematically compare methods on both dimensions. We compared five FC methods: Pearson's/full correlation (static, bivariate), lagged correlation (dynamic, bivariate), partial correlation (static, multivariate) and multivariate AR model with and without self-connections (dynamic, multivariate). We compared these methods by (i) assessing similarities between FC matrices, (ii) by comparing node centrality measures, and (iii) by comparing the patterns of brain-behavior associations. Although FC estimates did not differ as a function of sensitivity to temporal order, we observed differences between the multivariate and bivariate FC methods. The dynamic FC estimates were highly correlated with the static FC estimates, especially when comparing group-level FC matrices. Similarly, there were high correlations between the patterns of brain-behavior associations obtained using the dynamic and static FC methods. We conclude that the dynamic FC estimates represent information largely similar to that of the static FC.

A common symptom geometry of mood improvement under sertraline and placebo associated with distinct neural patterns.

Importance: Understanding the mechanisms of major depressive disorder (MDD) improvement is a key challenge to determine effective personalized treatments. Objective: To perform a secondary analysis quantifying neural-to-symptom relationships in MDD as a function of antidepressant treatment. Design: Double blind randomized controlled trial. Setting: Multicenter. Participants: Patients with early onset recurrent depression from the public Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study. Interventions: Either sertraline or placebo during 8 weeks (stage 1), and according to response a second line of treatment for 8 additional weeks (stage 2). Main Outcomes and Measures: To identify a data-driven pattern of symptom variations during these two stages, we performed a Principal Component Analysis (PCA) on the variations of individual items of four clinical scales measuring depression, anxiety, suicidal ideas and manic-like symptoms, resulting in a univariate measure of clinical improvement. We then investigated how initial clinical and neural factors predicted this measure during stage 1. To do so, we extracted resting-state global brain connectivity (GBC) at baseline at the individual level using a whole-brain functional network parcellation. In turn, we computed a linear model for each brain parcel with individual data-driven clinical improvement scores during stage 1 for each group. Results: 192 patients (127 women), age 37.7 years old (standard deviation: 13.5), were included. The first PC (PC1) capturing 20% of clinical variation was similar across treatment groups at stage 1 and stage 2, suggesting a reproducible pattern of symptom improvement. PC1 patients' scores significantly differed according to treatment during stage 1, whereas no difference of response was evidenced between groups with the Clinical Global Impressions (CGI). Baseline GBC correlated to stage 1 PC1 scores in the sertraline, but not in the placebo group. Conclusions and Relevance: Using data-driven reduction of symptoms scales, we identified a common profile of symptom improvement across placebo and sertraline. However, the neural patterns of baseline that mapped onto symptom improvement distinguished between treatment and placebo. Our results underscore that mapping from data-driven symptom improvement onto neural circuits is vital to detect treatment-responsive neural profiles that may aid in optimal patient selection for future trials.

Cortical Brain Perfusion and Cognitive Event Related Potentials in Patients with Psychomotor Retardation in Late Onset Depression.

BACKGROUND: Late onset depression is characterised by pronounced cognitive impairment, more somatic complaints and psychomotor retardation. Psychomotor slowing may be due to impairment in either motor or cognitive domain. Electrophysiology may be particularly convenient as a tool in studies of psychomotor retardation, as it can separate central cognitive processing from the motor processing. SUBJECTS AND METHODS: In this study we compared event related potentials (ERP) in the two groups of patients with late onset depression and psychomotor slowing as measured by reaction time (RT): a group of patients with lower RT was compared to a group with a higher RT. Twenty patients with late onset depression were included in the study after they had reached remission. Four weeks after reaching remission patients were reevaluated clinically using Hamilton Depression Rating Scale, Mini Mental State Examination, and with a computer version of the Stroop task. ERP, accuracy and RTs were simultaneously recorded. Both groups of patients aditionaly underwent a perfusion SPECT imaging. RESULTS: There were no differences between the short and long RT groups of patients in amplitudes of the late positive Stroop related potentials. The group of patients with longer RTs showed significant hyperperfusion in precentral gyrus, parietal regions, cuneus and hypoperfusion within insular, frontal, temporal and limbic (parahyppocampal gyrus and anterior cingulate) cortices, as well as cerebellum. CONCLUSION: We found no ERP differences between the two groups suggesting that although patients may differ on psychomotor retardation measured as RT, their cognitive abilities may be quite similar. Perfusion SPECT imaging however revealed a significant difference between them. This may be due to a process of compensation and applying different strategies to cope with cognitive impairment in the two groups.

What Individuals Experience During Visuo-Spatial Working Memory Task Performance: An Exploratory Phenomenological Study.

In experimental cognitive psychology, objects of inquiry are typically operationalized with psychological tasks. When interpreting results from such tasks, we focus primarily on behavioral measures such as reaction times and accuracy rather than experiences - i.e., phenomenology - associated with the task, and posit that the tasks elicit the desired cognitive phenomenon. Evaluating whether the tasks indeed elicit the desired phenomenon can be facilitated by understanding the experience during task performance. In this paper we explore the breadth of experiences that are elicited by and accompany task performance using in-depth phenomenological and qualitative methodology to gather subjective reports during the performance of a visuo-spatial change detection task. Thirty-one participants (18 females) were asked to remember either colors, orientations or positions of the presented stimuli and recall them after a short delay. Qualitative reports revealed rich experiential landscapes associated with the task-performance, suggesting a distinction between two broad classes of experience: phenomena at the front of consciousness and background feelings. The former includes cognitive strategies and aspects of metacognition, whereas the latter include more difficult-to-detect aspects of experience that comprise the overall sense of experience (e.g., bodily feelings, emotional atmosphere, mood). We focus primarily on the background feelings, since strategies of task-performance to a large extent map onto previously identified cognitive processes and discuss the methodological implications of our findings.

Neural Evidence for Different Types of Position Coding Strategies in Spatial Working Memory.

Sustained neural activity during the delay phase of spatial working memory tasks is compelling evidence for the neural correlate of active storage and maintenance of spatial information, however, it does not provide insight into specific mechanisms of spatial coding. This activity may reflect a range of processes, such as maintenance of a stimulus position or a prepared motor response plan. The aim of our study was to examine neural evidence for the use of different coding strategies, depending on the characteristics and demands of a spatial working memory task. Thirty-one (20 women, 23 ± 5 years) and 44 (23 women, 21 ± 2 years) participants performed a spatial working memory task while we measured their brain activity using fMRI in two separate experiments. Participants were asked to remember the position of a briefly presented target stimulus and, after a delay period, to use a joystick to indicate either the position of the remembered target or an indicated non-matching location. The task was designed so that the predictability of the response could be manipulated independently of task difficulty and memory retrieval process. We were particularly interested in contrasting conditions in which participants (i) could use prospective coding of the motor response or (ii) had to rely on retrospective sensory information. Prospective motor coding was associated with activity in somatomotor, premotor, and motor cortices and increased integration of brain activity with and within the somatomotor network. In contrast, retrospective sensory coding was associated with increased activity in parietal regions and increased functional connectivity with and within secondary visual and dorsal attentional networks. The observed differences in activation levels, dynamics of differences over trial duration, and integration of information within and between brain networks provide compelling evidence for the use of complementary spatial working memory strategies optimized to meet task demands.

Dynamic Seat Assessment for Enabled Restlessness of Children with Learning Difficulties.

Children with Attention-Deficit/Hyperactivity Disorder (ADHD) face a range of learning difficulties in the school environment, thus several strategies have been developed to enhance or optimise their performance in school. One possible way is to actively enable appropriate restlessness using dynamic seats. In this paper, an assessment of the efficacy of a dynamic seat while solving school task is presented and compared to classic chair and therapy ball. To test the effectiveness of active seat, a study that examined task solving performance while observing the intensity of movement, in-seat behaviour and psychophysiological responses (electrodermal activity, facial temperature) was designed. A total of 23 school-aged children participated in the study, 11 children with a combined type of ADHD and 12 children without disorders. Children with ADHD achieved the best results when sitting in the active seat, where the most intense movement and best in-seat behaviour was observed. At the same time, psychophysiological parameters indicate that when performing better at the task children with ADHD were not too challenged and were consequently less agitated. Results have suggested that for a better cognitive performance of children with ADHD, it is crucial to provide a comfortable and pleasant workspace that enables them the right amount of restlessness.

Reward and loss incentives improve spatial working memory by shaping trial-by-trial posterior frontoparietal signals.

Integrating motivational signals with cognition is critical for goal-directed activities. The mechanisms that link neural changes with motivated working memory continue to be understood. Here, we tested how externally cued and non-cued (internally represented) reward and loss impact spatial working memory precision and neural circuits in human subjects using fMRI. We translated the classic delayed-response spatial working memory paradigm from non-human primate studies to take advantage of a continuous numeric measure of working memory precision, and the wealth of translational neuroscience yielded by these studies. Our results demonstrated that both cued and non-cued reward and loss improved spatial working memory precision. Visual association regions of the posterior prefrontal and parietal cortices, specifically the precentral sulcus (PCS) and intraparietal sulcus (IPS), had increased BOLD signal during incentivized spatial working memory. A subset of these regions had trial-by-trial increases in BOLD signal that were associated with better working memory precision, suggesting that these regions may be critical for linking neural signals with motivated working memory. In contrast, regions straddling executive networks, including areas in the dorsolateral prefrontal cortex, anterior parietal cortex and cerebellum displayed decreased BOLD signal during incentivized working memory. While reward and loss similarly impacted working memory processes, they dissociated during feedback when money won or avoided in loss was given based on working memory performance. During feedback, the trial-by-trial amount and valence of reward/loss received was dissociated amongst regions such as the ventral striatum, habenula and periaqueductal gray. Overall, this work suggests motivated spatial working memory is supported by complex sensory processes, and that the IPS and PCS in the posterior frontoparietal cortices may be key regions for integrating motivational signals with spatial working memory precision.

Evaluation and comparison of most prevalent artifact reduction methods for EEG acquired simultaneously with fMRI.

Multimodal neuroimaging using EEG and fMRI provides deeper insights into brain function by improving the spatial and temporal resolution of the acquired data. However, simultaneous EEG-fMRI inevitably compromises the quality of the EEG and fMRI signals due to the high degree of interaction between the two systems. Fluctuations in the magnetic flux flowing through the participant and the EEG system, whether due to movement within the magnetic field of the scanner or to changes in magnetic field strength, induce electrical potentials in the EEG recordings that mask the much weaker electrical activity of the neuronal populations. A number of different methods have been proposed to reduce MR artifacts. We present an overview of the most commonly used methods and an evaluation of the methods using three sets of diverse EEG data. We limited the evaluation to open-access and easy-to-use methods and a reference signal regression method using a set of six carbon-wire loops (CWL), which allowed evaluation of their added value. The evaluation was performed by comparing EEG signals recorded outside the MRI scanner with artifact-corrected EEG signals recorded simultaneously with fMRI. To quantify and evaluate the quality of artifact reduction methods in terms of the spectral content of the signal, we analyzed changes in oscillatory activity during a resting-state and a finger tapping motor task. The quality of artifact reduction in the time domain was assessed using data collected during a visual stimulation task. In the study we utilized hierarchical Bayesian probabilistic modeling for statistical inference and observed significant differences between the evaluated methods in the success of artifact reduction and associated signal quality in both the frequency and time domains. In particular, the CWL system proved superior to the other methods evaluated in improving spectral contrast in the alpha and beta bands and in recovering visual evoked responses. Based on the results of the evaluation study, we proposed guidelines for selecting the optimal method for MR artifact reduction.

Deep learning in neuroimaging data analysis: Applications, challenges, and solutions.

Methods for the analysis of neuroimaging data have advanced significantly since the beginning of neuroscience as a scientific discipline. Today, sophisticated statistical procedures allow us to examine complex multivariate patterns, however most of them are still constrained by assuming inherent linearity of neural processes. Here, we discuss a group of machine learning methods, called deep learning, which have drawn much attention in and outside the field of neuroscience in recent years and hold the potential to surpass the mentioned limitations. Firstly, we describe and explain the essential concepts in deep learning: the structure and the computational operations that allow deep models to learn. After that, we move to the most common applications of deep learning in neuroimaging data analysis: prediction of outcome, interpretation of internal representations, generation of synthetic data and segmentation. In the next section we present issues that deep learning poses, which concerns multidimensionality and multimodality of data, overfitting and computational cost, and propose possible solutions. Lastly, we discuss the current reach of DL usage in all the common applications in neuroimaging data analysis, where we consider the promise of multimodality, capability of processing raw data, and advanced visualization strategies. We identify research gaps, such as focusing on a limited number of criterion variables and the lack of a well-defined strategy for choosing architecture and hyperparameters. Furthermore, we talk about the possibility of conducting research with constructs that have been ignored so far or/and moving toward frameworks, such as RDoC, the potential of transfer learning and generation of synthetic data.

autohrf-an R package for generating data-informed event models for general linear modeling of task-based fMRI data.

The analysis of task-related fMRI data at the level of individual participants is commonly based on general linear modeling (GLM), which allows us to estimate the extent to which the BOLD signal can be explained by the task response predictors specified in the event model. The predictors are constructed by convolving the hypothesized time course of neural activity with an assumed hemodynamic response function (HRF). However, our assumptions about the components of brain activity, including their onset and duration, may be incorrect. Their timing may also differ across brain regions or from person to person, leading to inappropriate or suboptimal models, poor fit of the model to actual data, and invalid estimates of brain activity. Here, we present an approach that uses theoretically driven models of task response to define constraints on which the final model is computationally derived using actual fMRI data. Specifically, we developed autohrf-an R package that enables the evaluation and data-driven estimation of event models for GLM analysis. The highlight of the package is the automated parameter search that uses genetic algorithms to find the onset and duration of task predictors that result in the highest fitness of GLM based on the fMRI signal under predefined constraints. We evaluated the usefulness of the autohrf package on two original datasets of task-related fMRI activity, a slow event-related spatial working memory study and a mixed state-item study using the flanker task, and on a simulated slow event-related working memory data. Our results suggest that autohrf can be used to efficiently construct and evaluate better task-related brain activity models to gain a deeper understanding of BOLD task response and improve the validity of model estimates. Our study also highlights the sensitivity of fMRI analysis with GLM to precise event model specification and the need for model evaluation, especially in complex and overlapping event designs.