Lipid clinic experience with bempedoic acid in three UK centres.

OBJECTIVE: Novel lipid-lowering therapies are being introduced. Few studies exist of the real-world effectiveness of adenosine-tri-phosphate citrate lyase inhibition with bempedoic acid. METHODS: This study audited bempedoic acid therapy in 216 consecutive patients from three hospital centres - a university hospital (n = 77) and two district general hospitals (n = 106 and 33). Cardiovascular disease (CVD) risk factors, prescription qualification criteria, efficacy and adverse effects were assessed. RESULTS: The population was aged 65.9 ± 11.0 years, 42% were male, 25% had type 2 diabetes, and 31% had familial hypercholesterolaemia. CVD was present in 19% and multibed vascular disease in 8%. Statin intolerance was reported in 92%. Bempedoic acid reduced total cholesterol by 1.58 ± 1.44 mmol/L (20%), LDL-C by 1.37 ± 1.31 mmol/L (27%), triglycerides by 0.22 mmol/L (2%) with an 0.06 mmol/L (1%) increase in HDL-C after 22 ± 9 months follow-up. An LDL-C <2.5 mmol/L was achieved in 40% and <2 mmol/L in 20%. Efficacy (r2 = .33) was predicted by baseline LDL-C (ß = .54; p <.001). No significant changes were seen in transaminases, creatinine, creatine kinase, urate or HbA1c. Treatment was discontinued by 33% of patients and occurred due to myalgia (43%), lack of efficacy (16%) and gastrointestinal adverse effects (15%). No cases of gout were observed. In a logistic regression only the number of previous drug classes not tolerated (ß = 1.60; p = .009) was a contributing factor to discontinuation. CONCLUSION: This audit suggests that bempedoic acid therapy is effective but that adverse effects and discontinuation are common. This suggests nocebo effects might be generalizable to all lipid-lowering drug therapies in susceptible individuals.

Longitudinal characterization of behavioral, morphological and transcriptomic changes in a tauopathy mouse model.

Neurodegenerative disorders, such as Alzheimer's disease (AD), have the gradual onset of neurobiological changes preceding clinical diagnosis by decades. To elucidate how brain dysfunction proceeds in neurodegenerative disorders, we performed longitudinal characterization of behavioral, morphological, and transcriptomic changes in a tauopathy mouse model, P301S transgenic mice. P301S mice exhibited cognitive deficits as early as 3 months old, and deficits in social preference and social cognition at 5-6 months. They had a significant decrease of arborization in basal dendrites of hippocampal pyramidal neurons from 3 months and apical dendrites of PFC pyramidal neurons at 9 months. Transcriptomic analysis of genome-wide changes revealed the enrichment of synaptic gene upregulation at 3 months of age, while most of these synaptic genes were downregulated in PFC and hippocampus of P301S mice at 9 months. These time-dependent changes in gene expression may lead to progressive alterations of neuronal structure and function, resulting in the manifestation of behavioral symptoms in tauopathies.

There Is no Theory-Free Measure of "Swaps" in Visual Working Memory Experiments.

Visual working memory is highly limited, and its capacity is tied to many indices of cognitive function. For this reason, there is much interest in understanding its architecture and the sources of its limited capacity. As part of this research effort, researchers often attempt to decompose visual working memory errors into different kinds of errors, with different origins. One of the most common kinds of memory error is referred to as a "swap," where people report a value that closely resembles an item that was not probed (e.g., an incorrect, non-target item). This is typically assumed to reflect confusions, like location binding errors, which result in the wrong item being reported. Capturing swap rates reliably and validly is of great importance because it permits researchers to accurately decompose different sources of memory errors and elucidate the processes that give rise to them. Here, we ask whether different visual working memory models yield robust and consistent estimates of swap rates. This is a major gap in the literature because in both empirical and modeling work, researchers measure swaps without motivating their choice of swap model. Therefore, we use extensive parameter recovery simulations with three mainstream swap models to demonstrate how the choice of measurement model can result in very large differences in estimated swap rates. We find that these choices can have major implications for how swap rates are estimated to change across conditions. In particular, each of the three models we consider can lead to differential quantitative and qualitative interpretations of the data. Our work serves as a cautionary note to researchers as well as a guide for model-based measurement of visual working memory processes.

Inhibition of histone methyltransferase Smyd3 rescues NMDAR and cognitive deficits in a tauopathy mouse model.

Pleiotropic mechanisms have been implicated in Alzheimer's disease (AD), including transcriptional dysregulation, protein misprocessing and synaptic dysfunction, but how they are mechanistically linked to induce cognitive deficits in AD is unclear. Here we find that the histone methyltransferase Smyd3, which catalyzes histone H3 lysine 4 trimethylation (H3K4me3) to activate gene transcription, is significantly elevated in prefrontal cortex (PFC) of AD patients and P301S Tau mice, a model of tauopathies. A short treatment with the Smyd3 inhibitor, BCI-121, rescues cognitive behavioral deficits, and restores synaptic NMDAR function and expression in PFC pyramidal neurons of P301S Tau mice. Fbxo2, which encodes an E3 ubiquitin ligase controlling the degradation of NMDAR subunits, is identified as a downstream target of Smyd3. Smyd3-induced upregulation of Fbxo2 in P301S Tau mice is linked to the increased NR1 ubiquitination. Fbxo2 knockdown in PFC leads to the recovery of NMDAR function and cognitive behaviors in P301S Tau mice. These data suggest an integrated mechanism and potential therapeutic strategy for AD.

Measuring memory is harder than you think: How to avoid problematic measurement practices in memory research.

We argue that critical areas of memory research rely on problematic measurement practices and provide concrete suggestions to improve the situation. In particular, we highlight the prevalence of memory studies that use tasks (like the "old/new" task: "have you seen this item before? yes/no") where quantifying performance is deeply dependent on counterfactual reasoning that depends on the (unknowable) distribution of underlying memory signals. As a result of this difficulty, different literatures in memory research (e.g., visual working memory, eyewitness identification, picture memory, etc.) have settled on a variety of fundamentally different metrics to get performance measures from such tasks (e.g., A', corrected hit rate, percent correct, d', diagnosticity ratios, K values, etc.), even though these metrics make different, contradictory assumptions about the distribution of latent memory signals, and even though all of their assumptions are frequently incorrect. We suggest that in order for the psychology and neuroscience of memory to become a more cumulative, theory-driven science, more attention must be given to measurement issues. We make a concrete suggestion: The default memory task for those simply interested in performance should change from old/new ("did you see this item'?") to two-alternative forced-choice ("which of these two items did you see?"). In situations where old/new variants are preferred (e.g., eyewitness identification; theoretical investigations of the nature of memory signals), receiver operating characteristic (ROC) analysis should be performed rather than a binary old/new task.

You cannot "count" how many items people remember in visual working memory: The importance of signal detection-based measures for understanding change detection performance.

Change detection tasks are commonly used to measure and understand the nature of visual working memory capacity. Across three experiments, we examine whether the nature of the memory signals used to perform change detection are continuous or all-or-none and consider the implications for proper measurement of performance. In Experiment 1, we find evidence from confidence reports that visual working memory is continuous in strength, with strong support for an equal variance signal detection model with no guesses or lapses. Experiments 2 and 3 test an implication of this, which is that K should confound response criteria and memory. We found K values increased by roughly 30% when criteria are shifted despite no change in the underlying memory signals. Overall, our data call into question a large body of work using threshold measures, like K, to analyze change detection data. This metric confounds response bias with memory performance and is inconsistent with the vast majority of visual working memory models, which propose variations in precision or strength are present in working memory. Instead, our data indicate an equal variance signal detection model (and thus, d')-without need for lapses or guesses-is sufficient to explain change detection performance. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

EGR3 regulates opioid-related nociception and motivation in male rats.

Chronic pain can be a debilitating condition, leading to profound changes in nearly every aspect of life. However, the reliance on opioids such as oxycodone for pain management is thought to initiate dependence and addiction liability. The neurobiological intersection at which opioids relieve pain and possibly transition to addiction is poorly understood. Using RNA sequencing pathway analysis in rats with complete Freund's adjuvant (CFA)-induced chronic inflammation, we found that the transcriptional signatures in the medial prefrontal cortex (mPFC; a brain region where pain and reward signals integrate) elicited by CFA in combination with oxycodone differed from those elicited by CFA or oxycodone alone. However, the expression of Egr3 was augmented in all animals receiving oxycodone. Furthermore, virus-mediated overexpression of EGR3 in the mPFC increased mechanical pain relief but not the affective aspect of pain in animals receiving oxycodone, whereas pharmacological inhibition of EGR3 via NFAT attenuated mechanical pain relief. Egr3 overexpression also increased the motivation to obtain oxycodone infusions in a progressive ratio test without altering the acquisition or maintenance of oxycodone self-administration. Taken together, these data suggest that EGR3 in the mPFC is at the intersection of nociceptive and addictive-like behaviors.

What You See Is What You Hear: Sounds Alter the Contents of Visual Perception.

Visual object recognition is not performed in isolation but depends on prior knowledge and context. Here, we found that auditory context plays a critical role in visual object perception. Using a psychophysical task in which naturalistic sounds were paired with noisy visual inputs, we demonstrated across two experiments (young adults; ns = 18-40 in Experiments 1 and 2, respectively) that the representations of ambiguous visual objects were shifted toward the visual features of an object that were related to the incidental sound. In a series of control experiments, we found that these effects were not driven by decision or response biases (ns = 40-85) nor were they due to top-down expectations (n = 40). Instead, these effects were driven by the continuous integration of audiovisual inputs during perception itself. Together, our results demonstrate that the perceptual experience of visual objects is directly shaped by naturalistic auditory context, which provides independent and diagnostic information about the visual world.

A convergent mechanism of high risk factors ADNP and POGZ in neurodevelopmental disorders.

ADNP and POGZ are two top-ranking risk factors for autism spectrum disorder and intellectual disability, but how they are linked to these neurodevelopmental disorders is largely unknown. Both ADNP and POGZ are chromatin regulators, which could profoundly affect gene transcription and cellular function in the brain. Using post-mortem tissue from patients with autism spectrum disorder, we found diminished expression of ADNP and POGZ in the prefrontal cortex, a region highly implicated in neurodevelopmental disorders. To understand the functional role of these neurodevelopmental disorder risk factors, we used viral-based gene transfer to investigate how Adnp or Pogz deficiency in mouse prefrontal cortex affects behavioural, transcriptomic and synaptic function. Mice with prefrontal cortex deficiency of Adnp or Pogz exhibited specific impairment of cognitive task performance. RNA-sequencing revealed that Adnp or Pogz deficiency induced prominent upregulation of overlapping genes enriched in neuroinflammation, similar to the elevation of pro-inflammatory genes in humans with neurodevelopmental disorders. Concomitantly, Adnp or Pogz deficiency led to the significant increase of pro-phagocytic microglial activation in prefrontal cortex, as well as the significant decrease of glutamatergic transmission and postsynaptic protein expression. These findings have uncovered the convergent functions of two top risk factors for autism spectrum disorder and intellectual disability in prefrontal cortex, providing a mechanism linking chromatin, transcriptional and synaptic dysregulation to cognitive deficits associated with neurodevelopmental disorders.

When did that happen? The dynamic unfolding of perceived musical narrative.

People readily imagine narratives in response to instrumental music. Although previous work has established that these narratives show broad intersubjectivity, it remains unclear whether these imagined stories are atemporal, or unfold systematically over the temporal extent of a musical excerpt. To investigate the dynamics of perceived musical narrative, we had participants first listen to 16 instrumental musical excerpts, which had previously been normed for factors of interest. While listening, participants continuously moved a slider to indicate their fluctuating perceptions of tension and relaxation. In a separate experimental session, participants reported the stories they imagined while listening to each excerpt, and then, while listening to the excerpts a final time, clicked a mouse to mark the time points at which they imagined new events in the ongoing imagined story. The time points of these event markings were not uniformly distributed throughout the excerpts, but were clustered at distinct moments, indicating that imagined narratives unfold in real time and entail general consensus about when listeners imagine events in the music. Moreover, the time points at which people tended to imagine events were correlated with the time points at which people tended to perceive salient changes in musical tension, as separately recorded within the first experimental session. The degree of alignment was greater for excerpts high in narrativity than those low in narrativity. Together, these results show that music can dynamically guide a listener's imagination and there is remarkable intersubjectivity in 'when' hear imagined story events in a piece of music.

Targeting histone demethylase LSD1 for treatment of deficits in autism mouse models.

Large-scale genetic studies have revealed that the most prominent genes disrupted in autism are chromatin regulators mediating histone methylation/demethylation, suggesting the central role of epigenetic dysfunction in this disorder. Here, we show that histone lysine 4 dimethylation (H3K4me2), a histone mark linked to gene activation, is significantly decreased in the prefrontal cortex (PFC) of autistic human patients and mutant mice with the deficiency of top-ranking autism risk factor Shank3 or Cul3. A brief treatment of the autism models with highly potent and selective inhibitors of the H3K4me2 demethylase LSD1 (KDM1A) leads to the robust rescue of core symptoms of autism, including social deficits and repetitive behaviors. Concomitantly, LSD1 inhibition restores NMDA receptor function in PFC and AMPA receptor-mediated currents in striatum of Shank3-deficient mice. Genome-wide RNAseq and ChIPseq reveal that treatment of Shank3-deficient mice with the LSD1 inhibitor restores the expression and H3K4me2 occupancy of downregulated genes enriched in synaptic signaling and developmental processes. The immediate early gene tightly linked to neuronal plasticity, Egr1, is on the top list of rescued genes. The diminished transcription of Egr1 is recapitulated in PFC of autistic human patients. Overexpression of Egr1 in PFC of Shank3-deficient mice ameliorates social preference deficits. These results have for the first time revealed an important role of H3K4me2 abnormality in ASD pathophysiology, and the therapeutic potential of targeting H3K4me2 demethylase LSD1 or the downstream molecule Egr1 for ASD.

Clinical Features and Changes in Insulin Requirements in People with Type 2 Diabetes Requiring Insulin When Hospitalised with SARS-CoV-2 Infection.

Background: Uncontrolled hyperglycaemia before and during hospitalisation is a risk factor for adverse outcomes in people with diabetes and SARS-CoV-2 infection. Insulin often at high doses is frequently required to manage hyperglycaemia associated with SARS-CoV-2 infection during hospitalisation. However, there is limited information on the clinical features and sequelae of people with type 2 diabetes (T2DM) not previously on insulin that require insulin as a new treatment when hospitalised with SARS-CoV-2 infection. Aims: To describe the clinical features and insulin treatment sequelae of 113 people with T2DM that required insulin as a new treatment when hospitalised with SARS-CoV-2 infection. Methods: A single-centre study of 113 people with T2DM who were not on insulin before their admission for SARS-CoV-2 infection. The primary aim of our study was to identify clinical and biochemical features that were associated with the need for insulin as a new treatment in people with known T2DM not on insulin treatment at the time of hospitalisation for SARS-CoV-2 infection. We also describe changes in insulin requirements at time of discharge from hospital and 6 weeks later during the first wave of SARS-CoV-2 infection (April-March 2020) in the UK. Clinical, biochemical, and anthropometric data were collected from electronic health records. Results: We observed that of 113 people with T2DM, 35% (n = 39) needed insulin as a new treatment during their hospitalisation for SARS-CoV-2 infection. People requiring insulin were younger, had a higher preadmission HbA1c, were more frequently on oral medication for diabetes before the admission, and were more likely to be obese (body mass index ≥30 kg/m2), with p ≤ 0.001 for all. In multivariable logistic regression analyses, we observed that younger age and higher HbA1c before admission were independently associated with needing insulin, with one-year increase in age associated with decreased odds of needing insulin initiation (OR 0.91, 95% CI 0.83-0.99), and increasing preadmission HbA1c by 1 mmol/mol associated with an increased odds of insulin initiation (OR 1.05, 95% CI 1.002-1.11) (p < 0.05 for both). Of the 39 people with T2DM who required insulin as a new treatment, 28% remained on insulin at the time of discharge with their insulin dose falling from 1.26 U/kg within the first 7 days of admission to 0.39 U/kg at discharge. At 6 weeks after discharge, 24% of people remained on insulin. Conclusion: More than one-third of people with T2DM not previously treated with insulin required new insulin treatment when hospitalised with SARS-CoV-2 infection, and of this group, 24% remained on insulin at 6 weeks after discharge. This study highlights the important variations of insulin requirements in people with T2DM new to insulin and the importance of a dedicated team for patient education and close follow-up.

High-Order Areas and Auditory Cortex Both Represent the High-Level Event Structure of Music.

Recent fMRI studies of event segmentation have found that default mode regions represent high-level event structure during movie watching. In these regions, neural patterns are relatively stable during events and shift at event boundaries. Music, like narratives, contains hierarchical event structure (e.g., sections are composed of phrases). Here, we tested the hypothesis that brain activity patterns in default mode regions reflect the high-level event structure of music. We used fMRI to record brain activity from 25 participants (male and female) as they listened to a continuous playlist of 16 musical excerpts and additionally collected annotations for these excerpts by asking a separate group of participants to mark when meaningful changes occurred in each one. We then identified temporal boundaries between stable patterns of brain activity using a hidden Markov model and compared the location of the model boundaries to the location of the human annotations. We identified multiple brain regions with significant matches to the observer-identified boundaries, including auditory cortex, medial prefrontal cortex, parietal cortex, and angular gyrus. From these results, we conclude that both higher-order and sensory areas contain information relating to the high-level event structure of music. Moreover, the higher-order areas in this study overlap with areas found in previous studies of event perception in movies and audio narratives, including regions in the default mode network.

Guidance of attention by working memory is a matter of representational fidelity.

Items that are held in visual working memory can guide attention toward matching features in the environment. Predominant theories propose that to guide attention, a memory item must be internally prioritized and given a special template status, which builds on the assumption that there are qualitatively distinct states in working memory. Here, we propose that no distinct states in working memory are necessary to explain why some items guide attention and others do not. Instead, we propose variations in attentional guidance arise because individual memories naturally vary in their representational fidelity, and only highly accurate memories automatically guide attention. Across a series of experiments and a simulation we show that (a) items in working memory vary naturally in representational fidelity; (b) attention is guided by all well-represented items, though frequently only one item is represented well enough to guide; and (c) no special working memory state for prioritized items is necessary to explain guidance. These findings challenge current models of attentional guidance and working memory and instead support a simpler account for how working memory and attention interact: Only the representational fidelity of memories, which varies naturally between items, determines whether and how strongly a memory representation guides attention. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures.

ASH1L, a histone methyltransferase, is identified as a top-ranking risk factor for autism spectrum disorder (ASD), however, little is known about the biological mechanisms underlying the link of ASH1L haploinsufficiency to ASD. Here we show that ASH1L expression and H3K4me3 level are significantly decreased in the prefrontal cortex (PFC) of postmortem tissues from ASD patients. Knockdown of Ash1L in PFC of juvenile mice induces the downregulation of risk genes associated with ASD, intellectual disability (ID) and epilepsy. These downregulated genes are enriched in excitatory and inhibitory synaptic function and have decreased H3K4me3 occupancy at their promoters. Furthermore, Ash1L deficiency in PFC causes the diminished GABAergic inhibition, enhanced glutamatergic transmission, and elevated PFC pyramidal neuronal excitability, which is associated with severe seizures and early mortality. Chemogenetic inhibition of PFC pyramidal neuronal activity, combined with the administration of GABA enhancer diazepam, rescues PFC synaptic imbalance and seizures, but not autistic social deficits or anxiety-like behaviors. These results have revealed the critical role of ASH1L in regulating synaptic gene expression and seizures, which provides insights into treatment strategies for ASH1L-associated brain diseases.

Epigenetic treatment of behavioral and physiological deficits in a tauopathy mouse model.

Epigenetic abnormality is implicated in neurodegenerative diseases associated with cognitive deficits, such as Alzheimer's disease (AD). A common feature of AD is the accumulation of neurofibrillary tangles composed of hyperphosphorylated tau. Transgenic mice expressing mutant P301S human tau protein develop AD-like progressive tau pathology and cognitive impairment. Here, we show that the euchromatic histone-lysine N-methyltransferase 2 (EHMT2) is significantly elevated in the prefrontal cortex (PFC) of P301S Tau mice (5-7 months old), leading to the increased repressive histone mark, H3K9me2, which is reversed by treatment with the selective EHMT inhibitor UNC0642. Behavioral assays show that UNC0642 treatment induces the robust rescue of spatial and recognition memory deficits in P301S Tau mice. Concomitantly, the diminished PFC neuronal excitability and glutamatergic synaptic transmission in P301S Tau mice are also normalized by UNC0642 treatment. In addition, EHMT inhibition dramatically attenuates the hyperphosphorylated tau level in PFC of P301S Tau mice. Transcriptomic analysis reveals that UNC0642 treatment of P301S Tau mice has normalized a number of dysregulated genes in PFC, which are enriched in cytoskeleton and extracellular matrix organization, ion channels and transporters, receptor signaling, and stress responses. Together, these data suggest that targeting histone methylation enzymes to adjust gene expression could be used to treat cognitive and synaptic deficits in neurodegenerative diseases linked to tauopathies.

Transcriptomic analysis of human brains with Alzheimer's disease reveals the altered expression of synaptic genes linked to cognitive deficits.

Alzheimer's disease is a progressive neurodegenerative disorder associated with memory loss and impaired executive function. The molecular underpinnings causing cognitive deficits in Alzheimer's disease are loosely understood. Here, we performed cross-study large-scale transcriptomic analyses of postmortem prefrontal cortex derived from Alzheimer's disease patients to reveal the role of aberrant gene expression in this disease. We identified that one of the most prominent changes in prefrontal cortex of Alzheimer's disease humans was the downregulation of genes in excitatory and inhibitory neurons that are associated with synaptic functions, particularly the SNARE-binding complex, which is essential for vesicle docking and neurotransmitter release. Comparing genomic data of Alzheimer's disease with proteomic data of cognitive trajectory, we found that many of the lost synaptic genes in Alzheimer's disease encode hub proteins whose increased abundance is required for cognitive stability. This study has revealed potential molecular targets for therapeutic intervention of cognitive decline associated with Alzheimer's disease.

Autism risk gene KMT5B deficiency in prefrontal cortex induces synaptic dysfunction and social deficits via alterations of DNA repair and gene transcription.

Large-scale genetic screening has identified KMT5B (SUV420H1), which encodes a histone H4 K20 di- and tri-methyltransferase highly expressed in prefrontal cortex (PFC), as a top-ranking high-risk gene for autism. However, the biological function of KMT5B in the brain is poorly characterized, and how KMT5B deficiency is linked to autism remains largely unknown. Here we knocked down Kmt5b in PFC and examined behavioral and electrophysiological changes, as well as underlying molecular mechanisms. Mice with Kmt5b deficiency in PFC display social deficits, a core symptom of autism, without the alteration of other behaviors. Kmt5b deficiency also produces deficits in PFC glutamatergic synaptic transmission, which is accompanied by the reduced synaptic expression of glutamate receptor subunits and associated proteins. Kmt5b deficiency-induced reduction of H4K20me2 impairs 53BP1-mediated DNA repair, leading to the elevation of p53 expression and its target gene Ddit4 (Redd1), which is implicated in synaptic impairment. RNA-sequencing data indicate that Kmt5b deficiency results in the upregulation of genes enriched in cellular stress response and ubiquitin-dependent protein degradation. Collectively, this study has revealed the functional role of Kmt5b in the PFC, and suggests that Kmt5b deficiency could cause autistic phenotypes by inducing synaptic dysfunction and transcriptional aberration.

Working Memory: How Much Is It Used in Natural Behavior?

A new study suggests that visual working memory usage is interestingly low during a more naturalistic virtual reality paradigm, compared to capacity estimates from traditional lab studies. This raises new questions about the use of working memory in everyday tasks.

BrainIAK: The Brain Imaging Analysis Kit.

Functional magnetic resonance imaging (fMRI) offers a rich source of data for studying the neural basis of cognition. Here, we describe the Brain Imaging Analysis Kit (BrainIAK), an open-source, free Python package that provides computationally optimized solutions to key problems in advanced fMRI analysis. A variety of techniques are presently included in BrainIAK: intersubject correlation (ISC) and intersubject functional connectivity (ISFC), functional alignment via the shared response model (SRM), full correlation matrix analysis (FCMA), a Bayesian version of representational similarity analysis (BRSA), event segmentation using hidden Markov models, topographic factor analysis (TFA), inverted encoding models (IEMs), an fMRI data simulator that uses noise characteristics from real data (fmrisim), and some emerging methods. These techniques have been optimized to leverage the efficiencies of high-performance compute (HPC) clusters, and the same code can be se amlessly transferred from a laptop to a cluster. For each of the aforementioned techniques, we describe the data analysis problem that the technique is meant to solve and how it solves that problem; we also include an example Jupyter notebook for each technique and an annotated bibliography of papers that have used and/or described that technique. In addition to the sections describing various analysis techniques in BrainIAK, we have included sections describing the future applications of BrainIAK to real-time fMRI, tutorials that we have developed and shared online to facilitate learning the techniques in BrainIAK, computational innovations in BrainIAK, and how to contribute to BrainIAK. We hope that this manuscript helps readers to understand how BrainIAK might be useful in their research.