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Most antidepressants do not independently treat impaired cognition associated with major depressive disorder (MDD). Elevated brain cortisol levels are associated with both MDD and cognitive impairment. Emestedastat is a brain-penetrant, intracellular cortisol synthesis inhibitor.
Aims
The XanaCIDD trial aimed to determine whether emestedastat 10 mg could improve both cognitive impairment and depression in a population with persistent MDD and cognitive impairment.
Method
Participants had a diagnosis of MDD, with persistent depression (Hamilton Rating Scale for Depression-17 ≥17) and cognitive impairment (coding test ≤0.5 s.d. of normal). Randomised treatment (1:1) was continued for 6 weeks (week 6), with 4 weeks’ blinded follow-up (week 10). The primary end-point was cognition (composite of attention/working memory) at week 6. Depression end-points included Montgomery–Åsberg Depression Rating Scale (MADRS) and Patient Global Impression of Severity (PGI-S). Analyses used a mixed model for repeated measures (cognitive impairment and MADRS one-sided tests, others two-sided) and Cohen’s d effect size. No adjustments were made for multiple comparisons.
Results
A total of 165 participants were enrolled and treated: 134 (81%) were on background antidepressants, 62% were female, mean prior number of MDD episodes was 10 and mean coding z-score was −1.47. There was no benefit on the primary cognitive end-point at week 6 (p = 0.17 favouring placebo), with the cognitive composite improving markedly in both groups without correlation to depressive symptoms or baseline characteristics (R2 ≤ 0.02). The trend towards benefit on the prespecified secondary depression end-point, MADRS, began at week 6 and was maximal at week 10 (2.7 points, Cohen’s d 0.43, p = 0.05). A trend towards potential emestedastat benefit in PGI-S scores was also maximal at week 10 (p = 0.12). Mild–moderate transaminase elevations were seen in 10% of emestedastat participants (≤2 times normal in 7 of 8 cases, 1 discontinuation) versus 1% of the placebo group.
Conclusions
There was no benefit of emestedastat on the primary end-point of cognitive impairment and a large placebo effect, without correlation of cognitive impairment to depression changes or baseline characteristics. Trends towards potential antidepressant activity suggest that emestedastat may be a novel antidepressant worthy of further investigation.
Selective serotonin reuptake inhibitors (SSRIs) are limited by inadequate response in a significant proportion of patients, slow onset, minimal cognitive benefit and side-effects. Preclinical studies suggest selective serotonin 4 receptor (5-HT4R) agonists may produce faster antidepressant effects via distinct mechanisms; however, there has been no experimental research in clinical populations to date.
Aims
To test whether the novel 5-HT4R partial agonist PF-04995274 produces early behavioural and neural changes in emotional cognition similar to SSRIs in patients with unmedicated major depressive disorder (MDD).
Method
In a double-blind, placebo-controlled trial, 90 participants with MDD were randomised to 7 days of PF-04995274 (15 mg), citalopram (20 mg) or placebo. Emotional processing was assessed using a behavioural facial expression recognition task and functional magnetic resonance imaging (fMRI) of implicit emotional face processing (days 6–9). Observer- and self-reported symptoms of depression were also measured at baseline and study end.
Results
As anticipated, citalopram reduced relative accuracy and increased relative reaction time to identify negative faces, with corresponding changes in neural activity (reduced left amygdala activation to emotional faces and valence-specific shifts in cortical regions). In contrast, PF-04995274 produced no change in behavioural negative bias or amygdala activity but increased medial-frontal cortex activation across valences. While this was not a clinical trial, both active treatments demonstrated an early treatment response with reduced observer-rated depression severity relative to placebo; PF-04995274 also reduced self-reported depression, state anxiety and negative affect.
Conclusions
PF-04995274 did not show the typical antidepressant profile of negative bias reductions observed with citalopram. Instead, it was associated with distinct increased medial-frontal activation during an emotional faces task, coupled with preliminary evidence of early clinical improvement, suggesting a potential alternative pathway for antidepressant effects. Findings support further clinical trials of 5-HT4R agonists and investigation of pro-cognitive and mood effects.
Mental health challenges are common in autistic individuals but there is limited research, particularly among preschool children.
Aims
To ascertain the nature and occurrence of mental health challenges in autistic preschool children, as well as their association with autistic traits and cognitive and adaptive functioning.
Method
We conducted a secondary analysis of data collected from children attending Autism Specific Early Learning and Care Centres across six states in Australia. The primary outcome of mental health challenges was assessed using the Child Behaviour Checklist (CBCL). The severity of autism and autistic traits, such as social communication differences and repetitive behaviours, alongside cognitive and adaptive functioning, were used as exposure variables. Multivariable linear regression analyses examined the associations among mental health challenges, autistic traits, cognitive level and adaptive functioning, and adjusted for key sociodemographic covariates.
Results
Among 760 children, about 76% scored above the clinical range of CBCL total problem scores. Mental health difficulties were significantly associated with greater severity of autistic traits, social communication differences and repetitive behaviours, and lower verbal developmental functioning and adaptive functioning. Additionally, sociodemographic determinants, such as children who were older, female or with an autistic sibling, were associated with higher risk of mental health difficulties, whereas culturally and linguistically diverse status, higher parental education and family income were protective against mental health challenges.
Conclusions
Our findings provide useful insights into the high prevalence of mental health difficulties among autistic preschool children, highlighting the significant association with autistic traits, cognitive and adaptive functioning levels and sociodemographic risk factors.
Borderline personality disorder (BPD) is characterised by instability in interpersonal relationships, self-image, and affect. Dysregulated negative emotional processing involving prefrontal and limbic circuits is considered a neural basis of BPD. However, it remains unclear how prefrontal modulation of social decision-making in BPD differs from non-psychiatric controls.
Methods:
To investigate social decision-making in response to unfairness, we conducted an functional magnetic resonance imaging study involving adults with a diagnosis of BPD (n = 77) and healthy controls (HCs; n = 60). Using an inequality aversion model, we derived parameters of social norm adaptation and inequality sensitivity from behavioural data during a modified ultimatum game designed to measure responses to offer norm shifts. Valence and salience signal-processing models isolated prefrontal activations related specifically to social norm prediction error.
Results:
Cumulative rejection rates indicated that individuals diagnosed with BPD exhibited consistent differences in overall offer rejection rates but similar adaptation to HC when responding to norm shifts. Preservation of normative social decision-making in BPD (no significant difference vs. HC) was evident in regression analyses of rejection rates and in reinforcement learning models, with no group differences observed in Rescorla–Wagner parameters. Furthermore, we detected no significant neural activation differences between groups, although ventral regions of the medial prefrontal cortex were preferentially involved in valence-related rather than salience-related polynomial modulation.
Conclusion:
Contrary to our hypotheses, neither behavioural nor neural responses to economic norm violations differed significantly between BPD and HC groups across one-shot games involving unknown partners. Future research could explore whether more personally relevant or higher-stress social contexts elicit differences not observed here.
Shame is a pervasive, multidimensional emotion influencing brain, body and social life. While shame can foster accountability, its toxic forms drive stigma, withdrawal and mental illness. We call for systemic, culturally sensitive interventions to transform phatological shame into healing, fostering empathy, accountability and psychological safety in care, education and policy.
This chapter introduces what I call the ‘predictive turn,’ in which cognitive processes traditionally described in terms of remembering the past are reoriented to face the future. Here, the first-order topic is the phenomenology of reading literary texts, including the emotions of surprise and interest, the senses of agency and presence, and the feelings of immersion and flow, whereas the second-order method triangulates among insights gained from theoretical cognitive neuroscience, cognitive philosophy, and cognitive literary studies. The first part explains how aspects of perception can be understood in terms of prediction, prediction errors, and the management of precision, or the evolving confidence that we place in our predictions, including those related to unfolding stories and their narration. The second part unpacks the relationship between memory and prediction, including revisiting the cognitivist concept of the schema and how it can be applied to literary intertextuality. The third part clarifies how predictive processing is related to movement, grounded language, and active inference, in which perceptual and motor systems work together to reduce prediction error. For literary texts, this might entail attending to the use of grounded or ‘embodied’ language (Kukkonen 2020), among other possibilities such as feelings of estrangement and narrative foregrounding.
How does the mind lend itself to artistic creation and appreciation? How should we study minds and arts in ways that transform our understanding of both? This book examines the concepts of art and cognition from the complementary perspectives of philosophy, the empirical sciences, and the humanities. Central chapters combine examples of visual art, music, literature, and film with the properties of cognition that they illuminate, including 4E cognition, predictive processing, and theories of affect and emotion. These aspects of cognition are undergoing theoretical shifts that complicate established understandings of the mind and its encounter with the arts. As the book takes stock of recent developments in aesthetics that have incorporated empirical findings (Naturalized Aesthetics), it also envisions a new generation of cognitive science with robust ties to history and literature (the Cognitive Humanities). In this way, Cognition and the Arts can be seen as a model of interdisciplinary scholarship.
A distinction between types of methods (understanding and explanation) that generate different kinds of evidence relevant to the psychiatric assessment is characterised. The distinction is animated with both non-clinical and clinical examples and exercises. Scepticism about the distinction is addressed, and three influential systems of psychiatric knowledge which collapse understanding and explanation in different ways are discussed. The argument is made that the distinction (analogous to the romantic/classic distinction) resurfaces and is compelling. However, another challenge becomes important – holism in psychiatric assessment – which the understanding/explanation distinction leaves in an unsatisfactory state.
Attention is critical to our daily lives, from simple acts of reading or listening to a conversation to the more demanding situations of trying to concentrate in a noisy environment or driving on a busy roadway. This book offers a concise introduction to the science of attention, featuring real-world examples and fascinating studies of clinical disorders and brain injuries. It introduces cognitive neuroscience methods and covers the different types and core processes of attention. The links between attention, perception, and action are explained, along with exciting new insights into the brain mechanisms of attention revealed by cutting-edge research. Learning tools – including an extensive glossary, chapter reviews, and suggestions for further reading – highlight key points and provide a scaffolding for use in courses. This book is ideally suited for graduate or advanced undergraduate students as well as for anyone interested in the role attention plays in our lives.
The Neuroscience of Language offers a remarkably accessible introduction to language in the mind and brain. Following the chain of communication from speaker to listener, it covers all fundamental concepts from speech production to auditory processing, speech sounds, word meaning, and sentence processing. The key methods of cognitive neuroscience are covered, as well as clinical evidence from neuropsychological patients and multimodal aspects of language including visual speech, gesture, and sign language. Over 80, full color figures are included to help communicate key concepts. The main text focuses on big-picture themes, while detailed studies and related anecdotes are presented in footnotes to provide interested students with many opportunities to dive deeper into specific topics. Throughout, language is placed within the larger context of the brain, illustrating the fascinating connections of language with other fields including cognitive science, linguistics, psychology, and speech and hearing science.
This chapter introduces the methods used in cognitive neuroscience to study language processing in the human brain. It begins by explaining the basics of neural signaling (such as the action potential) and then delves into various brain imaging techniques. Structural imaging methods like MRI and diffusion tensor imaging are covered, which reveal the brain’s anatomy. The chapter then explores functional imaging approaches that measure brain activity, including EEG, MEG, and fMRI. Each method’s spatial and temporal resolution are discussed. The text also touches on non-invasive brain stimulation techniques like TMS and tES. Throughout, the chapter emphasizes the importance of converging evidence from multiple methods to draw robust conclusions about brain function. Methodological considerations such as the need for proper statistical comparisons are highlighted. The chapter concludes with a discussion of how neurodegenerative diseases have informed our understanding of language in the brain. Overall, this comprehensive overview equips readers with the foundational knowledge needed to critically evaluate neuroscience research on language processing.
This chapter provides a comprehensive overview of the structural foundations of language in the human brain, tracing the development of localization theories from phrenology to modern neuroimaging. It introduces key anatomical terminology and landmarks, including major brain regions, gyri, and sulci. The chapter explores the evolution of language localization theories, highlighting influential figures like Broca and Wernicke, and the shift from single-region to network-based models of language processing. It discusses various approaches to brain mapping, including macroanatomical, microanatomical (cytoarchitectonic), and functional definitions. The chapter also covers important anatomical pathways, particularly the dorsal and ventral streams for speech processing, while noting that these simplified models may not fully capture the complexity of language networks. The chapter concludes by acknowledging the challenges in precisely labeling brain regions and the complementary nature of different naming conventions, setting the stage for deeper exploration of language neuroscience in subsequent chapters.
This chapter highlights several aspects of human communication that rely on brain regions outside the traditional fronto-temporal language network. Factors affecting the neural resources needed for communication include the task demands (including acoustic or linguistic aspects), and abilities of individual listeners. When speech is acoustically challenging, as may happen due to background noise or hearing loss, listeners must engage cognitive resources compared to those needed for understanding clear speech. The additional cognitive demands of acoustic challenge are seen most obviously through activity in prefrontal cortex. During conversations, talkers need to plan the content of what they are saying, as well as when to say it – processes that engage the left middle frontal gyrus. And the cerebellum, frequently overlooked in traditional neurobiological models of language, exhibits responses to processing both words and sentences. The chapter ends by concluding that many aspects of human communication rely on parts of the brain outside traditional “language regions,” and that the processes engaged depend a great deal on the specific task required and who is completing it.
This chapter introduces the idea of language as a means to communicate ideas to other people. The speech chain – following the path of language from the mind of the speaker through to an acoustic signal, eventually interpreted by the mind of the listener – is introduced as an organizational framework. Of special note, all of the stages between talker and listener can influence the effectiveness of communication. The chapter provides a summary of central challenges associated with spoken language, including categorical perception, time-constrained understanding, flexibility, and multimodal integration. It then introduces several “big picture” themes from the book: stability versus flexibility, the importance of context, bottom-up versus top-down processing, hierarchical organization, the role of task demands, and neuroanatomical considerations related to localization and lateralization.
Section 1.1 gives a brief overview of the field of cognitive neuroscience. Section 1.2 details the different types of memory. In Section 1.3, an overview of human brain anatomy is provided. Commonly known anatomic distinctions such as the frontal lobe, the parietal lobe, the temporal lobe, and the occipital lobe are reviewed, and more detailed anatomy is discussed. Section 1.4 highlights the importance of the medial temporal lobe in memory, which was discovered in the 1950s when this region was surgically removed from one individual. In Section 1.5, an overview of brain sensory regions is provided, such as the regions associated with visual perception and auditory perception. In Section 1.6, the regions of the brain that control memory retrieval are considered, which include part of the frontal cortex, the parietal cortex, and the medial temporal lobe. Section 1.7 provides an overview of the organization of this book.
In 1978, William Alwyn Lishman's Organic Psychiatry: The Psychological Consequences of Cerebral Disorder was published, fostering the development of neuropsychiatry and leading to the recognition of Lishman as the father of neuropsychiatry. This article is a narrative account of his personal struggles, as well as conceptual dilemmas he dealt with while writing this book, and how through its four editions it has evolved to become an anchor for psychiatrists as they seek to develop understanding of the workings of the brain, and a beacon for them when they discuss clinical implications of diagnosis with patients and families.
Perspectives on how to define, operationalize, and measure insight have evolved due to developments in theory, methodology, and technology. Research on insight can be broken into several waves. In the first wave, Gestalt psychologists introduced the concept of insight as a discontinuous form of learning and problem solving that arises from changes in one’s global representation of a problem, in opposition to contemporary associationist views. In the second wave, psychologists examined insight in deliberate contrast with analytical problem-solving and found that insight involves nonreportable mental operations leading to a discrete, all-or-none availability of representational change. In the third wave, thanks to advances in behavioral methods and neuroimaging technology, cognitive neuroscientists began to examine how insight occurs in the brain with the goal of studying the neural states that co-occur with and precede insight to better understand its cognitive mechanisms. The advances made during these initial waves enabled the proliferation of research on insight over recent decades and inspired new discoveries. This chapter provides a brief retrospective on the first two waves of insight research and a more in-depth overview of the third wave of research on the cognitive neuroscience of insight, and ends by discussing current and future directions in insight research
Approximately 10–18% of the adult population experience some form of anxiety when viewing clusters of small holes. ‘Trypophobia’ has been the subject of much discussion within the peer-reviewed literature, news outlets, health-related websites and social media. However, there is some scepticism surrounding the phenomenon. It is often stated that the condition is not recognised by the American Psychiatric Association, and not listed as a phobia in the DSM-5. It has also been claimed that trypophobia is no more than a particularly successful internet meme. In this editorial, I argue that such criticisms are misplaced. There is, for instance, no list of phobias in the DSM-5; only criteria that determine phobia classification. Using these criteria, as well as personal testimonials, trypophobia is clearly a phobia. Furthermore, the meme hypothesis cannot account for the fact that the phenomenon existed long before the internet.