Seven Tesla Evidence for Columnar and Rostral-Caudal Organization of the Human Periaqueductal Gray Response in the Absence of Threat: A Working Memory Study.

The periaqueductal gray (PAG) is a small midbrain structure that surrounds the cerebral aqueduct, regulates brain-body communication, and is often studied for its role in "fight-or-flight" and "freezing" responses to threat. We used ultra-high-field 7 T fMRI to resolve the PAG in humans and distinguish it from the cerebral aqueduct, examining its in vivo function during a working memory task (N = 87). Both mild and moderate cognitive demands elicited spatially similar patterns of whole-brain blood oxygenation level-dependent (BOLD) response, and moderate cognitive demand elicited widespread BOLD increases above baseline in the brainstem. Notably, these brainstem increases were not significantly greater than those in the mild demand condition, suggesting that a subthreshold brainstem BOLD increase occurred for mild cognitive demand as well. Subject-specific masks were group aligned to examine PAG response. In PAG, both mild and moderate demands elicited a well-defined response in ventrolateral PAG, a region thought to be functionally related to anticipated painful threat in humans and nonhuman animals-yet, the present task posed only the most minimal (if any) "threat," with the cognitive tasks used being approximately as challenging as remembering a phone number. These findings suggest that the PAG may play a more general role in visceromotor regulation, even in the absence of threat.

A functional account of stimulation-based aerobic glycolysis and its role in interpreting BOLD signal intensity increases in neuroimaging experiments.

In aerobic glycolysis, oxygen is abundant, and yet cells metabolize glucose without using it, decreasing their ATP per glucose yield by 15-fold. During task-based stimulation, aerobic glycolysis occurs in localized brain regions, presenting a puzzle: why produce ATP inefficiently when, all else being equal, evolution should favor the efficient use of metabolic resources? The answer is that all else is not equal. We propose that a tradeoff exists between efficient ATP production and the efficiency with which ATP is spent to transmit information. Aerobic glycolysis, despite yielding little ATP per glucose, may support neuronal signaling in thin (< 0.5 µm), information-efficient axons. We call this the efficiency tradeoff hypothesis. This tradeoff has potential implications for interpretations of task-related BOLD "activation" observed in fMRI. We hypothesize that BOLD "activation" may index local increases in aerobic glycolysis, which support signaling in thin axons carrying "bottom-up" information, or "prediction error"-i.e., the BIAPEM (BOLD increases approximate prediction error metabolism) hypothesis. Finally, we explore implications of our hypotheses for human brain evolution, social behavior, and mental disorders.

Improving the study of brain-behavior relationships by revisiting basic assumptions.

Neuroimaging research has been at the forefront of concerns regarding the failure of experimental findings to replicate. In the study of brain-behavior relationships, past failures to find replicable and robust effects have been attributed to methodological shortcomings. Methodological rigor is important, but there are other overlooked possibilities: most published studies share three foundational assumptions, often implicitly, that may be faulty. In this paper, we consider the empirical evidence from human brain imaging and the study of non-human animals that calls each foundational assumption into question. We then consider the opportunities for a robust science of brain-behavior relationships that await if scientists ground their research efforts in revised assumptions supported by current empirical evidence.

Allostasis as a core feature of hierarchical gradients in the human brain.

This paper integrates emerging evidence from two broad streams of scientific literature into one common framework: (a) hierarchical gradients of functional connectivity that reflect the brain's large-scale structural architecture (e.g., a lamination gradient in the cerebral cortex); and (b) approaches to predictive processing and one of its specific instantiations called allostasis (i.e., the predictive regulation of energetic resources in the service of coordinating the body's internal systems). This synthesis begins to sketch a coherent, neurobiologically inspired framework suggesting that predictive energy regulation is at the core of human brain function, and by extension, psychological and behavioral phenomena, providing a shared vocabulary for theory building and knowledge accumulation.

Allostasis refers to the process by which the brain anticipates the needs of the body and attempts to meet those needs before they arise, and is one specific instantiation of a broader predictive processing framework. In this perspective article, we propose that allostasis is a basic function of the human brain subserved by an intrinsic architecture composed of two hierarchical functional gradients. Our framework, based on a synthesis of multimodal and multiscale evidence across species, begins to sketch a coherent, neurobiologically inspired research program suggesting that predictive energy regulation is at the core of human brain function, and by extension, psychological and behavioral phenomena, providing a shared vocabulary for theory building and knowledge accumulation.

The sense of should: A biologically-based framework for modeling social pressure.

What is social pressure, and how could it be adaptive to conform to others' expectations? Existing accounts highlight the importance of reputation and social sanctions. Yet, conformist behavior is multiply determined: sometimes, a person desires social regard, but at other times she feels obligated to behave a certain way, regardless of any reputational benefit-i.e. she feels a sense of should. We develop a formal model of this sense of should, beginning from a minimal set of biological premises: that the brain is predictive, that prediction error has a metabolic cost, and that metabolic costs are prospectively avoided. It follows that unpredictable environments impose metabolic costs, and in social environments these costs can be reduced by conforming to others' expectations. We elaborate on a sense of should's benefits and subjective experience, its likely developmental trajectory, and its relation to embodied mental inference. From this individualistic metabolic strategy, the emergent dynamics unify social phenomenon ranging from status quo biases, to communication and motivated cognition. We offer new solutions to long-studied problems (e.g. altruistic behavior), and show how compliance with arbitrary social practices is compelled without explicit sanctions. Social pressure may provide a foundation in individuals on which societies can be built.

Beginning with biology: "Aspects of cognition" exist in the service of the brain's overall function as a resource-regulator.

Lieder and Griffiths rightly urge that computational cognitive models be constrained by resource usage, but they should go further. The brain's primary function is to regulate resource usage. As a consequence, resource usage should not simply select among algorithmic models of "aspects of cognition." Rather, "aspects of cognition" should be understood as existing in the service of resource management.

Acute and chronic stress exposure predicts 1-year recurrence in adult outpatients with residual depression symptoms following response to treatment.

BACKGROUND: One of the strongest predictors of depression recurrence in those who respond to treatment is the presence of residual depressive symptoms. Our goal was to examine stressful life event exposure as a mechanism of recurrence in previously depressed patients with residual depression symptoms. That is, we predicted that higher levels of residual symptoms will significantly predict exposure to acute life events that will then heighten prospective recurrence risk. METHODS: Participants included 68 adult outpatients with major depression (42 women; age 18-60) who completed a 12-month naturalistic follow-up after achieving remission in a 20-week randomized, open label trial of interpersonal psychotherapy, cognitive-behavioral therapy, or antidepressant medication. Depression recurrence was defined as the reemergence of an episode of major depression as determined by structured interview. Acute life events and chronic stressors were assessed at the end of follow-up using a contextual interview. RESULTS: Posttreatment depression scores significantly prospectively predicted an increased risk for recurrence, and acute life events in the follow-up period. Cox regression survival analyses modeling life events as time-dependent covariates showed that life event exposure mediated the relation of residual symptoms to recurrence even controlling for chronic stress. CONCLUSIONS: Our findings implicate residual symptoms in heightening depression recurrence risk through exposure to stressful life events. Depression recurrence adds significantly to the burden of the disorder. Therefore, rigorous follow-up of patients targeting the stressful context has the potential to prevent a lifelong pattern of illness.