Differential relational memory impairment in temporal lobe epilepsy.

OBJECTIVE: Temporal lobe epilepsy (TLE) is typically associated with pathology of the hippocampus, a key structure involved in relational memory, including episodic, semantic, and spatial memory processes. While it is widely accepted that TLE-associated hippocampal alterations underlie memory deficits, it remains unclear whether impairments relate to a specific cognitive domain or multiple ones. METHODS: We administered a recently validated task paradigm to evaluate episodic, semantic, and spatial memory in 24 pharmacoresistant TLE patients and 50 age- and sex-matched healthy controls. We carried out two-way analyses of variance to identify memory deficits in individuals with TLE relative to controls across different relational memory domains, and used partial least squares correlation to identify factors contributing to variations in relational memory performance across both cohorts. RESULTS: Compared to controls, TLE patients showed marked impairments in episodic and spatial memory, with mixed findings in semantic memory. Even when additionally controlling for age, sex, and overall cognitive function, between-group differences persisted along episodic and spatial domains. Moreover, age, diagnostic group, and hippocampal volume were all associated with relational memory behavioral phenotypes. SIGNIFICANCE: Our behavioral findings show graded deficits across relational memory domains in people with TLE, which provides further insights into the complex pattern of cognitive impairment in the condition.

Serotonergic psychedelic drugs LSD and psilocybin reduce the hierarchical differentiation of unimodal and transmodal cortex.

Lysergic acid diethylamide (LSD) and psilocybin are serotonergic psychedelic compounds with potential in the treatment of mental health disorders. Past neuroimaging investigations have revealed that both compounds can elicit significant changes to whole-brain functional organization and dynamics. A recent proposal linked past findings into a unified model and hypothesized reduced whole-brain hierarchical organization as a key mechanism underlying the psychedelic state, but this has yet to be directly tested. We applied a non-linear dimensionality reduction technique previously used to map hierarchical connectivity gradients to assess cortical organization in the LSD and psilocybin state from two previously published pharmacological resting-state fMRI datasets (N = 15 and 9, respectively). Results supported our primary hypothesis: The principal gradient of cortical connectivity, describing a hierarchy from unimodal to transmodal cortex, was significantly flattened under both drugs relative to their respective placebo conditions. Between-condition contrasts revealed that this was driven by a reduction of functional differentiation at both hierarchical extremes - default and frontoparietal networks at the upper end, and somatomotor at the lower. Gradient-based connectivity mapping indicated that this was underpinned by a disruption of modular unimodal connectivity and increased unimodal-transmodal crosstalk. Results involving the second and third gradient, which, respectively represent axes of sensory and executive differentiation, also showed significant alterations across both drugs. These findings provide support for a recent mechanistic model of the psychedelic state relevant to therapeutic applications of psychedelics. More fundamentally, we provide the first evidence that macroscale connectivity gradients are sensitive to an acute pharmacological manipulation, supporting a role for psychedelics as scientific tools to perturb cortical functional organization.

Neural activity associated with self, other, and object-based counterfactual thinking.

Previous research has shown that autobiographical episodic counterfactual thinking-i.e., mental simulations about alternative ways in which one's life experiences could have occurred-engages the brain's default network (DN). However, it remains unknown whether or not the DN is also engaged during impersonal counterfactual thoughts, specifically those involving other people or objects. The current study compares brain activity during counterfactual simulations involving the self, others and objects. In addition, counterfactual thoughts involving others were manipulated in terms of similarity and familiarity with the simulated characters. The results indicate greater involvement of DN during person-based (i.e., self and other) as opposed to object-based counterfactual simulations. However, the involvement of different regions of the DN during other-based counterfactual simulations was modulated by how close and/or similar the simulated character was perceived to be by the participant. Simulations involving unfamiliar characters preferentially recruited dorsomedial prefrontal cortex. Simulations involving unfamiliar similar characters, characters with whom participants identified personality traits, recruited lateral temporal gyrus. Finally, our results also revealed differential coupling of right hippocampus with lateral prefrontal and temporal cortex during counterfactual simulations involving familiar similar others, but with left transverse temporal gyrus and medial frontal and inferior temporal gyri during counterfactual simulations involving either oneself or unfamiliar dissimilar others. These results suggest that different brain mechanisms are involved in the simulation of personal and impersonal counterfactual thoughts, and that the extent to which regions associated with autobiographical memory are recruited during the simulation of counterfactuals involving others depends on the perceived similarity and familiarity with the simulated individuals.

Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer's pathology.

There is considerable debate whether Alzheimer's disease (AD) originates in basal forebrain or entorhinal cortex. Here we examined whether longitudinal decreases in basal forebrain and entorhinal cortex grey matter volume were interdependent and sequential. In a large cohort of age-matched older adults ranging from cognitively normal to AD, we demonstrate that basal forebrain volume predicts longitudinal entorhinal degeneration. Models of parallel degeneration or entorhinal origin received negligible support. We then integrated volumetric measures with an amyloid biomarker sensitive to pre-symptomatic AD pathology. Comparison between cognitively matched normal adult subgroups, delineated according to the amyloid biomarker, revealed abnormal degeneration in basal forebrain, but not entorhinal cortex. Abnormal degeneration in both basal forebrain and entorhinal cortex was only observed among prodromal (mildly amnestic) individuals. We provide evidence that basal forebrain pathology precedes and predicts both entorhinal pathology and memory impairment, challenging the widely held belief that AD has a cortical origin.