Abstract The piriform cortex (PCx), commonly considered to be the primary olfactory sensory cortex, differs from other mammalian sensory cortices by not displaying a stimulus-specific spatial organization, but rather displaying widely distributed odor-evoked activity. However, there is evidence of a PCx spatial organization based on output neuron targeting. Here, we performed double-labeled retrograde tracing to reveal neuronal populations of PCx output neurons that project to two regions affiliated with different behavioral significance, the basolateral amygdala (BLA) and lateral orbitofrontal cortex (LO) networks. We found that PCx neurons projecting to BLA and LO are distinct in spatial distribution with minimal overlap, supporting the hypothesis that while odor input is distributed randomly across the PCx, PCx output neurons are organized into target-specific neuronal populations that potentially serve as functional units for odor encoding and odor-guided behavior.

Cortical thickness alterations in afro-descendants with schizophrenia and bipolar disorder: An exploratory analysis.

BackgroundAlzheimer's disease is characterized by accumulation of amyloid‐β (Aβ) plaques and tau tangles. Aβ deposition typically begins in neocortical regions years before onset of cognitive decline, while tau pathology spreads systematically through select brain regions, typically described as Braak stages (I‐VI). The impact of regional Aβ on tau propagation remains a key research focus.MethodWe examined the associations between regional Aβ and tau burden measured by positron emission tomography (PET) in 192 participants without dementia (14 with mild cognitive impairment [MCI]) in the BIOCARD cohort, of whom 52 (27%) were Aβ positive. Amyloid status was assessed using standardized uptake value ratios (SUVR) obtained from the medial orbitofrontal cortex (OFC), lateral OFC, precuneus, posterior cingulate, anterior cingulate, parietal, temporal, and superior frontal regions using 11C‐PIB PET. Tau burden was quantified using 18F‐MK6240 PET across 29 brain regions, assigned to each of the Braak stages. Associations were examined with stepwise and hierarchical regressions, covarying for age, sex, education, and ApoE4 status.ResultIn stepwise regression analyses for Braak stages (I‐II), amyloid in the medial OFC emerged as significantly associated with tau burden (β = 1.45, t = 4.75, p <.001 for Braak‐I; β = 0.80, t = 3.58, p <.001 for Braak‐II), while in later Braak stages, amyloid in the precuneus emerged as significantly associated with tau burden (β = 0.57, t = 9.59, p <.001for Braak‐III; β = 1.54, t = 3.76, p <.001 for Braak‐IV; β = 0.39, t = 5.90, p <.001 for Braak‐V; and β = 0.17, t = 2.30, p <.05 for Braak‐VI). Subsequent hierarchical regressions showed that including other Aβ regions did not significantly alter the proportion of variance explained for any Braak stage (Figure 1).ConclusionAmyloid‐tau interactions show regional specificity with medial OFC amyloid burden showing a strong association with early tau pathology accumulation while amyloid in the precuneus is selectively associated with tau in later stages. These findings suggest that localized measures of amyloid burden may enhance early detection and show utility in understanding amyloid‐tau dynamics.

BackgroundResearch reveals an association between frailty and mild behavioural impairment (MBI), both of which have been individually associated with cognitive impairment leading to dementia. However, their combined effect remains understudied. This study explores a potential “behavioural frailty,” the co‐occurrence of prefrailty and MBI, and its association with cortical thickness in a Southeast Asian cohort.Method795 community‐dwelling participants were recruited from the Biomarker and Cognition Study Singapore, all of whom had completed the 34‐item Mild Behavioural Impairment Checklist, Fried Frailty Phenotype (FFP) questionnaire, neuropsychological assessment, and had undergone a T1‐weighted 3T magnetic resonance imaging (MRI). Participants were classified as MBI‐positive based on established cut‐off of ≥5.5, and prefrail based on presence of ≥1 criteria on the FFP. Structural MRI was acquired from T1‐weighted MPRAGE sequence and images pre‐processed using FreeSurfer version 7.2. Observation of participant characteristics, group differences and regression were performed using SPSS, with statistical significance set a p <0.05.ResultMean age of participants were 59.44±9.10 with 61.9% female. 25.7% were prefrail, while 5.9% had prefrailty with MBI. Significant differences in white matter hyperintensity volume and neurofilament‐light mean concentration was observed between the groups. The right hemisphere presented significant differences in cortical thickness were observed in the insula, transverse temporal, temporal, supramarginal, superior temporal, pars orbitalis, parahippocampal and entorhinal regions. While the left hemisphere presented significant differences in the cortical thickness of the insula, temporal pole, parahippocampal and entorhinal regions. Prefrailty without MBI were significantly associated with reduced cortical thickness in the right pars orbitalis, right parahippocampal and left parahippocampal. While significant associations were observed between decreased cortical thickness in the right insula, right temporal, left lateral orbitofrontal and left entorhinal with the co‐occurrence of prefrailty and MBI. All associations were adjusted for age, gender, education years, intracranial volume, and global cognition scores.ConclusionFindings provide an overview of structural correlates associated to presence of prefrailty with and without MBI. “Behavioral frailty” was associated with cortical thinning in the right insula, right temporal lobe, left lateral orbitofrontal cortex, and left entorhinal cortex, which are engaged in various cognitive and emotional functions in the brain.

Emotion regulation emerges during childhood and engages prefrontal brain systems. While most developmental studies focus on the neural underpinnings of negative emotion regulation, less is known about the neuroanatomical correlates of positive emotion regulation. In adults, prefrontal areas in the left hemisphere are critical for positive emotion regulation, but whether this association is present in children is unknown. We investigated whether smaller gray matter volume in left prefrontal regions related to worse positive emotion regulation in children with and without dyslexia. Because dyslexia is a neurodevelopmental disorder of reading in which there may be greater variability in left prefrontal structures, it offers a unique window into the neural basis of positive emotion regulation. Sixty-nine children (ages 7-13) were asked to hide their feelings while watching film clips that elicited either amusement or disgust, and evaluate their emotion regulation performance. Parents reported on children's everyday emotion regulation. Across the sample, children with smaller volumes in left prefrontal regions (i.e., lateral orbitofrontal cortex and dorsolateral prefrontal cortex) had greater facial behavior (i.e., suggesting worse positive emotion regulation) yet more positive self-reported emotion regulation success during the amusement trial (i.e., suggesting more favorable self-evaluation). These regions did not relate to disgust regulation, however. Children with more positive views of their emotion regulation success also had better everyday parent-reported emotion regulation. Results suggest that positive emotion regulation in childhood relies on left prefrontal regions and a more optimistic view of one's emotion regulation abilities, regardless of one's actual emotional behavior, may confer real-world advantages.

Hippocampal-prefrontal functional magnetic resonance imaging signature of suicidal ideation in major depressive disorder.

BackgroundAlzheimer’s disease is characterized by accumulation of amyloid‐β (Aβ) plaques and tau tangles. Aβ deposition typically begins in neocortical regions years before onset of cognitive decline, while tau pathology spreads systematically through select brain regions, typically described as Braak stages (I‐VI). The impact of regional Aβ on tau propagation remains a key research focus.MethodWe examined the associations between regional Aβ and tau burden measured by positron emission tomography (PET) in 192 participants without dementia (14 with mild cognitive impairment [MCI]) in the BIOCARD cohort, of whom 52 (27%) were Aβ positive. Amyloid status was assessed using standardized uptake value ratios (SUVR) obtained from the medial orbitofrontal cortex (OFC), lateral OFC, precuneus, posterior cingulate, anterior cingulate, parietal, temporal, and superior frontal regions using 11C‐PIB PET. Tau burden was quantified using 18F‐MK6240 PET across 29 brain regions, assigned to each of the Braak stages. Associations were examined with stepwise and hierarchical regressions, covarying for age, sex, education, and ApoE4 status.ResultIn stepwise regression analyses for Braak stages (I‐II), amyloid in the medial OFC emerged as significantly associated with tau burden (β = 1.45, t = 4.75, p <.001 for Braak‐I; β = 0.80, t = 3.58, p <.001 for Braak‐II), while in later Braak stages, amyloid in the precuneus emerged as significantly associated with tau burden (β = 0.57, t = 9.59, p <.001for Braak‐III; β = 1.54, t = 3.76, p <.001 for Braak‐IV; β = 0.39, t = 5.90, p <.001 for Braak‐V; and β = 0.17, t = 2.30, p <.05 for Braak‐VI). Subsequent hierarchical regressions showed that including other Aβ regions did not significantly alter the proportion of variance explained for any Braak stage (Figure 1).ConclusionAmyloid‐tau interactions show regional specificity with medial OFC amyloid burden showing a strong association with early tau pathology accumulation while amyloid in the precuneus is selectively associated with tau in later stages. These findings suggest that localized measures of amyloid burden may enhance early detection and show utility in understanding amyloid‐tau dynamics.

BackgroundAutomated natural language processing (NLP) of connected speech is a potential biomarker for incipient Alzheimer’s disease (AD). We previously demonstrated that NLP analysis of autobiographical narratives provides the highest specificity for distinguishing prodromal AD from amyloid‐negative healthy older adults. Here we determine the underlying neuroanatomical basis.MethodWe analyzed automatically transcribed autobiographical interviews from 118 Flemish‐speaking individuals —64 amyloid‐PET–negative healthy controls and 54 biomarker‐proven prodromal AD patients—covering five life periods (childhood, adolescence, early adulthood, late adulthood, past year). A transformer model generated 768‐dimensional embeddings per interview period. We also extracted cortical thicknesses of 68 Desikan–Killiany (34 per hemisphere) and intracranial‐volume‐adjusted left and right hippocampal volumes from T1‐weighted MRIs using FreeSurfer. Representational similarity analysis (RSA) was used to determine Spearman correlations between subject‐wise dissimilarity matrices based on speech embeddings and on brain morphometry controlling for age, sex and education through partial correlation. Significance was evaluated by permutation testing with Bonferroni correction. Principal‐component analysis (PCA) on cortical thickness identified regions driving inter‐subject variance.ResultIn healthy amyloid‐negative older adults, between‐subject similarity of embeddings from childhood, adolescence and early‐adulthood narratives significantly correlated with the between‐subject similarity in brain morphometry (Spearman ρ = 0.300, 0.207, 0.174; p =0.00026, 0.012, 0.044, resp.). This was mainly driven by the correlation between cortical thickness and embeddings from narrative (Spearman ρ = 0.300, p =0.013). The second PCA component (encompassing mostly bilateral pars orbitalis, lateral orbitofrontal, insular and inferior temporal cortices and the right middle temporal cortex) significantly correlated with the speech embeddings. Among these regions.ConclusionIn cognitively healthy, amyloid‐negative older adults, the semantic structure of autobiographical memory partly relates to orbitofrontal, inferior frontal and lateral temporal cortical thickness patterns, with a temporal gradient. This coupling is lost in prodromal AD, likely due to neurodegeneration of lateral temporal regions implicated in autobiographical memory.

BackgroundReduced cerebrospinal fluid (CSF) clearance is a suggested pathological feature of Alzheimer's disease (AD). There is increasing evidence from non‐human studies that the nasal mucosa may serve as a CSF drainage site, particularly through the cribriform plate into the nose. We explored this pathway using dynamic PET with [1‐11C]‐Butanol, a radiotracer with high permeability and minimal brain binding, to examine the relationship between egress from the brain and the nasal turbinates, particularly in the context of amyloid pathology.MethodsCognitively normal subjects (n = 24; 65+ years) underwent 60 minutes of dynamic PET [1‐11C]Butanol imaging. The cohort consisted of 8 amyloid PET Aβ+ and 16 amyloid PET Aβ‐ participants. Regions of interest (ROI) included the lateral orbitofrontal cortex (LOF), cribriform plate, and the superior, middle and inferior nasal turbinates. Time‐activity curves were analyzed to model tracer influx, egress, and area under the curve (AUC) to assess drainage kinetics.ResultsSubstantial positive correlations were observed between tracer kinetics in the LOF and turbinates (Spearman correlation r = 0.658, p < 0.001), indicating a functional connection between brain and nasal clearance pathways. In subjects with amyloid positivity, tracer input into and egress from the nasal turbinates were significantly reduced, as indicated by time‐activity curves (TACs) from [1‐11C]‐Butanol administration. More specifically, there was a significant main effect of Aβ subgroup (F(1,22) = 4.641, p = 0.0424) on egress from the LOF, as well as input into (F(1,22) = 10.24, p = 0.0041) and egress out of (F(1,22) = 11.36, p = 0.0028) the turbinates, by Repeated Measures Two‐Way ANOVA, such that Aβ+ individuals had less influx and slower clearance across time.ConclusionThe findings suggest that the nasal pathway may serve as a viable route for CSF drainage in humans, with brain amyloid deposition impairing the drainage efficiency. These results provide novel insights into the relationship between brain amyloid pathology and the nasal clearance mechanism, warranting further investigation into the role of peripheral neurovascular pathways as potential biomarkers for AD. Understanding these mechanisms could pave the way for developing innovative interventions aimed at enhancing drainage pathways and mitigating the impact of amyloid burden on neurodegenerative processes.

BackgroundAlterations in the gut microbiota can influence the onset and progression of Alzheimer's disease through the gut‐brain axis. Dysbiosis may trigger inflammation and immune dysfunction, contributing to key Alzheimer’s disease pathologies. Recent studies suggest that probiotics may help delay cognitive decline and reduce inflammation.MethodIn our previous study, we selected KLP301, a multi‐strain probiotic culture, based on its antioxidant activity, anti‐inflammatory effects, and intestinal colonization ability. In this human study, 20 participants were assigned to the experimental group and received KLP301 for 52 weeks, while another 20 participants in the control group received maltodextrin for the same period. Brain structural images were obtained using MRI at baseline and after 52 weeks of administration. Changes in brain structure between the two time points were compared and analyzed between the control and experimental groups.ResultThe group administered KLP301 showed a smaller reduction in cortical thickness change in the left isthmus of the cingulate gyrus and the right cuneus compared to the control group. The decrease in subcortical volume change in the right caudate was also less pronounced in the KLP301 group. Furthermore, the KLP301 group exhibited a significantly attenuated reduction in cortical surface area change in the left lateral orbitofrontal cortex, right rostral middle frontal gyrus, left parahippocampal gyrus, and right parahippocampal gyrus compared to the control group.ConclusionKLP301 multi‐strain probiotic culture may suppress brain atrophy in subjects with MCI, highlighting its potential as a health functional food for the prevention and management of Alzheimer's disease.

A major challenge for adaptive agents is achieving behavioral flexibility without compromising stability-particularly in goal-directed learning within uncertain environments. Agents must adjust as goals shift while maintaining resilience against noisy signals, necessitating the delicate tradeoff: balancing flexibility for goal pursuit with stability for preventing erratic behavior. To investigate how the brain navigates this dilemma, we combined model simulations with behavioral and fMRI data collected during a goal-directed learning task under varying levels of uncertainty. Our simulations revealed that model-free learning struggles with the flexibility-stability trade-off, whereas model-based learning allows for flexible goal pursuit with varying degrees of stability. Interestingly, human participants displayed both stable and flexible goal-directed behavior. The fMRI data uncovered the underlying mechanism: goals and uncertainty are represented as factorized embeddings in the lateral prefrontal and orbitofrontal cortex. Notably, the neural separability of goals and their resilience to uncertainty in these regions correlated with participants' behavioral flexibility and stability.

A central challenge in psychiatry is the need for improved diagnostic accuracy and treatment efficacy. Recent dimensional frameworks like the Research Domain Criteria (RDoC) initiative address this by promoting a transdiagnostic approach to identify shared neural mechanisms across psychiatric disorders. Here, we conducted a transdiagnostic meta-analysis of resting-state fMRI studies that employed amplitude-based measures of spontaneous brain activity-the amplitude of low-frequency fluctuations/fractional ALFF (ALFF/fALFF) and regional homogeneity (ReHo). Our results revealed that patients, compared to healthy controls, exhibited significantly elevated ALFF/fALFF in the lateral orbitofrontal cortex, anterior insula, and caudate, as well as increased ReHo in the ventrolateral prefrontal cortex but reduced ReHo in the middle occipital gyrus. These regions were then subjected to resting-state functional connectivity and functional decoding analyses based on a dataset of 110 healthy participants, allowing for a data-driven inference on psychophysiological functions. These regions and their networks are mapped onto systems implicated in cognitive control, social functioning, emotional processing, and sensory perception. Collectively, our findings delineate a suite of transdiagnostic neural aberrations reflected in resting-state activity, thereby advancing the neurobiological validation of the dimensional frameworks and highlighting potential common targets for therapeutic intervention.

BackgroundCognitive dysfunction is one of the most debilitating non-motor symptoms of Parkinson's disease (PD). This study aimed to explore the interplay between altered neurotransmitter activities, including dopamine and acetylcholine, and brain metabolism in cognitive decline in PD.MethodsWe enrolled 172 PD patients (mean ± SD age 69.8 ± 8.6 years; 93 females) who underwent brain magnetic resonance imaging, N-(3-[18F]fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (18F-FP-CIT) positron emission tomography (PET), 18F-fluorodeoxyglucose (FDG) PET, and neuropsychological testing. General linear models and mediation analyses were used to investigate the association between striatal dopamine transporter (DAT) availability or basal forebrain (BF) volume, brain metabolism, and domain-specific cognitive scores.ResultsA significant relationship between caudate dopamine depletion and posterior BF atrophy was found in PD patients. Caudate and putaminal dopamine depletion were associated with altered brain metabolism in regions where PD patients showed decreased metabolism compared with healthy controls, whereas atrophy in the posterior BF was associated with hypometabolism in the lateral prefrontal, orbitofrontal, inferior parietal, and lateral temporal cortices as well as in the precuneus, with a significant interaction between caudate DAT availability and posterior BF volume. Caudate dopamine depletion was associated with visuospatial, memory, and executive dysfunction, whereas posterior BF atrophy was additionally associated with attention. Mediation analyses revealed that visuospatial dysfunction was associated with caudate dopamine depletion or posterior BF atrophy via altered brain metabolism, while executive dysfunction was linked to both directly and through metabolism changes.ConclusionsCaudate dopaminergic and posterior BF cholinergic deficits are interrelated and affect cognition in a domain-specific manner, either directly or through the mediation of altered brain metabolism.

Altered cortical alpha modulations and connectivity in complex regional pain syndrome.

Distinct contributions of anterior and posterior orbitofrontal cortex to outcome-guided behavior.

Assessing orbitofrontal cortex volume as a predictor of subjective response to alcohol during early adolescence.

Background/Objectives: Sensory-specific satiety (SSS) refers to the decrease in pleasantness of a food after repeated consumption, while other foods remain appealing. Despite its significance in hedonic food perception, the underlying mechanisms of SSS remain poorly understood. This study aimed to investigate the neurobiological basis of SSS and its relationship with body weight and hedonic food perception. Methods: Twenty-three healthy individuals with varying body weights underwent functional magnetic resonance imaging during a novel gustatory stimulation procedure. SSS was induced by repeated exposure to glucose, during which the hedonic perception of a neutral stimulus increased. Results: We found that SSS was associated with a network of brain regions related to reward and taste processing, including the lateral orbitofrontal cortex. Increased activation in the medial prefrontal cortex was related to both the expectation and receipt of a neutral stimulus with increased hedonic value during SSS. Finally, higher body weight was related to decreased activation in the medial prefrontal cortex, whereas an increased tendency for food craving was associated with increased activation of the lateral orbitofrontal cortex during SSS. Conclusions: Our results extend previous findings of an orbitofrontal-cortex-mediated shift in hedonic perception of food during SSS and show that the medial prefrontal cortex plays a crucial role in reward value modulation during SSS. Furthermore, our results indicate that increased BMI and trait food craving are associated with altered reward processing during SSS. Taken together, our results provide new insights into the neural mechanisms underlying changes in hedonic food perception during SSS.

Converging evidence suggests that orbitofrontal cortex (OFC) subregions subserve distinct roles in decision-making across a variety of tasks. Cost/benefit decisions can require an organism to choose between options based on information available in the environment (externally guided) and knowledge from experience (internally guided). Studies in humans have implicated both medial and lateral subdivisions of OFC (mOFC, lOFC) in externally and internally guided choice, yet rodent studies have primarily focused on OFC regulation of internally guided decisions. To address this gap, we examined how inactivation of these OFC subregions alters cue-guided, probabilistic decision-making using a "Blackjack" task. Male rats were required to choose between a certain, 1-pellet small reward and larger, 4-pellet reward delivered with varying probability, signaled trail-to-trial with explicit auditory stimuli indicating whether the odds of receiving the larger reward was good (50%) or poor (12.5%). Inactivation of the mOFC or lOFC induced generalized decreases or increases in large/risky choice, respectively, that were associated with opposite effects on loss (but not win) sensitivity and on rats' likelihood of making consecutive choices of the small/certain option. Inactivation of the adjacent anterior agranular insular cortex had no effect. Inactivation of either OFC subregion also disrupted cue-guided reward magnitude discrimination, where tones signal which action delivered a deterministic larger reward, but did not affect a simpler conditional discrimination involving choice between rewarded and unrewarded actions. Together these data highlight complementary yet heterogeneous roles for different OFC regions in using discriminative stimuli to guide action toward higher-value targets.

SUMMARYThe lateral orbitofrontal cortex (OFC) is critical for flexibly adjusting choices when outcome values change. Anterior and posterior parts of the human lateral OFC differ in cytoarchitecture and connectivity, but whether these subregions make differential contributions to outcome-guided (i.e., goal-directed) behavior remains unclear. Outcome-guided behavior requires (a) representations of stimulus–outcome associations and (b) inferring the current value of options when making decisions. Here, we test whether these two functions are differentially supported by the posterior (pOFC) and anterior (aOFC) parts of the lateral OFC, using transcranial magnetic stimulation (TMS) to selectively disrupt activity in functional networks centered on the pOFC and aOFC during a two-day outcome devaluation task. Participants (n = 48) received pOFC or aOFC network-targeted TMS either on day 1 before learning associations between visual stimuli and sweet or savory food odors, or on day 2 before a meal that selectively devalued one of these outcomes, followed by a choice test. TMS targeting pOFC, but not aOFC, before the meal on day 2 disrupted outcome-guided behavior, as measured by choices of stimuli predicting non-sated rewards in the post-meal choice test. In contrast, TMS targeting aOFC, but not pOFC, before learning on day 1 similarly impaired behavior in the post-meal choice test on day 2. These findings demonstrate that anterior and posterior parts of the lateral OFC make distinct contributions to outcome-guided behavior by supporting learning of stimulus–outcome associations and inferring the current value of options, respectively.

BackgroundAlthough previous research has identified functional abnormalities in visual pathways and gray matter areas linked to visual processing in patients with rhegmatogenous retinal detachment (RRD), the precise nature and extent of cortical functional and structural disruptions in these individuals remain insufficiently explored. This study aimed to characterize cortical changes in RRD and investigate their utility as neuroimaging markers.MethodsThis study used surface-based independent component analysis (ICA) and morphological measurement techniques to investigate cortical functional and structural changes in RRD patients. Subsequently, it applied support vector machine (SVM) and SHapley Additive exPlanations (SHAP) methods to classify RRD patients and healthy controls (HCs), identifying key brain regions that contribute most to the prediction model.ResultsIn terms of cortical function, the RRD patients showed significant increases in functional connectivity (FC) in the visual, cognitive, auditory, and motor networks (voxel P<0.001, cluster P<0.05), as well as a significant enhancement in functional network connectivity (FNC) between the visual network (VN) and sensorimotor network (SMN) (P<0.01) compared to the HCs. The RRD patients exhibited significant cortical thinning in the left hemisphere lateral occipital cortex (lh_lateraloccipital), right hemisphere pericalcarine cortex (rh_pericalcarine), and right hemisphere lateral orbitofrontal cortex (rh_lateralorbitofrontal) regions (voxel P<0.01, cluster P<0.05) in the cortical structure. Notably, the FC value in the VN1 region showed the best classification performance in both the SVM and SHAP analyses.ConclusionsThis study found pronounced functional and structural abnormalities in the cortex of RRD patients, potentially linked to cognitive and visual dysfunction. Notably, FC alterations in the VN1 region may act as a robust neuroimaging indicator capable of distinguishing individuals with RRD from HCs. Our results offer novel insights into the underlying neuropathological processes of RRD, and underscore the value of early neuroimaging markers for timely diagnosis and clinical intervention.