Pub Date : 2026-03-01Epub Date: 2025-11-12DOI: 10.1016/j.bpsc.2025.10.019
Francisco Reyes-Madrigal , Pablo León-Ortiz , Kenneth Wengler , Helena P. Bachmann , Nicholas M. Singletary , María Ortuño , Xiangling Mao , Luis F. Rivera-Chávez , Melanie Malacara , Dikoma C. Shungu , Guillermo Horga , Camilo de la Fuente-Sandoval
Background
In vivo neuroimaging studies documenting the relationship between dopamine and GABA (gamma-aminobutyric acid) or glutamate in schizophrenia are scarce and have often involved patients in chronic phases of the disorder, which complicates distinguishing medication effects from illness progression.
Methods
We examined the contrast ratio of neuromelanin-sensitive magnetic resonance imaging (NM-MRI), a proxy for dopaminergic function, in the substantia nigra (SN) and ventral tegmental area (VTA) and its association with striatal and medial prefrontal GABA and the sum of glutamate and glutamine (Glx), measured by proton magnetic resonance spectroscopy, in 23 never-medicated patients with first-episode psychosis (FEP) and 22 age- and sex-matched healthy control participants. All participants were recruited at the Instituto Nacional de Neurología y Neurocirugía in Mexico City. All imaging studies were performed on a 3T MRI scanner.
Results
The SN-VTA NM-MRI contrast showed a positive correlation with Glx in the striatum; striatal GABA levels were not associated with the NM-MRI contrast. In the medial prefrontal cortex, we failed to identify correlations between Glx or GABA and the NM-MRI contrast.
Conclusions
The current study provides preliminary evidence of the association between striatal glutamate and a novel validated proxy for dopaminergic function in antipsychotic-naïve individuals with FEP. Future research, using a longitudinal design, on these combined MRI biomarkers as predictors of treatment response is warranted.
背景：体内神经影像学研究很少记录多巴胺和γ-氨基丁酸（GABA）或谷氨酸在精神分裂症中的关系，而且经常涉及精神分裂症慢性期的患者，这使得区分药物效果和疾病进展变得复杂。方法：我们检测了23例首发精神病（FEP）患者和22例年龄和性别匹配的健康对照者的黑质和腹侧被盖区（SN-VTA）的神经黑色素敏感磁共振成像（NM-MRI）的对比比率及其与纹状体和内侧前额叶GABA的关联，以及质子磁共振波谱测量的谷氨酸和谷氨酰胺（Glx）的总量。所有参与者都是在墨西哥城国立研究所Neurología y Neurocirugía招募的。所有影像学研究均在3T MRI扫描仪上进行。结果：在被试中，黑质SN-VTA NM-MRI对比显示纹状体Glx与黑质正相关；纹状体GABA水平与NM-MRI对比无关。在内侧前额叶皮层，我们无法通过NM-MRI对比确定Glx或GABA之间的相关性。结论：目前的研究提供了纹状体谷氨酸与antipsychotic-naïve FEP个体多巴胺能功能的新验证代理之间关联的初步证据。未来的研究，使用纵向设计，这些联合MRI生物标志物作为治疗反应的预测因素是有必要的。
{"title":"The Relationship Between Neuromelanin, Glutamate, and GABA in First-Episode Psychosis: A Multimodal Magnetic Resonance Imaging Study","authors":"Francisco Reyes-Madrigal , Pablo León-Ortiz , Kenneth Wengler , Helena P. Bachmann , Nicholas M. Singletary , María Ortuño , Xiangling Mao , Luis F. Rivera-Chávez , Melanie Malacara , Dikoma C. Shungu , Guillermo Horga , Camilo de la Fuente-Sandoval","doi":"10.1016/j.bpsc.2025.10.019","DOIUrl":"10.1016/j.bpsc.2025.10.019","url":null,"abstract":"<div><h3>Background</h3><div>In vivo neuroimaging studies documenting the relationship between dopamine and GABA (gamma-aminobutyric acid) or glutamate in schizophrenia are scarce and have often involved patients in chronic phases of the disorder, which complicates distinguishing medication effects from illness progression.</div></div><div><h3>Methods</h3><div>We examined the contrast ratio of neuromelanin-sensitive magnetic resonance imaging (NM-MRI), a proxy for dopaminergic function, in the substantia nigra (SN) and ventral tegmental area (VTA) and its association with striatal and medial prefrontal GABA and the sum of glutamate and glutamine (Glx), measured by proton magnetic resonance spectroscopy, in 23 never-medicated patients with first-episode psychosis (FEP) and 22 age- and sex-matched healthy control participants. All participants were recruited at the Instituto Nacional de Neurología y Neurocirugía in Mexico City. All imaging studies were performed on a 3T MRI scanner.</div></div><div><h3>Results</h3><div>The SN-VTA NM-MRI contrast showed a positive correlation with Glx in the striatum; striatal GABA levels were not associated with the NM-MRI contrast. In the medial prefrontal cortex, we failed to identify correlations between Glx or GABA and the NM-MRI contrast.</div></div><div><h3>Conclusions</h3><div>The current study provides preliminary evidence of the association between striatal glutamate and a novel validated proxy for dopaminergic function in antipsychotic-naïve individuals with FEP. Future research, using a longitudinal design, on these combined MRI biomarkers as predictors of treatment response is warranted.</div></div>","PeriodicalId":54231,"journal":{"name":"Biological Psychiatry-Cognitive Neuroscience and Neuroimaging","volume":"11 3","pages":"Pages 310-319"},"PeriodicalIF":4.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145524864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-03-05DOI: 10.1016/S2451-9022(26)00035-2
{"title":"Guide for Authors","authors":"","doi":"10.1016/S2451-9022(26)00035-2","DOIUrl":"10.1016/S2451-9022(26)00035-2","url":null,"abstract":"","PeriodicalId":54231,"journal":{"name":"Biological Psychiatry-Cognitive Neuroscience and Neuroimaging","volume":"11 3","pages":"Pages A5-A11"},"PeriodicalIF":4.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147417476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-03-05DOI: 10.1016/j.bpsc.2026.01.003
Dustin Scheinost , Marisa N. Spann
{"title":"Using Fetal, Infant, and Toddler Neuroimaging to Understand Brain Changes After Prenatal Exposure to Opioids","authors":"Dustin Scheinost , Marisa N. Spann","doi":"10.1016/j.bpsc.2026.01.003","DOIUrl":"10.1016/j.bpsc.2026.01.003","url":null,"abstract":"","PeriodicalId":54231,"journal":{"name":"Biological Psychiatry-Cognitive Neuroscience and Neuroimaging","volume":"11 3","pages":"Pages 259-260"},"PeriodicalIF":4.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147373759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-09-20DOI: 10.1016/j.bpsc.2025.09.010
Guangrui Yang , Hao Huang , Jingxuan Wang , Shuxiao Shi, Xuanwei Jiang, Zixuan Zhang, Meng Chen, Nannan Feng, Lan Xu, Xihao Du, Victor W. Zhong
Background
Early-life factors before age 18 years significantly influence depression risk, but their differential contributions and biological mechanisms remain understudied.
Methods
In this prospective UK Biobank study (N = 104,035), an early-life factor score (ELFS) was constructed using elastic net Cox models incorporating 15 early-life factors, including perinatal conditions, childhood adversities, physical development, and social-environmental exposures. Cox models were used to assess associations of both individual factors and the ELFS with depression. We conducted a genome-wide association study (GWAS) to identify genetic variants, Mendelian randomization to assess causality, and linear regression to examine associations with brain structures and blood markers. Structural equation modeling (SEM) was used to explore biological pathways linking early-life factors to depression.
Results
During the follow-up period (median = 14.6 years), 4168 participants developed depression. Each 1-point increase in the ELFS was associated with a 49% higher depression risk. Individuals with a high ELFS showed a 2.8-fold higher risk than individuals with a low ELFS. GWAS identified 46 significant single nucleotide polymorphisms associated with the ELFS, mapped to 17 genes including FOXP2, with enrichment in metabolic pathways. Mendelian randomization analysis supported the causal relationship between the ELFS and depression. A higher ELFS was associated with smaller volumes particularly in brain regions linked to emotion regulation and with altered inflammation and lipid metabolism. SEM integrating multilevel evidence revealed biological pathways linking early-life factors, brain structure, immunometabolic markers, and depression.
Conclusions
Early-life factors collectively influenced depression risk through an integrated score capturing differential factor contributions. Multiple biological pathways involving brain structure and immunometabolic markers were identified, providing insights into potential mechanisms linking early-life factors to depression.
{"title":"Integrated Early-Life Factors and Depression: A Multilevel Investigation of Brain Structural, Immunometabolic, and Genetic Mechanisms","authors":"Guangrui Yang , Hao Huang , Jingxuan Wang , Shuxiao Shi, Xuanwei Jiang, Zixuan Zhang, Meng Chen, Nannan Feng, Lan Xu, Xihao Du, Victor W. Zhong","doi":"10.1016/j.bpsc.2025.09.010","DOIUrl":"10.1016/j.bpsc.2025.09.010","url":null,"abstract":"<div><h3>Background</h3><div>Early-life factors before age 18 years significantly influence depression risk, but their differential contributions and biological mechanisms remain understudied.</div></div><div><h3>Methods</h3><div>In this prospective UK Biobank study (<em>N</em> = 104,035), an early-life factor score (ELFS) was constructed using elastic net Cox models incorporating 15 early-life factors, including perinatal conditions, childhood adversities, physical development, and social-environmental exposures. Cox models were used to assess associations of both individual factors and the ELFS with depression. We conducted a genome-wide association study (GWAS) to identify genetic variants, Mendelian randomization to assess causality, and linear regression to examine associations with brain structures and blood markers. Structural equation modeling (SEM) was used to explore biological pathways linking early-life factors to depression.</div></div><div><h3>Results</h3><div>During the follow-up period (median = 14.6 years), 4168 participants developed depression. Each 1-point increase in the ELFS was associated with a 49% higher depression risk. Individuals with a high ELFS showed a 2.8-fold higher risk than individuals with a low ELFS. GWAS identified 46 significant single nucleotide polymorphisms associated with the ELFS, mapped to 17 genes including <em>FOXP2</em>, with enrichment in metabolic pathways. Mendelian randomization analysis supported the causal relationship between the ELFS and depression. A higher ELFS was associated with smaller volumes particularly in brain regions linked to emotion regulation and with altered inflammation and lipid metabolism. SEM integrating multilevel evidence revealed biological pathways linking early-life factors, brain structure, immunometabolic markers, and depression.</div></div><div><h3>Conclusions</h3><div>Early-life factors collectively influenced depression risk through an integrated score capturing differential factor contributions. Multiple biological pathways involving brain structure and immunometabolic markers were identified, providing insights into potential mechanisms linking early-life factors to depression.</div></div>","PeriodicalId":54231,"journal":{"name":"Biological Psychiatry-Cognitive Neuroscience and Neuroimaging","volume":"11 3","pages":"Pages 290-299"},"PeriodicalIF":4.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145126378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-03-05DOI: 10.1016/j.bpsc.2025.12.008
Claire O’Callaghan
{"title":"Training a Lens on the Locus Coeruleus–Noradrenergic System in Late-Life Depression","authors":"Claire O’Callaghan","doi":"10.1016/j.bpsc.2025.12.008","DOIUrl":"10.1016/j.bpsc.2025.12.008","url":null,"abstract":"","PeriodicalId":54231,"journal":{"name":"Biological Psychiatry-Cognitive Neuroscience and Neuroimaging","volume":"11 3","pages":"Pages 263-264"},"PeriodicalIF":4.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147373732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-05-22DOI: 10.1016/j.bpsc.2025.05.009
Baktash Babadi , Daphne J. Holt , Roger B.H. Tootell
Background
A key challenge in understanding the neurobehavioral mechanisms of psychotic disorders (PDs) is identifying the level and interactions of the affected brain regions. The early visual system, with its hierarchical structure, offers a model for studying such mechanisms. Specifically, variations in visual contrast are detected as early as in the retina, whereas binocular depth perception emerges at a higher level, in the visual cortex. Comparing these processes within individuals can provide insights into the mechanisms and progression of perceptual deficits in PDs.
Methods
Psychophysical sensitivity to stimulus contrast and binocular disparity were assessed in 53 participants with PDs and 58 demographically matched healthy control participants (HCs). Across the 2 tasks, the physical features of the stimuli were matched except for the primary variable of interest. Psychometric functions were fitted to the performance of each participant, and the normalized area under the psychometric curves quantified the average performance across stimulus strengths.
Results
The PD group showed significantly impaired performance in both visual contrast detection (p < .007) and binocular depth perception (p < .021) compared with the HC group. In the PD but not the HC group, the performance levels across the 2 tasks were correlated with each other. A direct comparison revealed a more pronounced deficit in depth perception than in contrast detection in the PD group. Differences in psychometric parameters (i.e., threshold, flatness, and lapse rate) revealed additional cognitive and attentional dysfunctions in the PD group.
Conclusions
These findings provide evidence for a progressive accumulation of deficits through the visual hierarchy in psychosis.
{"title":"Visual Deficits in Contrast and Depth Perception in Psychotic Disorders: Implications for a Neural Hierarchy","authors":"Baktash Babadi , Daphne J. Holt , Roger B.H. Tootell","doi":"10.1016/j.bpsc.2025.05.009","DOIUrl":"10.1016/j.bpsc.2025.05.009","url":null,"abstract":"<div><h3>Background</h3><div>A key challenge in understanding the neurobehavioral mechanisms of psychotic disorders (PDs) is identifying the level and interactions of the affected brain regions. The early visual system, with its hierarchical structure, offers a model for studying such mechanisms. Specifically, variations in visual contrast are detected as early as in the retina, whereas binocular depth perception emerges at a higher level, in the visual cortex. Comparing these processes within individuals can provide insights into the mechanisms and progression of perceptual deficits in PDs.</div></div><div><h3>Methods</h3><div>Psychophysical sensitivity to stimulus contrast and binocular disparity were assessed in 53 participants with PDs and 58 demographically matched healthy control participants (HCs). Across the 2 tasks, the physical features of the stimuli were matched except for the primary variable of interest. Psychometric functions were fitted to the performance of each participant, and the normalized area under the psychometric curves quantified the average performance across stimulus strengths.</div></div><div><h3>Results</h3><div>The PD group showed significantly impaired performance in both visual contrast detection (<em>p</em> < .007) and binocular depth perception (<em>p</em> < .021) compared with the HC group. In the PD but not the HC group, the performance levels across the 2 tasks were correlated with each other. A direct comparison revealed a more pronounced deficit in depth perception than in contrast detection in the PD group. Differences in psychometric parameters (i.e., threshold, flatness, and lapse rate) revealed additional cognitive and attentional dysfunctions in the PD group.</div></div><div><h3>Conclusions</h3><div>These findings provide evidence for a progressive accumulation of deficits through the visual hierarchy in psychosis.</div></div>","PeriodicalId":54231,"journal":{"name":"Biological Psychiatry-Cognitive Neuroscience and Neuroimaging","volume":"11 3","pages":"Pages 320-328"},"PeriodicalIF":4.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144144871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-09-20DOI: 10.1016/j.bpsc.2025.09.011
Josepheen De Asis-Cruz , Jung-Hoon Kim , Kushal Kapse , Yao Wu , Stephanie L. Merhar , Carla M. Bann , Jamie E. Newman , Nicole Mack , Sara B. DeMauro , Namasivayam Ambalavanan , Scott A. Lorch , Deanne Wilson-Costello , Brenda B. Poindexter , Myriam Peralta-Carcelen , Jonathan M. Davis , Catherine Limperopoulos
Background
The neural bases of adverse neurodevelopmental outcomes in antenatal opioid exposure are poorly understood. Very limited in vivo human newborn imaging studies have reported disrupted functional connectivity (FC) in limbic and reward-related brain regions, but these studies used small samples and lacked matched controls. Our objective was to compare brain FC in antenatal opioid-exposed and unexposed newborns to study the impact of opioid exposure on early brain development.
Methods
Resting-state functional magnetic resonance imaging (rs-fMRI) data were collected using 3T MRI at 4 centers as part of the prospective, observational OBOE (Outcomes of Babies with Opioid Exposure) study. We used seed-based correlation analysis to estimate the FC of 93 brain regions. Voxelwise linear regression with covariate adjustment and correction for multiple comparisons was used to determine significant between-group differences. FC differences based on opioid type were also investigated.
Results
We evaluated 248 rs-fMRI scans (158 opioid-exposed/90 unexposed). Canonical sensorimotor and higher-order resting-state network maps in exposed newborns (mean ± SD postmenstrual age at MRI = 42.80 ± 2.2 weeks, 53 male) were comparable to control newborns (42.82 ± 1.9 weeks, 88 male; Dice indices > 0.9 across 7 networks). Exposed newborns showed decreased FC from seeds in bilateral pre- and left postcentral gyri, bilateral orbitofrontal regions, and cerebellum and increased FC from seeds in peri-opercular, subcortical (e.g., amygdala, hippocampus, and putamen), and mid-to-superior occipital regions (familywise error rate, α < 0.05). Connectivity from 23 of 93 (24.7%) seeds differed between groups. Methadone- and buprenorphine-exposed newborns showed disrupted regional FC compared with control newborns, but there were no FC differences between them.
Conclusions
In a large sample of antenatally opioid-exposed newborns, we found altered organization of brain functional networks, particularly in integrative sensorimotor-affective circuits.
{"title":"Disrupted Brain Connectivity in Newborns Following Antenatal Opioid Exposure","authors":"Josepheen De Asis-Cruz , Jung-Hoon Kim , Kushal Kapse , Yao Wu , Stephanie L. Merhar , Carla M. Bann , Jamie E. Newman , Nicole Mack , Sara B. DeMauro , Namasivayam Ambalavanan , Scott A. Lorch , Deanne Wilson-Costello , Brenda B. Poindexter , Myriam Peralta-Carcelen , Jonathan M. Davis , Catherine Limperopoulos","doi":"10.1016/j.bpsc.2025.09.011","DOIUrl":"10.1016/j.bpsc.2025.09.011","url":null,"abstract":"<div><h3>Background</h3><div>The neural bases of adverse neurodevelopmental outcomes in antenatal opioid exposure are poorly understood. Very limited in vivo human newborn imaging studies have reported disrupted functional connectivity (FC) in limbic and reward-related brain regions, but these studies used small samples and lacked matched controls. Our objective was to compare brain FC in antenatal opioid-exposed and unexposed newborns to study the impact of opioid exposure on early brain development.</div></div><div><h3>Methods</h3><div>Resting-state functional magnetic resonance imaging (rs-fMRI) data were collected using 3T MRI at 4 centers as part of the prospective, observational OBOE (Outcomes of Babies with Opioid Exposure) study. We used seed-based correlation analysis to estimate the FC of 93 brain regions. Voxelwise linear regression with covariate adjustment and correction for multiple comparisons was used to determine significant between-group differences. FC differences based on opioid type were also investigated.</div></div><div><h3>Results</h3><div>We evaluated 248 rs-fMRI scans (158 opioid-exposed/90 unexposed). Canonical sensorimotor and higher-order resting-state network maps in exposed newborns (mean ± SD postmenstrual age at MRI = 42.80 ± 2.2 weeks, 53 male) were comparable to control newborns (42.82 ± 1.9 weeks, 88 male; Dice indices > 0.9 across 7 networks). Exposed newborns showed decreased FC from seeds in bilateral pre- and left postcentral gyri, bilateral orbitofrontal regions, and cerebellum and increased FC from seeds in peri-opercular, subcortical (e.g., amygdala, hippocampus, and putamen), and mid-to-superior occipital regions (familywise error rate, α < 0.05). Connectivity from 23 of 93 (24.7%) seeds differed between groups. Methadone- and buprenorphine-exposed newborns showed disrupted regional FC compared with control newborns, but there were no FC differences between them.</div></div><div><h3>Conclusions</h3><div>In a large sample of antenatally opioid-exposed newborns, we found altered organization of brain functional networks, particularly in integrative sensorimotor-affective circuits.</div></div>","PeriodicalId":54231,"journal":{"name":"Biological Psychiatry-Cognitive Neuroscience and Neuroimaging","volume":"11 3","pages":"Pages 265-278"},"PeriodicalIF":4.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145126437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-10-17DOI: 10.1016/j.bpsc.2025.10.005
Sirichat Sookud , Ingrid Martin , Claire M. Gillan , Toby Wise
Background
Diminished use of goal-directed (model-based) decision making is a hallmark of transdiagnostic compulsivity, promoting an overreliance on inflexible and habitual behaviors. However, the origin of this impairment remains unclear. Here, we tested the hypothesis that these impairments arise due to uncertainty within the internal world model that subserves goal-directed decision making.
Methods
We adapted a validated gamified decision-making task to characterize how individuals build an internal model of an environment, pairing these data with computational modeling to uncover the exact mechanisms underpinning behavior and quantify individual differences. Two samples of participants (a discovery sample and a preregistered replication sample, n = 551 and 1322, respectively) performed the task, and we also acquired longitudinal data over 2-week and 3-month periods to assess task reliability and stability of behavior over time.
Results
In the discovery and replication samples, we found that individuals higher in compulsivity and intrusive thought learned more slowly and formed a less certain representation of the task’s structure. This uncertainty mediated the link between compulsive symptoms and use of goal-directed behavior. Behavior in the task was relatively stable over a 3-month (n = 385) and 1-year (n = 326) period and did not predict changes in symptoms.
Conclusions
Our results suggest that reliance on habitual behaviors seen in individuals with high levels of compulsive symptoms result from a tendency to form less certain internal models of the external world. Given the stability of this behavior and its links to symptoms, this may represent a trait-level vulnerability for this symptom dimension.
{"title":"Impaired Goal-Directed Planning in Transdiagnostic Compulsivity Is Explained by Uncertainty About Learned Task Structure","authors":"Sirichat Sookud , Ingrid Martin , Claire M. Gillan , Toby Wise","doi":"10.1016/j.bpsc.2025.10.005","DOIUrl":"10.1016/j.bpsc.2025.10.005","url":null,"abstract":"<div><h3>Background</h3><div>Diminished use of goal-directed (model-based) decision making is a hallmark of transdiagnostic compulsivity, promoting an overreliance on inflexible and habitual behaviors. However, the origin of this impairment remains unclear. Here, we tested the hypothesis that these impairments arise due to uncertainty within the internal world model that subserves goal-directed decision making.</div></div><div><h3>Methods</h3><div>We adapted a validated gamified decision-making task to characterize how individuals build an internal model of an environment, pairing these data with computational modeling to uncover the exact mechanisms underpinning behavior and quantify individual differences. Two samples of participants (a discovery sample and a preregistered replication sample, <em>n</em> = 551 and 1322, respectively) performed the task, and we also acquired longitudinal data over 2-week and 3-month periods to assess task reliability and stability of behavior over time.</div></div><div><h3>Results</h3><div>In the discovery and replication samples, we found that individuals higher in compulsivity and intrusive thought learned more slowly and formed a less certain representation of the task’s structure. This uncertainty mediated the link between compulsive symptoms and use of goal-directed behavior. Behavior in the task was relatively stable over a 3-month (<em>n</em> = 385) and 1-year (<em>n</em> = 326) period and did not predict changes in symptoms.</div></div><div><h3>Conclusions</h3><div>Our results suggest that reliance on habitual behaviors seen in individuals with high levels of compulsive symptoms result from a tendency to form less certain internal models of the external world. Given the stability of this behavior and its links to symptoms, this may represent a trait-level vulnerability for this symptom dimension.</div></div>","PeriodicalId":54231,"journal":{"name":"Biological Psychiatry-Cognitive Neuroscience and Neuroimaging","volume":"11 3","pages":"Pages 357-365"},"PeriodicalIF":4.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-10-17DOI: 10.1016/j.bpsc.2025.10.007
Diana Valdés Cabrera , Navona Calarco , Clifford M. Cassidy , Aristotle Voineskos , Breno S. Diniz , Yuliya S. Nikolova
Background
Late-life depression (LLD) is a risk factor for age-related cognitive decline. Postmortem studies have highlighted pathological changes in the locus coeruleus (LC) and its projections as potential early cognitive vulnerability markers. Here, we used a novel individualized multimodal magnetic resonance imaging (MRI) approach to characterize the cognitive correlates of LC microstructure and connectivity in participants with LLD and age-matched never-depressed (ND) control participants.
Methods
Diffusion-weighted and LC-sensitive MRI were acquired for 52 participants (LLD: n = 26, 19 female, age 67.8 ± 5.48 years; ND: n = 26, 12 female, age 69.8 ± 7.62 years). Using LC-sensitive MRI to localize the LC in each participant’s native space, we computed diffusion metrics (fractional anisotropy [FA] and mean diffusivity [MD]) for the LC and its projections to the hippocampus (Hp), reconstructed with constrained spherical deconvolution tractography. Associations of FA and MD with diagnosis and cognitive performance were evaluated with analyses of covariance and Pearson correlations, respectively, adjusted for demographic/disease covariates and multiple testing (Bonferroni-corrected p < .05).
Results
Higher MD (F1,45 = 10.07, p = .003) was observed in the LC of individuals with LLD relative to ND control participants. Conversely, no group differences emerged in the LC-Hp pathway. In the combined LLD-ND sample, accounting for LLD diagnosis, lower FA in the LC and its hippocampal projections were associated with worse processing speed (LC: word reading r = −0.47; LC–medial temporal lobe [MTL]: word reading r = −0.46, color naming r = −0.49; all ps ≤ .0007) and executive functions (LC-MTL: inhibition r = −0.50, inhibition/switching r = −0.45, number/letter sequencing r = −0.40; all ps ≤ .0033).
Conclusions
Neuronal injury of the LC may be a marker for LLD. Alternatively, the microstructural status of LC-Hp projections may be a biomarker more specific to age-related cognitive deterioration, irrespective of depression diagnosis.
{"title":"Locus Coeruleus Microstructure and Connectivity as Novel Markers of Depression and Cognitive Dysfunction in Older Adults","authors":"Diana Valdés Cabrera , Navona Calarco , Clifford M. Cassidy , Aristotle Voineskos , Breno S. Diniz , Yuliya S. Nikolova","doi":"10.1016/j.bpsc.2025.10.007","DOIUrl":"10.1016/j.bpsc.2025.10.007","url":null,"abstract":"<div><h3>Background</h3><div>Late-life depression (LLD) is a risk factor for age-related cognitive decline. Postmortem studies have highlighted pathological changes in the locus coeruleus (LC) and its projections as potential early cognitive vulnerability markers. Here, we used a novel individualized multimodal magnetic resonance imaging (MRI) approach to characterize the cognitive correlates of LC microstructure and connectivity in participants with LLD and age-matched never-depressed (ND) control participants.</div></div><div><h3>Methods</h3><div>Diffusion-weighted and LC-sensitive MRI were acquired for 52 participants (LLD: <em>n</em> = 26, 19 female, age 67.8 ± 5.48 years; ND: <em>n</em> = 26, 12 female, age 69.8 ± 7.62 years). Using LC-sensitive MRI to localize the LC in each participant’s native space, we computed diffusion metrics (fractional anisotropy [FA] and mean diffusivity [MD]) for the LC and its projections to the hippocampus (Hp), reconstructed with constrained spherical deconvolution tractography. Associations of FA and MD with diagnosis and cognitive performance were evaluated with analyses of covariance and Pearson correlations, respectively, adjusted for demographic/disease covariates and multiple testing (Bonferroni-corrected <em>p</em> < .05).</div></div><div><h3>Results</h3><div>Higher MD (<em>F</em><sub>1,45</sub> = 10.07, <em>p</em> = .003) was observed in the LC of individuals with LLD relative to ND control participants. Conversely, no group differences emerged in the LC-Hp pathway. In the combined LLD-ND sample, accounting for LLD diagnosis, lower FA in the LC and its hippocampal projections were associated with worse processing speed (LC: word reading <em>r</em> = −0.47; LC–medial temporal lobe [MTL]: word reading <em>r</em> = −0.46, color naming <em>r</em> = −0.49; all <em>p</em>s ≤ .0007) and executive functions (LC-MTL: inhibition <em>r</em> = −0.50, inhibition/switching <em>r</em> = −0.45, number/letter sequencing <em>r</em> = −0.40; all <em>p</em>s ≤ .0033).</div></div><div><h3>Conclusions</h3><div>Neuronal injury of the LC may be a marker for LLD. Alternatively, the microstructural status of LC-Hp projections may be a biomarker more specific to age-related cognitive deterioration, irrespective of depression diagnosis.</div></div>","PeriodicalId":54231,"journal":{"name":"Biological Psychiatry-Cognitive Neuroscience and Neuroimaging","volume":"11 3","pages":"Pages 366-377"},"PeriodicalIF":4.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145330695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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