Pub Date : 2025-04-23DOI: 10.1523/jneurosci.0164-25.2025
Maria Luisa Valle
{"title":"A Novel APP Knock-In Mouse Model to Study the Protective Effects of the Icelandic Mutation In Vivo.","authors":"Maria Luisa Valle","doi":"10.1523/jneurosci.0164-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0164-25.2025","url":null,"abstract":"","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"7 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872100","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 : 2025-04-23DOI: 10.1523/jneurosci.2302-24.2025
Jae-Chang Kim,Lydia Hellrung,Stephan Nebe,Philippe N Tobler
The insula processes errors in the prediction of risky, motivationally relevant outcomes, and thereby is thought to respond similarly to better than predicted and worse than predicted outcomes. However, the nature of the encoded risk prediction error signals remained unclear. Moreover, the insula was proposed to preferentially process events and stimuli in the aversive domain, rather than in a domain-general fashion. Here we aimed to illuminate these issues. Within a Pavlovian task, participants (n=41; 19 women) rated both cues and outcomes, allowing us to quantify not only objective but also trial-specific subjective risk prediction errors. We found preferential coding of subjective risk prediction errors in the anterior insula and adjacent frontal cortex. This contrasted with preferential coding of objective risk prediction errors in the mid-insula. The anterior insula encoded the subjective risk prediction errors not only at the time of outcomes, but also at the time of cues, in-line with a temporally fine-grained computation of these prediction errors. Cue-induced subjective risk prediction error signals occurred predominantly in the aversive domain, while outcome-induced subjective risk prediction error signals occurred also in the appetitive domain. Domain-specific analyses of risk prediction errors elicited by the preceding outcome at the time of the next cue indicated that the anterior insula updates risk predictions more strongly in the aversive than the appetitive domain. Together, our findings specify the nature of risk prediction errors processed by the anterior insula as subjective, time-resolved, and partly domain-general (outcome), partly domain-preferential (cue), thereby reconciling apparently disparate lines of research.Significant Statement The anterior insula is a hub of the salience network, thought to process both good and bad surprises. However, salience needs defining and the nature of salience signals in anterior insula remained unclear. Here, we define salience as risk and use a Pavlovian task with subjectively evaluated cues and liquid outcomes, allowing us to determine unsigned surprise, i.e., risk prediction errors, at both time points. In a double dissociation, subjective risk prediction error signals occurred preferentially in anterior insula and objective signals in mid-insula. We also show that subjective risk prediction errors are preferentially encoded for aversive rather than appetitive cues. These findings unify divergent frameworks of insula function, specifying the insula's nuanced role in salience processing for motivated behavior.
{"title":"The anterior insula processes a time-resolved subjective risk prediction error.","authors":"Jae-Chang Kim,Lydia Hellrung,Stephan Nebe,Philippe N Tobler","doi":"10.1523/jneurosci.2302-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.2302-24.2025","url":null,"abstract":"The insula processes errors in the prediction of risky, motivationally relevant outcomes, and thereby is thought to respond similarly to better than predicted and worse than predicted outcomes. However, the nature of the encoded risk prediction error signals remained unclear. Moreover, the insula was proposed to preferentially process events and stimuli in the aversive domain, rather than in a domain-general fashion. Here we aimed to illuminate these issues. Within a Pavlovian task, participants (n=41; 19 women) rated both cues and outcomes, allowing us to quantify not only objective but also trial-specific subjective risk prediction errors. We found preferential coding of subjective risk prediction errors in the anterior insula and adjacent frontal cortex. This contrasted with preferential coding of objective risk prediction errors in the mid-insula. The anterior insula encoded the subjective risk prediction errors not only at the time of outcomes, but also at the time of cues, in-line with a temporally fine-grained computation of these prediction errors. Cue-induced subjective risk prediction error signals occurred predominantly in the aversive domain, while outcome-induced subjective risk prediction error signals occurred also in the appetitive domain. Domain-specific analyses of risk prediction errors elicited by the preceding outcome at the time of the next cue indicated that the anterior insula updates risk predictions more strongly in the aversive than the appetitive domain. Together, our findings specify the nature of risk prediction errors processed by the anterior insula as subjective, time-resolved, and partly domain-general (outcome), partly domain-preferential (cue), thereby reconciling apparently disparate lines of research.Significant Statement The anterior insula is a hub of the salience network, thought to process both good and bad surprises. However, salience needs defining and the nature of salience signals in anterior insula remained unclear. Here, we define salience as risk and use a Pavlovian task with subjectively evaluated cues and liquid outcomes, allowing us to determine unsigned surprise, i.e., risk prediction errors, at both time points. In a double dissociation, subjective risk prediction error signals occurred preferentially in anterior insula and objective signals in mid-insula. We also show that subjective risk prediction errors are preferentially encoded for aversive rather than appetitive cues. These findings unify divergent frameworks of insula function, specifying the insula's nuanced role in salience processing for motivated behavior.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"8 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872020","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}
Neuropathic pain is one of the most intractable pain conditions associated with tumor growth compressing and damaging nerves. A troublesome hallmark symptom of neuropathic pain is hypersensitivity to innocuous stimuli, known as "tactile allodynia," which is often refractory to currently available analgesics. Diurnal variations in pain hypersensitivity are common in patients with cancer, but the underlying mechanisms are enigmatic. Herein, we report that spinal expression of lipocalin-2 (LCN2) enhances pain sensitivity of NCTC2472 fibrosarcoma-implanted male mice during specific stages of the diurnal cycle. As the tumor grew, interleukin-6 (IL-6) levels increased in the spinal cord of the mice. Increased IL-6 levels stimulated LCN2 expression in spinal microglia, but this expression was periodically repressed by the circadian clock components REV-ERBα and REV-ERBβ. Notably, intra-spinal dorsal horn injection of lentiviral vectors expressing REV-ERBα or REV-ERBβ in tumor-bearing mice alleviated tactile allodynia. Furthermore, intrathecal injection of SR9009, a synthetic agonist of REV-ERBs, also attenuated cancer-induced pain hypersensitivity, accompanied by suppressing spinal LCN2 expression. These results suggest that temporal elevation of LCN2 expression decreases the threshold of tactile pain hypersensitivity induced by tumor growth. We propose that the circadian clock component of REV-ERBs is an effective target for alleviation of cancer-induced tactile allodynia, identifying a new class of analgesic agents.Significance statement Spinal expression of lipocalin-2 (LCN2) enhances pain sensitivity of NCTC2472 fibrosarcoma-implanted mice during specific stages of the diurnal cycle. Following tumor growth, an increase in interleukin-6 (IL-6) levels within spinal cord induces the microglial expression of LCN2, which is periodically suppressed by the circadian clock components REV-ERBα and REV-ERBβ. The temporal elevation of LCN2 expression decreases the threshold of tactile allodynia induced by tumor growth. Enhanced expression of REV-ERBs in spinal microglial and their pharmacological activation by the synthetic agonist SR9009 alleviate cancer-induced pain hypersensitivity. These findings reveal the circadian machinery affecting cancer-associated intractable pain and propose that REV-ERBs are an effective target for alleviation of cancer-associated neuropathic pain.
{"title":"The circadian clock component REV-ERBs is an analgesic target for cancer-induced tactile pain hypersensitivity.","authors":"Sai Yasukochi,Wakaba Yamakawa,Marie Taniguchi,Sayaka Itoyama,Akito Tsuruta,Naoki Kusunose,Tomoaki Yamauchi,Risako Nakamura,Naoya Matsunaga,Shigehiro Ohdo,Satoru Koyanagi","doi":"10.1523/jneurosci.1969-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.1969-24.2025","url":null,"abstract":"Neuropathic pain is one of the most intractable pain conditions associated with tumor growth compressing and damaging nerves. A troublesome hallmark symptom of neuropathic pain is hypersensitivity to innocuous stimuli, known as \"tactile allodynia,\" which is often refractory to currently available analgesics. Diurnal variations in pain hypersensitivity are common in patients with cancer, but the underlying mechanisms are enigmatic. Herein, we report that spinal expression of lipocalin-2 (LCN2) enhances pain sensitivity of NCTC2472 fibrosarcoma-implanted male mice during specific stages of the diurnal cycle. As the tumor grew, interleukin-6 (IL-6) levels increased in the spinal cord of the mice. Increased IL-6 levels stimulated LCN2 expression in spinal microglia, but this expression was periodically repressed by the circadian clock components REV-ERBα and REV-ERBβ. Notably, intra-spinal dorsal horn injection of lentiviral vectors expressing REV-ERBα or REV-ERBβ in tumor-bearing mice alleviated tactile allodynia. Furthermore, intrathecal injection of SR9009, a synthetic agonist of REV-ERBs, also attenuated cancer-induced pain hypersensitivity, accompanied by suppressing spinal LCN2 expression. These results suggest that temporal elevation of LCN2 expression decreases the threshold of tactile pain hypersensitivity induced by tumor growth. We propose that the circadian clock component of REV-ERBs is an effective target for alleviation of cancer-induced tactile allodynia, identifying a new class of analgesic agents.Significance statement Spinal expression of lipocalin-2 (LCN2) enhances pain sensitivity of NCTC2472 fibrosarcoma-implanted mice during specific stages of the diurnal cycle. Following tumor growth, an increase in interleukin-6 (IL-6) levels within spinal cord induces the microglial expression of LCN2, which is periodically suppressed by the circadian clock components REV-ERBα and REV-ERBβ. The temporal elevation of LCN2 expression decreases the threshold of tactile allodynia induced by tumor growth. Enhanced expression of REV-ERBs in spinal microglial and their pharmacological activation by the synthetic agonist SR9009 alleviate cancer-induced pain hypersensitivity. These findings reveal the circadian machinery affecting cancer-associated intractable pain and propose that REV-ERBs are an effective target for alleviation of cancer-associated neuropathic pain.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"1 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872095","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 : 2025-04-22DOI: 10.1523/jneurosci.1001-24.2025
Carolina Fernandes-Henriques,Yuval Guetta,Mia Sclar,Rebecca Zhang,Yuka Miura,Katherine R Surrence,Allyson K Friedman,Ekaterina Likhtik
Fear extinction is critical for decreasing fear responses to a stimulus that no longer poses a threat. While it is known that the infralimbic region (IL) of the medial prefrontal cortex mediates retrieval of an extinction memory through projections to the basolateral amygdala (BLA), IL pathways contributing to extinction learning are not well-understood. Given the dense projection from the IL to the substantia innominata-ventral pallidum (SI/VP), an area that processes aversive and appetitive cues, we compared how the IL-SI/VP functions in extinction compared to the IL-BLA pathway in male mice. Using retrograde tracing, we demonstrate that IL projections to the SI/VP originate from superficial (L2/3) and deep cortical layers (L5), and that they are denser than IL projections to the BLA. Next, combining retrograde tracing with labeling for the immediate early gene cFos, we show increased activity of L5 IL-SI/VP output during extinction learning and increased activity of L2/3 IL-BLA output during extinction retrieval. Then, using in vitro recordings, we demonstrate that neurons in the IL-SI/VP pathway are more excitable during extinction learning than retrieval. Finally, using optogenetics we inactivate the IL-SI/VP pathway, and show that this increases defensive freezing during extinction learning and re-extinction, without affecting memory. Taken together, we demonstrate that the IL-SI/VP pathway is active during extinction learning, when it constrains the defensive freezing response. We propose that the IL acts as a switchboard operator, increasing IL L5 communication with the SI/VP during extinction learning, and IL L2/3 communication with the BLA during extinction retrieval.Significance Statement Fear extinction is a widely used behavioral approach to decrease conditioned fear, and projections from the infralimbic cortex to the amygdala are known to mediate extinction memory retrieval. However, less is known about the role of infralimbic pathways in extinction learning. We use neuroanatomical tracing, behavior, slice recordings, and circuit manipulation to show that infralimbic output to the substantia innominata-ventral pallidum, a region that processes aversive and appetitive stimuli, is denser than to the amygdala, and is more active during extinction learning than retrieval, when it acts to constrain the defensive freezing response. Thus, we posit that during extinction the infralimbic uses several lines of communication, one with the substantia innominata-ventral pallidum during learning one with the amygdala during retrieval.
{"title":"Infralimbic projections to the substantia innominata-ventral pallidum constrain defensive behavior during extinction learning.","authors":"Carolina Fernandes-Henriques,Yuval Guetta,Mia Sclar,Rebecca Zhang,Yuka Miura,Katherine R Surrence,Allyson K Friedman,Ekaterina Likhtik","doi":"10.1523/jneurosci.1001-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.1001-24.2025","url":null,"abstract":"Fear extinction is critical for decreasing fear responses to a stimulus that no longer poses a threat. While it is known that the infralimbic region (IL) of the medial prefrontal cortex mediates retrieval of an extinction memory through projections to the basolateral amygdala (BLA), IL pathways contributing to extinction learning are not well-understood. Given the dense projection from the IL to the substantia innominata-ventral pallidum (SI/VP), an area that processes aversive and appetitive cues, we compared how the IL-SI/VP functions in extinction compared to the IL-BLA pathway in male mice. Using retrograde tracing, we demonstrate that IL projections to the SI/VP originate from superficial (L2/3) and deep cortical layers (L5), and that they are denser than IL projections to the BLA. Next, combining retrograde tracing with labeling for the immediate early gene cFos, we show increased activity of L5 IL-SI/VP output during extinction learning and increased activity of L2/3 IL-BLA output during extinction retrieval. Then, using in vitro recordings, we demonstrate that neurons in the IL-SI/VP pathway are more excitable during extinction learning than retrieval. Finally, using optogenetics we inactivate the IL-SI/VP pathway, and show that this increases defensive freezing during extinction learning and re-extinction, without affecting memory. Taken together, we demonstrate that the IL-SI/VP pathway is active during extinction learning, when it constrains the defensive freezing response. We propose that the IL acts as a switchboard operator, increasing IL L5 communication with the SI/VP during extinction learning, and IL L2/3 communication with the BLA during extinction retrieval.Significance Statement Fear extinction is a widely used behavioral approach to decrease conditioned fear, and projections from the infralimbic cortex to the amygdala are known to mediate extinction memory retrieval. However, less is known about the role of infralimbic pathways in extinction learning. We use neuroanatomical tracing, behavior, slice recordings, and circuit manipulation to show that infralimbic output to the substantia innominata-ventral pallidum, a region that processes aversive and appetitive stimuli, is denser than to the amygdala, and is more active during extinction learning than retrieval, when it acts to constrain the defensive freezing response. Thus, we posit that during extinction the infralimbic uses several lines of communication, one with the substantia innominata-ventral pallidum during learning one with the amygdala during retrieval.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"7 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866390","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 : 2025-04-22DOI: 10.1523/jneurosci.0044-25.2025
Puti Wen,Lowell W Thompson,Ari Rosenberg,Michael S Landy,Bas Rokers
How does the brain process 3D motion? Here, we focused on the human motion complex (hMT+), extending insights from monkey studies. Using 3D-motion stimuli containing perspective and/or stereoscopic cues, we investigated the hierarchy within the motion complex in humans of both sexes to understand the neural mechanisms underlying motion perception. On each trial we decoded 3D motion direction (toward/away) based on the BOLD response in primary visual cortex (V1), and areas MT, MST, and FST within hMT+. We found that 3D-motion direction could be reliably decoded from all four areas, but with distinct patterns of cue preference. MT showed greatest accuracy with perspective cues, whereas FST showed greatest accuracy with stereoscopic cues. While motion direction could be decoded in V1 and MST, these results could be explained by retinotopic variation in the BOLD response that depended on motion direction. In contrast, MT and FST were less impacted by retinotopic biases in the BOLD response. We also identified significant behavioral differences between participants: some were proficient at using stereoscopic cues and others performed near chance. Good behavioral performance with stereoscopic cues was accompanied by better decoding performance in FST but not in MT. A control experiment that eliminated 3D-motion percepts for stereoscopic stimuli, but not perspective stimuli, revealed that unlike MT, decoding accuracy in FST was influenced by perceptual components of 3D motion. Our findings support that MT and FST play distinct roles in the analysis of visual motion and are key in the transformation of retinal input into perceptual report.Significance statement Visual motion representations are elaborated hierarchically across distinct regions of the primate brain. In humans, the hMT+ complex contains multiple subdivisions including homologues of non-human primate (NHP) motion areas MT and MST. Using fMRI localizers, hMT+ was recently found to include a third subdivision consistent with NHP area FST. Here, we show that human FST and MT, like their NHP counterparts, are functionally distinguishable based on the representation of 3D motion. Most notably, we find a perceptual representation of 3D motion in human FST, but not MT, that is distinct from the patterns of motion found on the retinae. Our findings reveal that the human visual motion-processing network extends crucially beyond MT to represent complex, perceptual motion signals.
{"title":"Single-Trial fMRI Decoding of 3D Motion with Stereoscopic and Perspective Cues.","authors":"Puti Wen,Lowell W Thompson,Ari Rosenberg,Michael S Landy,Bas Rokers","doi":"10.1523/jneurosci.0044-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0044-25.2025","url":null,"abstract":"How does the brain process 3D motion? Here, we focused on the human motion complex (hMT+), extending insights from monkey studies. Using 3D-motion stimuli containing perspective and/or stereoscopic cues, we investigated the hierarchy within the motion complex in humans of both sexes to understand the neural mechanisms underlying motion perception. On each trial we decoded 3D motion direction (toward/away) based on the BOLD response in primary visual cortex (V1), and areas MT, MST, and FST within hMT+. We found that 3D-motion direction could be reliably decoded from all four areas, but with distinct patterns of cue preference. MT showed greatest accuracy with perspective cues, whereas FST showed greatest accuracy with stereoscopic cues. While motion direction could be decoded in V1 and MST, these results could be explained by retinotopic variation in the BOLD response that depended on motion direction. In contrast, MT and FST were less impacted by retinotopic biases in the BOLD response. We also identified significant behavioral differences between participants: some were proficient at using stereoscopic cues and others performed near chance. Good behavioral performance with stereoscopic cues was accompanied by better decoding performance in FST but not in MT. A control experiment that eliminated 3D-motion percepts for stereoscopic stimuli, but not perspective stimuli, revealed that unlike MT, decoding accuracy in FST was influenced by perceptual components of 3D motion. Our findings support that MT and FST play distinct roles in the analysis of visual motion and are key in the transformation of retinal input into perceptual report.Significance statement Visual motion representations are elaborated hierarchically across distinct regions of the primate brain. In humans, the hMT+ complex contains multiple subdivisions including homologues of non-human primate (NHP) motion areas MT and MST. Using fMRI localizers, hMT+ was recently found to include a third subdivision consistent with NHP area FST. Here, we show that human FST and MT, like their NHP counterparts, are functionally distinguishable based on the representation of 3D motion. Most notably, we find a perceptual representation of 3D motion in human FST, but not MT, that is distinct from the patterns of motion found on the retinae. Our findings reveal that the human visual motion-processing network extends crucially beyond MT to represent complex, perceptual motion signals.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"108 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866561","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 : 2025-04-22DOI: 10.1523/jneurosci.0911-24.2025
Leila Montaser-Kouhsari,Jonathan Nicholas,Raphael T Gerraty,Daphna Shohamy
Patients with Parkinson's disease are impaired at incremental reward-based learning. It is typically assumed that this impairment reflects a loss of striatal dopamine. However, many open questions remain about the nature of reward-based learning deficits in Parkinson's disease. Recent studies have found that even simple reward-based learning tasks rely on a combination of cognitive and computational strategies, including one-shot episodic memory. These findings raise questions about how incremental learning and episodic memory contribute to decision-making in Parkinson's disease. We tested healthy participants (n=26; 14 males and 12 females) and patients with Parkinson's disease (n=26; 16 males and 10 females), both on and off dopamine replacement medication, on a task designed to differentiate between the contributions of incremental learning and episodic memory to reward-based learning and decision-making. We found that Parkinson's patients performed equally well as healthy controls when using episodic memory, but were impaired at incremental reward-based learning. Dopamine replacement medication remediated this deficit and enhanced subsequent episodic memory for the value of motivationally relevant stimuli. These results demonstrate that while Parkinson's patients are impaired at learning about reward from trial-and-error, their ability to encode memories for the value of one-shot experiences is intact.Significance Statement Parkinson's disease involves disruptions to the striatum and its dopaminergic inputs, leading to motor and cognitive impairment. The exact nature of the cognitive impairment is unclear. We found that individuals with Parkinson's disease are impaired at gradual, incremental learning of value, but retain the ability to rapidly learn value based on a single event, referred to as episodic memory. Dopamine replacement remediates the incremental learning impairments while enhancing episodic memory. These findings shed light on the extent to which different forms of memory are impacted by dopamine loss in Parkinson's disease.
{"title":"Differentiating reinforcement learning and episodic memory in value-based decisions in Parkinson's Disease.","authors":"Leila Montaser-Kouhsari,Jonathan Nicholas,Raphael T Gerraty,Daphna Shohamy","doi":"10.1523/jneurosci.0911-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0911-24.2025","url":null,"abstract":"Patients with Parkinson's disease are impaired at incremental reward-based learning. It is typically assumed that this impairment reflects a loss of striatal dopamine. However, many open questions remain about the nature of reward-based learning deficits in Parkinson's disease. Recent studies have found that even simple reward-based learning tasks rely on a combination of cognitive and computational strategies, including one-shot episodic memory. These findings raise questions about how incremental learning and episodic memory contribute to decision-making in Parkinson's disease. We tested healthy participants (n=26; 14 males and 12 females) and patients with Parkinson's disease (n=26; 16 males and 10 females), both on and off dopamine replacement medication, on a task designed to differentiate between the contributions of incremental learning and episodic memory to reward-based learning and decision-making. We found that Parkinson's patients performed equally well as healthy controls when using episodic memory, but were impaired at incremental reward-based learning. Dopamine replacement medication remediated this deficit and enhanced subsequent episodic memory for the value of motivationally relevant stimuli. These results demonstrate that while Parkinson's patients are impaired at learning about reward from trial-and-error, their ability to encode memories for the value of one-shot experiences is intact.Significance Statement Parkinson's disease involves disruptions to the striatum and its dopaminergic inputs, leading to motor and cognitive impairment. The exact nature of the cognitive impairment is unclear. We found that individuals with Parkinson's disease are impaired at gradual, incremental learning of value, but retain the ability to rapidly learn value based on a single event, referred to as episodic memory. Dopamine replacement remediates the incremental learning impairments while enhancing episodic memory. These findings shed light on the extent to which different forms of memory are impacted by dopamine loss in Parkinson's disease.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"2 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866671","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}
Facilitation of visual search by repeated distractor contexts is typically studied employing distractor configurations that are 100% predictive of the target location. Yet, real-world contexts vary in predictivity. We used electroencephalography (EEG) in human participants of either sex to explore how visual search facilitation arises from two distinct processing modes - contextual guidance and context suppression - that depend on the predictivity of distractor contexts, comparing repeated distractor arrangements that were either predictive or non-predictive of target location against a baseline of non-repeated arrangements. In Experiment 1, we manipulated context predictivity by shifting repeated contexts from predictive to non-predictive and vice versa, while in Experiment 2, we restricted repeated contexts to one side of the display to assess lateralized effects of the two processing modes. Both types of contexts behaviorally facilitated visual search, but facilitation was larger with predictive contexts. Making predictive contexts non-predictive reduced the facilitation while rendering non-predictive contexts predictive failed to produce gains. Half-display predictive contexts facilitated target detection on both sides, while non-predictive contexts facilitated same-side target detection only. EEG analyses revealed that predictive contexts triggered an early N1pc (guidance signal), followed by an enhanced N2pc (attentional selection) and an increased contralateral delay activity (CDA, indexing working memory processing of the target) in occipito-parietal regions, indicative of contextual guidance boosting the entire processing chain. By contrast, non-predictive contexts produced only an increased N2pc accompanied by reduced CDA, consistent with context suppression. These differential patterns demonstrate contextual guidance and context suppression to operate as electrophysiologically distinct processing modes.Significance Statement This study shows that the brain acquires two distinct processing strategies - contextual guidance and distractor suppression, respectively - depending on how reliably a learned visual context predicts the location of a searched-for target. Compared to non-repeated contexts, predictive contexts engendered enhanced responses in a sequence of lateralized event-related potentials, reflecting early signaling of the target location (N1pc), attentional engagement (N2pc), and processing of the target in working memory (CDA) - indicative of the brain operating in target-directed contextual-guidance mode. Non-predictive contexts, by contrast, only facilitated attentional engagement (increased N2pc), with scant (if any) representation of the context in working memory (reduced CDA) - indicative of the brain suppressing the distractor context to single out the target, so as to optimize search performance.
{"title":"Statistical context learning in visual search: distinct electrophysiological signatures of contextual guidance and context suppression.","authors":"Siyi Chen 陈思佚,Nika Merkuš,Shao-Yang Tsai 蔡劭扬,Si Cheng 程思,Hermann J Müller,Zhuanghua Shi 施壮华","doi":"10.1523/jneurosci.2186-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.2186-24.2025","url":null,"abstract":"Facilitation of visual search by repeated distractor contexts is typically studied employing distractor configurations that are 100% predictive of the target location. Yet, real-world contexts vary in predictivity. We used electroencephalography (EEG) in human participants of either sex to explore how visual search facilitation arises from two distinct processing modes - contextual guidance and context suppression - that depend on the predictivity of distractor contexts, comparing repeated distractor arrangements that were either predictive or non-predictive of target location against a baseline of non-repeated arrangements. In Experiment 1, we manipulated context predictivity by shifting repeated contexts from predictive to non-predictive and vice versa, while in Experiment 2, we restricted repeated contexts to one side of the display to assess lateralized effects of the two processing modes. Both types of contexts behaviorally facilitated visual search, but facilitation was larger with predictive contexts. Making predictive contexts non-predictive reduced the facilitation while rendering non-predictive contexts predictive failed to produce gains. Half-display predictive contexts facilitated target detection on both sides, while non-predictive contexts facilitated same-side target detection only. EEG analyses revealed that predictive contexts triggered an early N1pc (guidance signal), followed by an enhanced N2pc (attentional selection) and an increased contralateral delay activity (CDA, indexing working memory processing of the target) in occipito-parietal regions, indicative of contextual guidance boosting the entire processing chain. By contrast, non-predictive contexts produced only an increased N2pc accompanied by reduced CDA, consistent with context suppression. These differential patterns demonstrate contextual guidance and context suppression to operate as electrophysiologically distinct processing modes.Significance Statement This study shows that the brain acquires two distinct processing strategies - contextual guidance and distractor suppression, respectively - depending on how reliably a learned visual context predicts the location of a searched-for target. Compared to non-repeated contexts, predictive contexts engendered enhanced responses in a sequence of lateralized event-related potentials, reflecting early signaling of the target location (N1pc), attentional engagement (N2pc), and processing of the target in working memory (CDA) - indicative of the brain operating in target-directed contextual-guidance mode. Non-predictive contexts, by contrast, only facilitated attentional engagement (increased N2pc), with scant (if any) representation of the context in working memory (reduced CDA) - indicative of the brain suppressing the distractor context to single out the target, so as to optimize search performance.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"123 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849501","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 : 2025-04-17DOI: 10.1523/jneurosci.1684-24.2025
Yan Chen,Xiangyue Xiao,Zhicai Dong,Junhua Ding,Sara Cruz,Ming Zhang,Yuhan Lu,Nai Ding,Charlène Aubinet,Steven Laureys,Haibo Di
Recent research suggests that the detection of preserved cognitive function can assist in the diagnosis and prognosis of patients with disorders of consciousness (DoC). This study investigates EEG signals as indicators of neural activity associated with the processing of transitional probabilities during a learning paradigm in patients with DoC. By examining the sensitivity to transitional probabilities across levels of consciousness, we aim to assess the potential value of this indicator in clinical diagnosis and prognosis.We collected EEG recordings from 51 DoC patients (10 female) and 26 healthy controls (9 female). EEG activity was recorded while participants listened to artificial vocabulary speech sequences before and after the learning phase. Inter-trial phase coherence (ITPC) was used to examine differences in neural responses in different learning phases.Results showed that minimally conscious patients showed a significant increase in the word-tracking response after the learning phase, similar to healthy controls. Moreover, their learning-mediated word-rate ITPC difference correlated significantly with their Coma Recovery Scale-Revised score and 6-month outcome. However, these correlations were absent in unresponsive wakefulness syndrome patients. Crucially, differences in vocabulary ITPC before and after the learning phase effectively discriminated between healthy controls and patients, as well as between minimally conscious and unresponsive wakefulness syndrome patients. Combining EEG indicators with clinical performance accurately predicted patients' prognosis.In conclusion, the language learning paradigm has the potential to contribute to both diagnosis and prognosis in this challenging population, thereby significantly reducing prognostic uncertainty in medical decision-making and benefiting the rehabilitation of DoC patients.Significance Statement This study explores the electroencephalogram sensitivity to changes in transitional probabilities during a learning paradigm, and its relationship to diagnosis and prognosis in patients with disorders of consciousness (DoC). Our results demonstrated that minimally conscious patients exhibited a significant increase in inter-trial phase coherence values at word frequencies after the learning phase, similar to healthy controls, suggesting retained language ability. In contrast, patients with unresponsive wakefulness syndrome did not show such improvements. Combining electroencephalogram indicators with clinical assessments in a predictive model could improve the accuracy of diagnosis and prognosis of patients. In sum, this objective measurement of brain responses could reduce the prognostic uncertainty in clinical decision making and better guide the care and rehabilitation of DoC patients.
{"title":"Clinical diagnostic and prognostic value of residual language learning ability in patients with disorders of consciousness.","authors":"Yan Chen,Xiangyue Xiao,Zhicai Dong,Junhua Ding,Sara Cruz,Ming Zhang,Yuhan Lu,Nai Ding,Charlène Aubinet,Steven Laureys,Haibo Di","doi":"10.1523/jneurosci.1684-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.1684-24.2025","url":null,"abstract":"Recent research suggests that the detection of preserved cognitive function can assist in the diagnosis and prognosis of patients with disorders of consciousness (DoC). This study investigates EEG signals as indicators of neural activity associated with the processing of transitional probabilities during a learning paradigm in patients with DoC. By examining the sensitivity to transitional probabilities across levels of consciousness, we aim to assess the potential value of this indicator in clinical diagnosis and prognosis.We collected EEG recordings from 51 DoC patients (10 female) and 26 healthy controls (9 female). EEG activity was recorded while participants listened to artificial vocabulary speech sequences before and after the learning phase. Inter-trial phase coherence (ITPC) was used to examine differences in neural responses in different learning phases.Results showed that minimally conscious patients showed a significant increase in the word-tracking response after the learning phase, similar to healthy controls. Moreover, their learning-mediated word-rate ITPC difference correlated significantly with their Coma Recovery Scale-Revised score and 6-month outcome. However, these correlations were absent in unresponsive wakefulness syndrome patients. Crucially, differences in vocabulary ITPC before and after the learning phase effectively discriminated between healthy controls and patients, as well as between minimally conscious and unresponsive wakefulness syndrome patients. Combining EEG indicators with clinical performance accurately predicted patients' prognosis.In conclusion, the language learning paradigm has the potential to contribute to both diagnosis and prognosis in this challenging population, thereby significantly reducing prognostic uncertainty in medical decision-making and benefiting the rehabilitation of DoC patients.Significance Statement This study explores the electroencephalogram sensitivity to changes in transitional probabilities during a learning paradigm, and its relationship to diagnosis and prognosis in patients with disorders of consciousness (DoC). Our results demonstrated that minimally conscious patients exhibited a significant increase in inter-trial phase coherence values at word frequencies after the learning phase, similar to healthy controls, suggesting retained language ability. In contrast, patients with unresponsive wakefulness syndrome did not show such improvements. Combining electroencephalogram indicators with clinical assessments in a predictive model could improve the accuracy of diagnosis and prognosis of patients. In sum, this objective measurement of brain responses could reduce the prognostic uncertainty in clinical decision making and better guide the care and rehabilitation of DoC patients.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"418 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849429","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 : 2025-04-17DOI: 10.1523/jneurosci.1504-24.2025
Justin M Campbell,Tyler S Davis,Daria Nesterovich Anderson,Amir Arain,Zachary W Davis,Cory S Inman,Elliot H Smith,John D Rolston
Understanding the spatiotemporal dynamics of neural signal propagation is fundamental to unraveling the complexities of brain function. Emerging evidence suggests that cortico-cortical evoked potentials (CCEPs) resulting from single-pulse electrical stimulation may be used to characterize the patterns of information flow between and within brain networks. At present, the basic spatiotemporal dynamics of CCEP propagation cortically and subcortically are incompletely understood. We hypothesized that single-pulse electrical stimulation evokes neural traveling waves detectable in the three-dimensional space sampled by intracranial stereoelectroencephalography. Across a cohort of 21 adult males and females with intractable epilepsy, we delivered 17,631 stimulation pulses and recorded CCEP responses in 1,019 electrode contacts. The distance between each pair of electrode contacts was approximated using three different metrics (Euclidean distance, path length, and geodesic distance), representing direct, tractographic, and transcortical propagation, respectively. For each robust CCEP, we extracted amplitude-, spectral-, and phase-based features to identify traveling waves emanating from the site of stimulation. Many evoked responses to stimulation appear to propagate as traveling waves (∼14-28%, ∼5-19% with false-discovery rate correction), despite sparse sampling throughout the brain. These stimulation-evoked traveling waves exhibited biologically plausible propagation velocities (range 0.1-9.6 m/s). Our results reveal that direct electrical stimulation elicits neural activity with variable spatiotemporal dynamics that can be modeled as a traveling wave.Significance Statement Using single-pulse stimulation, we identify a subset of intracranial evoked potentials that propagate as neural traveling waves. Our results were robust across a range of distinct but complementary analysis methods. The identification of stimulation-evoked traveling waves may help to better characterize the pathways traversed by spontaneous, pathological, or task-evoked traveling waves and distinguish biologically plausible propagation from volume-conducted signals.
{"title":"Macroscale traveling waves evoked by single-pulse stimulation of the human brain.","authors":"Justin M Campbell,Tyler S Davis,Daria Nesterovich Anderson,Amir Arain,Zachary W Davis,Cory S Inman,Elliot H Smith,John D Rolston","doi":"10.1523/jneurosci.1504-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.1504-24.2025","url":null,"abstract":"Understanding the spatiotemporal dynamics of neural signal propagation is fundamental to unraveling the complexities of brain function. Emerging evidence suggests that cortico-cortical evoked potentials (CCEPs) resulting from single-pulse electrical stimulation may be used to characterize the patterns of information flow between and within brain networks. At present, the basic spatiotemporal dynamics of CCEP propagation cortically and subcortically are incompletely understood. We hypothesized that single-pulse electrical stimulation evokes neural traveling waves detectable in the three-dimensional space sampled by intracranial stereoelectroencephalography. Across a cohort of 21 adult males and females with intractable epilepsy, we delivered 17,631 stimulation pulses and recorded CCEP responses in 1,019 electrode contacts. The distance between each pair of electrode contacts was approximated using three different metrics (Euclidean distance, path length, and geodesic distance), representing direct, tractographic, and transcortical propagation, respectively. For each robust CCEP, we extracted amplitude-, spectral-, and phase-based features to identify traveling waves emanating from the site of stimulation. Many evoked responses to stimulation appear to propagate as traveling waves (∼14-28%, ∼5-19% with false-discovery rate correction), despite sparse sampling throughout the brain. These stimulation-evoked traveling waves exhibited biologically plausible propagation velocities (range 0.1-9.6 m/s). Our results reveal that direct electrical stimulation elicits neural activity with variable spatiotemporal dynamics that can be modeled as a traveling wave.Significance Statement Using single-pulse stimulation, we identify a subset of intracranial evoked potentials that propagate as neural traveling waves. Our results were robust across a range of distinct but complementary analysis methods. The identification of stimulation-evoked traveling waves may help to better characterize the pathways traversed by spontaneous, pathological, or task-evoked traveling waves and distinguish biologically plausible propagation from volume-conducted signals.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"26 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849465","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 : 2025-04-16DOI: 10.1523/jneurosci.2288-24.2025
Ningyu Zhang,Huanghe Ye
{"title":"Bridging Species Differences in Rule Switching: How Humans and Monkeys Solve the Same Wisconsin Card Sorting Task.","authors":"Ningyu Zhang,Huanghe Ye","doi":"10.1523/jneurosci.2288-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.2288-24.2025","url":null,"abstract":"","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"17 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849430","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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