RESUMEN
Effective evaluation of costs and benefits is a core survival capacity that in humans is considered as optimal, "rational" decision-making. This capacity is vulnerable in neuropsychiatric disorders and in the aftermath of chronic stress, in which aberrant choices and high-risk behaviors occur. We report that chronic stress exposure in rodents produces abnormal evaluation of costs and benefits resembling non-optimal decision-making in which choices of high-cost/high-reward options are sharply increased. Concomitantly, alterations in the task-related spike activity of medial prefrontal neurons correspond with increased activity of their striosome-predominant striatal projection neuron targets and with decreased and delayed striatal fast-firing interneuron activity. These effects of chronic stress on prefronto-striatal circuit dynamics could be blocked or be mimicked by selective optogenetic manipulation of these circuits. We suggest that altered excitation-inhibition dynamics of striosome-based circuit function could be an underlying mechanism by which chronic stress contributes to disorders characterized by aberrant decision-making under conflict. VIDEO ABSTRACT.
Asunto(s)
Toma de Decisiones , Corteza Prefrontal/fisiopatología , Estrés Fisiológico , Animales , Ganglios Basales/metabolismo , Interneuronas/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Vías Nerviosas , Optogenética , Ratas , Ratas Long-EvansRESUMEN
People tend to intervene in others' injustices by either punishing the transgressor or helping the victim. Injustice events often occur under stressful circumstances. However, how acute stress affects a third party's intervention in injustice events remains open. Here, we show a stress-induced shift in third parties' willingness to engage in help instead of punishment by acting on emotional salience and central-executive and theory-of-mind networks. Acute stress decreased the third party's willingness to punish the violator and the severity of the punishment and increased their willingness to help the victim. Computational modeling revealed a shift in preference of justice recovery from punishment the offender toward help the victim under stress. This finding is consistent with the increased dorsolateral prefrontal engagement observed with higher amygdala activity and greater connectivity with the ventromedial prefrontal cortex in the stress group. A brain connectivity theory-of-mind network predicted stress-induced justice recovery in punishment. Our findings suggest a neurocomputational mechanism of how acute stress reshapes third parties' decisions by reallocating neural resources in emotional, executive, and mentalizing networks to inhibit punishment bias and decrease punishment severity.
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Castigo , Estrés Psicológico , Humanos , Castigo/psicología , Masculino , Estrés Psicológico/fisiopatología , Estrés Psicológico/psicología , Femenino , Adulto , Adulto Joven , Corteza Prefrontal/fisiología , Corteza Prefrontal/fisiopatología , Emociones/fisiología , Justicia Social , Encéfalo/fisiología , Imagen por Resonancia MagnéticaRESUMEN
Choosing whether to exert effort to obtain rewards is fundamental to human motivated behavior. However, the neural dynamics underlying the evaluation of reward and effort in humans is poorly understood. Here, we report an exploratory investigation into this with chronic intracranial recordings from the prefrontal cortex (PFC) and basal ganglia (BG; subthalamic nuclei and globus pallidus) in people with Parkinson's disease performing a decision-making task with offers that varied in levels of reward and physical effort required. This revealed dissociable neural signatures of reward and effort, with BG beta (12 to 20 Hz) oscillations tracking effort on a single-trial basis and PFC theta (4 to 7 Hz) signaling previous trial reward, with no effects of net subjective value. Stimulation of PFC increased overall acceptance of offers and sensitivity to reward while decreasing the impact of effort on choices. This work uncovers oscillatory mechanisms that guide fundamental decisions to exert effort for reward across BG and PFC, supports a causal role of PFC for such choices, and seeds hypotheses for future studies.
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Ganglios Basales , Toma de Decisiones , Enfermedad de Parkinson , Corteza Prefrontal , Recompensa , Ritmo Teta , Humanos , Corteza Prefrontal/fisiología , Corteza Prefrontal/fisiopatología , Toma de Decisiones/fisiología , Ganglios Basales/fisiología , Ganglios Basales/fisiopatología , Masculino , Ritmo Teta/fisiología , Femenino , Enfermedad de Parkinson/fisiopatología , Persona de Mediana Edad , Ritmo beta/fisiología , AncianoRESUMEN
Increasing evidence suggests that mental health and physical health are linked by neural systems that jointly regulate somatic physiology and high-level cognition. Key systems include the ventromedial prefrontal cortex and the related default-mode network. These systems help to construct models of the 'self-in-context', compressing information across time and sensory modalities into conceptions of the underlying causes of experience. Self-in-context models endow events with personal meaning and allow predictive control over behaviour and peripheral physiology, including autonomic, neuroendocrine and immune function. They guide learning from experience and the formation of narratives about the self and one's world. Disorders of mental and physical health, especially those with high co-occurrence and convergent alterations in the functionality of the ventromedial prefrontal cortex and the default-mode network, could benefit from interventions focused on understanding and shaping mindsets and beliefs about the self, illness and treatment.
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Encéfalo/fisiología , Ego , Estado de Salud , Salud Mental , Encéfalo/fisiopatología , Mapeo Encefálico , Humanos , Imagen por Resonancia Magnética , Red Nerviosa/fisiología , Red Nerviosa/fisiopatología , Corteza Prefrontal/fisiología , Corteza Prefrontal/fisiopatologíaRESUMEN
Fragile X syndrome (FXS) is a genetic cause of intellectual disability and autism spectrum disorder. The mesocorticolimbic system, which includes the prefrontal cortex (PFC), basolateral amygdala (BLA), and nucleus accumbens core (NAcC), is essential for regulating socioemotional behaviors. We employed optogenetics to compare the functional properties of the BLAâNAcC, PFCâNAcC, and reciprocal PFCâBLA pathways in Fmr1-/y::Drd1a-tdTomato male mice. In FXS mice, the PFCâBLA reciprocal pathway was unaffected, while significant synaptic modifications occurred in the BLA/PFCâNAcC pathways. We observed distinct changes in D1 striatal projection neurons (SPNs) and separate modifications in D2 SPNs. In FXS mice, the BLA/PFCâNAcC-D2 SPN pathways demonstrated heightened synaptic strength. Focusing on the BLAâNAcC pathway, linked to autistic symptoms, we found increased AMPAR and NMDAR currents and elevated spine density in D2 SPNs. Conversely, the amplified firing probability of BLAâNAcC-D1 SPNs was not accompanied by increased synaptic strength, AMPAR and NMDAR currents, or spine density. These pathway-specific alterations resulted in an overall enhancement of excitatory-to-spike coupling, a physiologically relevant index of how efficiently excitatory inputs drive neuronal firing, in both BLAâNAcC-D1 and BLAâNAcC-D2 pathways. Finally, the absence of fragile X messenger ribonucleoprotein 1 (FMRP) led to impaired long-term depression specifically in BLAâD1 SPNs. These distinct alterations in synaptic transmission and plasticity within circuits targeting the NAcC highlight the potential role of postsynaptic mechanisms in selected SPNs in the observed circuit-level changes. This research underscores the heightened vulnerability of the NAcC in the context of FMRP deficiency, emphasizing its pivotal role in the pathophysiology of FXS.
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Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Síndrome del Cromosoma X Frágil , Núcleo Accumbens , Animales , Síndrome del Cromosoma X Frágil/fisiopatología , Síndrome del Cromosoma X Frágil/metabolismo , Síndrome del Cromosoma X Frágil/genética , Ratones , Masculino , Núcleo Accumbens/metabolismo , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Vías Nerviosas/fisiopatología , Optogenética , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiopatología , Ratones Endogámicos C57BL , Complejo Nuclear Basolateral/metabolismo , Complejo Nuclear Basolateral/fisiopatología , Ratones Noqueados , Neuronas/metabolismo , Neuronas/fisiología , Plasticidad Neuronal/fisiologíaRESUMEN
Anxiety-related disorders respond to cognitive behavioral therapies, which involved the medial prefrontal cortex (mPFC). Previous studies have suggested that subregions of the mPFC have different and even opposite roles in regulating innate anxiety. However, the specific causal targets of their descending projections in modulating innate anxiety and stress-induced anxiety have yet to be fully elucidated. Here, we found that among the various downstream pathways of the prelimbic cortex (PL), a subregion of the mPFC, PL-mediodorsal thalamic nucleus (MD) projection, and PL-ventral tegmental area (VTA) projection exhibited antagonistic effects on anxiety-like behavior, while the PL-MD projection but not PL-VTA projection was necessary for the animal to guide anxiety-related behavior. In addition, MD-projecting PL neurons bidirectionally regulated remote but not recent fear memory retrieval. Notably, restraint stress induced high-anxiety state accompanied by strengthening the excitatory inputs onto MD-projecting PL neurons, and inhibiting PL-MD pathway rescued the stress-induced anxiety. Our findings reveal that the activity of PL-MD pathway may be an essential factor to maintain certain level of anxiety, and stress increased the excitability of this pathway, leading to inappropriate emotional expression, and suggests that targeting specific PL circuits may aid the development of therapies for the treatment of stress-related disorders.
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Ansiedad , Vías Nerviosas , Corteza Prefrontal , Estrés Psicológico , Animales , Ansiedad/psicología , Ansiedad/fisiopatología , Masculino , Estrés Psicológico/psicología , Estrés Psicológico/fisiopatología , Corteza Prefrontal/fisiopatología , Vías Nerviosas/fisiopatología , Vías Nerviosas/fisiología , Ratones , Miedo/fisiología , Miedo/psicología , Ratones Endogámicos C57BL , Área Tegmental Ventral/fisiopatología , Tálamo/fisiopatología , Núcleo Talámico Mediodorsal/fisiología , Núcleo Talámico Mediodorsal/fisiopatologíaRESUMEN
We describe evidence for dissociable roles of the medial and lateral orbitofrontal cortex (OFC) in major depressive disorder (MDD) from structure, functional activation, functional connectivity, metabolism, and neurochemical systems. The reward-related medial orbitofrontal cortex has lower connectivity and less reward sensitivity in MDD associated with anhedonia symptoms; and the non-reward related lateral OFC has higher functional connectivity and more sensitivity to non-reward/aversive stimuli in MDD associated with negative bias symptoms. Importantly, we propose that conventional antidepressants act to normalize the hyperactive lateral (but not medial) OFC to reduce negative bias in MDD; while other treatments are needed to operate on the medial OFC to reduce anhedonia, with emerging evidence suggesting that ketamine may act in this way. The orbitofrontal cortex is the key cortical region in emotion and reward, and the current review presents much new evidence about the different ways that the medial and lateral OFC are involved in MDD.
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Anhedonia , Trastorno Depresivo Mayor , Corteza Prefrontal , Humanos , Anhedonia/fisiología , Antidepresivos/uso terapéutico , Antidepresivos/farmacología , Trastorno Depresivo Mayor/fisiopatología , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/tratamiento farmacológico , Emociones/fisiología , Ketamina/uso terapéutico , Ketamina/farmacología , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiopatología , RecompensaRESUMEN
Despite a theory that an imbalance in goal-directed versus habitual systems serve as building blocks of compulsions, research has yet to delineate how this occurs during arbitration between the two systems in obsessive-compulsive disorder. Inspired by a brain model in which the inferior frontal cortex selectively gates the putamen to guide goal-directed or habitual actions, this study aimed to examine whether disruptions in the arbitration process via the fronto-striatal circuit would underlie imbalanced decision-making and compulsions in patients. Thirty patients with obsessive-compulsive disorder [mean (standard deviation) age = 26.93 (6.23) years, 12 females (40%)] and 30 healthy controls [mean (standard deviation) age = 24.97 (4.72) years, 17 females (57%)] underwent functional MRI scans while performing the two-step Markov decision task, which was designed to dissociate goal-directed behaviour from habitual behaviour. We employed a neurocomputational model to account for an uncertainty-based arbitration process, in which a prefrontal arbitrator (i.e. inferior frontal gyrus) allocates behavioural control to a more reliable strategy by selectively gating the putamen. We analysed group differences in the neural estimates of uncertainty of each strategy. We also compared the psychophysiological interaction effects of system preference (goal-directed versus habitual) on fronto-striatal coupling between groups. We examined the correlation between compulsivity score and the neural activity and connectivity involved in the arbitration process. The computational model captured the subjects' preferences between the strategies. Compared with healthy controls, patients had a stronger preference for the habitual system (t = -2.88, P = 0.006), which was attributed to a more uncertain goal-directed system (t = 2.72, P = 0.009). Before the allocation of controls, patients exhibited hypoactivity in the inferior frontal gyrus compared with healthy controls when this region tracked the inverse of uncertainty (i.e. reliability) of goal-directed behaviour (P = 0.001, family-wise error rate corrected). When reorienting behaviours to reach specific goals, patients exhibited weaker right ipsilateral ventrolateral prefronto-putamen coupling than healthy controls (P = 0.001, family-wise error rate corrected). This hypoconnectivity was correlated with more severe compulsivity (r = -0.57, P = 0.002). Our findings suggest that the attenuated top-down control of the putamen by the prefrontal arbitrator underlies compulsivity in obsessive-compulsive disorder. Enhancing fronto-striatal connectivity may be a potential neurotherapeutic approach for compulsivity and adaptive decision-making.
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Toma de Decisiones , Objetivos , Imagen por Resonancia Magnética , Trastorno Obsesivo Compulsivo , Humanos , Femenino , Adulto , Masculino , Imagen por Resonancia Magnética/métodos , Trastorno Obsesivo Compulsivo/fisiopatología , Trastorno Obsesivo Compulsivo/diagnóstico por imagen , Trastorno Obsesivo Compulsivo/psicología , Incertidumbre , Toma de Decisiones/fisiología , Adulto Joven , Modelos Neurológicos , Conducta Compulsiva/fisiopatología , Corteza Prefrontal/fisiopatología , Corteza Prefrontal/diagnóstico por imagen , Putamen/fisiopatología , Putamen/diagnóstico por imagen , Encéfalo/fisiopatología , Encéfalo/diagnóstico por imagen , Simulación por ComputadorRESUMEN
Spontaneous and conversational laughter are important socio-emotional communicative signals. Neuroimaging findings suggest that non-autistic people engage in mentalizing to understand the meaning behind conversational laughter. Autistic people may thus face specific challenges in processing conversational laughter, due to their mentalizing difficulties. Using fMRI, we explored neural differences during implicit processing of these two types of laughter. Autistic and non-autistic adults passively listened to funny words, followed by spontaneous laughter, conversational laughter, or noise-vocoded vocalizations. Behaviourally, words plus spontaneous laughter were rated as funnier than words plus conversational laughter, and the groups did not differ. However, neuroimaging results showed that non-autistic adults exhibited greater medial prefrontal cortex activation while listening to words plus conversational laughter, than words plus genuine laughter, while autistic adults showed no difference in medial prefrontal cortex activity between these two laughter types. Our findings suggest a crucial role for the medial prefrontal cortex in understanding socio-emotionally ambiguous laughter via mentalizing. Our study also highlights the possibility that autistic people may face challenges in understanding the essence of the laughter we frequently encounter in everyday life, especially in processing conversational laughter that carries complex meaning and social ambiguity, potentially leading to social vulnerability. Therefore, we advocate for clearer communication with autistic people.
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Trastorno Autístico , Mapeo Encefálico , Encéfalo , Risa , Imagen por Resonancia Magnética , Humanos , Risa/fisiología , Risa/psicología , Masculino , Femenino , Adulto , Trastorno Autístico/fisiopatología , Trastorno Autístico/diagnóstico por imagen , Trastorno Autístico/psicología , Adulto Joven , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Encéfalo/fisiología , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/fisiopatología , Corteza Prefrontal/fisiología , Estimulación AcústicaRESUMEN
BACKGROUND AND AIMS: Chronic stress associates with cardiovascular disease, but mechanisms remain incompletely defined. Advanced imaging was used to identify stress-related neural imaging phenotypes associated with atherosclerosis. METHODS: Twenty-seven individuals with post-traumatic stress disorder (PTSD), 45 trauma-exposed controls without PTSD, and 22 healthy controls underwent 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI). Atherosclerotic inflammation and burden were assessed using 18F-FDG PET (as maximal target-to-background ratio, TBR max) and MRI, respectively. Inflammation was assessed using high-sensitivity C-reactive protein (hsCRP) and leucopoietic imaging (18F-FDG PET uptake in spleen and bone marrow). Stress-associated neural network activity (SNA) was assessed on 18F-FDG PET as amygdala relative to ventromedial prefrontal cortex (vmPFC) activity. MRI diffusion tensor imaging assessed the axonal integrity (AI) of the uncinate fasciculus (major white matter tract connecting vmPFC and amygdala). RESULTS: Median age was 37 years old and 54% of participants were female. There were no significant differences in atherosclerotic inflammation between participants with PTSD and controls; adjusted mean difference in TBR max (95% confidence interval) of the aorta 0.020 (-0.098, 0.138), and of the carotids 0.014 (-0.091, 0.119). Participants with PTSD had higher hsCRP, spleen activity, and aorta atherosclerotic burden (normalized wall index). Participants with PTSD also had higher SNA and lower AI. Across the cohort, carotid atherosclerotic burden (standard deviation of wall thickness) associated positively with SNA and negatively with AI independent of Framingham risk score. CONCLUSIONS: In this study of limited size, participants with PTSD did not have higher atherosclerotic inflammation than controls. Notably, impaired cortico-limbic interactions (higher amygdala relative to vmPFC activity or disruption of their intercommunication) associated with carotid atherosclerotic burden. Larger studies are needed to refine these findings.
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Enfermedades de las Arterias Carótidas , Tomografía de Emisión de Positrones , Trastornos por Estrés Postraumático , Humanos , Femenino , Masculino , Adulto , Trastornos por Estrés Postraumático/fisiopatología , Trastornos por Estrés Postraumático/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/fisiopatología , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Imagen por Resonancia Magnética , Persona de Mediana Edad , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/fisiopatología , Amígdala del Cerebelo/diagnóstico por imagen , Amígdala del Cerebelo/fisiopatología , Radiofármacos , Estudios de Casos y Controles , Estrés Psicológico/fisiopatología , Estrés Psicológico/complicacionesRESUMEN
Internet gaming disorder (IGD) prompts inquiry into how feedback from prior gaming rounds influences subsequent risk-taking behavior and potential neural mechanisms. Forty-two participants, including 15 with IGD and 27 health controls (HCs), underwent a sequential risk-taking task. Hierarchy Bayesian modeling was adopted to measure risky propensity, behavioral consistence, and affection by emotion ratings from last trial. Concurrent electroencephalogram and functional near-infrared spectroscopy (EEG-fNIRS) recordings were performed to demonstrate when, where and how the previous-round feedback affects the decision making to the next round. We discovered that the IGD illustrated heightened risk-taking propensity as compared to the HCs, indicating by the computational modeling (p = 0.028). EEG results also showed significant time window differences in univariate and multivariate pattern analysis between the IGD and HCs after the loss of the game. Further, reduced brain activation in the prefrontal cortex during the task was detected in IGD as compared to that of the control group. The findings underscore the importance of understanding the aberrant decision-making processes in IGD and suggest potential implications for future interventions and treatments aimed at addressing this behavioral addiction.
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Toma de Decisiones , Electroencefalografía , Trastorno de Adicción a Internet , Humanos , Masculino , Toma de Decisiones/fisiología , Trastorno de Adicción a Internet/fisiopatología , Trastorno de Adicción a Internet/diagnóstico por imagen , Adulto Joven , Adulto , Femenino , Espectroscopía Infrarroja Corta/métodos , Asunción de Riesgos , Juegos de Video/psicología , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/fisiopatología , Imagen Multimodal , Retroalimentación Psicológica/fisiología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatologíaRESUMEN
Social pain, a multifaceted emotional response triggered by interpersonal rejection or criticism, profoundly impacts mental well-being and social interactions. While prior research has implicated the right ventrolateral prefrontal cortex (rVLPFC) in mitigating social pain, the precise neural mechanisms and downstream effects on subsequent social attitudes remain elusive. This study employed transcranial magnetic stimulation (TMS) integrated with fMRI recordings during a social pain task to elucidate these aspects. Eighty participants underwent either active TMS targeting the rVLPFC (n = 41) or control stimulation at the vertex (n = 39). Our results revealed that TMS-induced rVLPFC facilitation significantly reduced self-reported social pain, confirming the causal role of the rVLPFC in social pain relief. Functional connectivity analyses demonstrated enhanced interactions between the rVLPFC and the dorsolateral prefrontal cortex, emphasizing the collaborative engagement of prefrontal regions in emotion regulation. Significantly, we observed that negative social feedback led to negative social attitudes, whereas rVLPFC activation countered this detrimental effect, showcasing the potential of the rVLPFC as a protective buffer against adverse social interactions. Moreover, our study uncovered the impact role of the hippocampus in subsequent social attitudes, a relationship particularly pronounced during excitatory TMS over the rVLPFC. These findings offer promising avenues for improving mental health within the intricate dynamics of social interactions. By advancing our comprehension of the neural mechanisms underlying social pain relief, this research introduces novel intervention strategies for individuals grappling with social distress. Empowering individuals to modulate rVLPFC activation may facilitate reshaping social attitudes and successful reintegration into communal life.
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Imagen por Resonancia Magnética , Corteza Prefrontal , Estimulación Magnética Transcraneal , Humanos , Estimulación Magnética Transcraneal/métodos , Masculino , Femenino , Adulto Joven , Corteza Prefrontal/fisiología , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/fisiopatología , Adulto , Actitud , Interacción Social , Dolor/fisiopatología , Dolor/psicología , Mapeo Encefálico/métodos , Corteza Prefontal Dorsolateral/fisiología , Corteza Prefontal Dorsolateral/diagnóstico por imagenRESUMEN
Prefrontal cortical (PFC) dysfunction has been linked to disorders exhibiting deficits in cognitive performance, attention, motivation, and impulse control. Neurons of the PFC are susceptible to glutamatergic excitotoxicity, an effect associated with cortical degeneration in frontotemporal disorders (FTDs). PFC susceptibility to environmental toxicant exposure, one possible contributor to sporadic FTD, has not been systematically studied. Here, we tested the ability of a well-known environmental neurotoxicant, methylmercury (MeHg), to induce hyperexcitability in medial prefrontal cortex (mPFC) excitatory pyramidal neurons, using whole cell patch-clamp recording. Acute MeHg exposure (20 µM) produced significant mPFC dysfunction, with a shift in the excitatory to inhibitory (E-I) balance toward increased excitability. Both excitatory postsynaptic current (EPSC) and inhibitory postsynaptic current (IPSC) charges were significantly increased after MeHg exposure. MeHg increased EPSC frequency, but there was no observable effect on IPSC frequency, EPSC amplitude or IPSC amplitude. Neither evoked AMPA receptor- nor NMDA receptor-mediated EPSC amplitudes were affected by MeHg. However, excitatory synapses experienced a significant reduction in paired-pulse depression and probability of release. In addition, MeHg induced temporal synchrony in spontaneous IPSCs, reflecting mPFC inhibitory network dysfunction. MeHg exposure also produced increased intrinsic excitability in mPFC neurons, with an increase in action potential firing rate. The observed effects of MeHg on mPFC reflect key potential mechanisms for neuropsychological symptoms from MeHg poisoning. Therefore, MeHg has a significant effect on mPFC circuits known to contribute to cognitive and emotional function and might contribute to etiology of neurodegenerative diseases, such as FTD.NEW & NOTEWORTHY Prefrontal cortical neurons are highly susceptible to glutamatergic excitotoxicity associated with neuronal degeneration in frontal dementia and to environmental toxicant exposure, one potential contributor to FTD. However, this has not been systematically studied. Our results demonstrate that methylmercury exposure leads to hyperexcitability of prefrontal cortical neurons by shifting excitatory to inhibitory (E-I) balance and raising sensitivity for spiking. Our results provide a mechanism by which environmental neurotoxicants may contribute to pathogenesis of diseases such as FTD.
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Potenciales Postsinápticos Excitadores , Compuestos de Metilmercurio , Corteza Prefrontal , Células Piramidales , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiopatología , Animales , Compuestos de Metilmercurio/toxicidad , Masculino , Células Piramidales/efectos de los fármacos , Células Piramidales/fisiología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Ratas , Ratas Sprague-Dawley , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Potenciales Postsinápticos Inhibidores/fisiología , Red Nerviosa/efectos de los fármacos , Red Nerviosa/fisiopatologíaRESUMEN
The temporal component of episodic memory has been recognized as a sensitive behavioral marker in early stage of Alzheimer's disease (AD) patients. However, parallel studies in AD animals are currently lacking, and the underlying neural circuit mechanisms remain poorly understood. Using a novel AppNL-G-F knock-in (APP-KI) rat model, the developmental changes of temporal order memory (TOM) and the relationship with medial prefrontal cortex and perirhinal cortex (mPFC-PRH) circuit were determined through in vivo electrophysiology and microimaging technique. We observed a deficit in TOM performance during the object temporal order memory task (OTOMT) in APP-KI rats at 6 month old, which was not evident at 3 or 4 months of age. Alongside behavioral changes, we identified a gradually extensive and aggravated regional activation and functional alterations in the mPFC and PRH during the performance of OTOMT, which occurred prior to the onset of TOM deficits. Moreover, coherence analysis showed that the functional connectivity between the mPFC and PRH could predict the extent of future behavioral performance. Further analysis revealed that the aberrant mPFC-PRH interaction mainly attributed to the progressive deterioration of synaptic transmission, information flow and network coordination from mPFC to PRH, suggesting the mPFC dysfunction maybe the key area of origin underlying the early changes of TOM. These findings identify a pivotal role of the mPFC-PRH circuit in mediating the TOM deficits in the early stage of AD, which holds promising clinical translational value and offers potential early biological markers for predicting AD memory progression.
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Enfermedad de Alzheimer , Corteza Perirrinal , Corteza Prefrontal , Animales , Corteza Prefrontal/fisiopatología , Corteza Perirrinal/fisiología , Enfermedad de Alzheimer/fisiopatología , Ratas , Masculino , Trastornos de la Memoria/fisiopatología , Modelos Animales de Enfermedad , Ratas Transgénicas , Vías Nerviosas/fisiopatología , Memoria EpisódicaRESUMEN
Studies of the impact of brain injury on memory processes often focus on the quantity and episodic richness of those recollections. Here, we argue that the organization of one's recollections offers critical insights into the impact of brain injury on functional memory. It is well-established in studies of word list memory that free recall of unrelated words exhibits a clear temporal organization. This temporal contiguity effect refers to the fact that the order in which word lists are recalled reflects the original presentation order. Little is known, however, about the organization of recall for semantically rich materials, nor how recall organization is impacted by hippocampal damage and memory impairment. The present research is the first study, to our knowledge, of temporal organization in semantically rich narratives in three groups: (1) Adults with bilateral hippocampal damage and severe declarative memory impairment, (2) adults with bilateral ventromedial prefrontal cortex (vmPFC) damage and no memory impairment, and (3) demographically matched non-brain-injured comparison participants. We find that although the narrative recall of adults with bilateral hippocampal damage reflected the temporal order in which those narratives were experienced above chance levels, their temporal contiguity effect was significantly attenuated relative to comparison groups. In contrast, individuals with vmPFC damage did not differ from non-brain-injured comparison participants in temporal contiguity. This pattern of group differences yields insights into the cognitive and neural systems that support the use of temporal organization in recall. These data provide evidence that the retrieval of temporal context in narrative recall is hippocampal-dependent, whereas damage to the vmPFC does not impair the temporal organization of narrative recall. This evidence of limited but demonstrable organization of memory in participants with hippocampal damage and amnesia speaks to the power of narrative structures in supporting meaningfully organized recall despite memory impairment.
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Amnesia , Hipocampo , Recuerdo Mental , Humanos , Hipocampo/patología , Hipocampo/diagnóstico por imagen , Hipocampo/fisiopatología , Recuerdo Mental/fisiología , Masculino , Femenino , Persona de Mediana Edad , Amnesia/fisiopatología , Amnesia/patología , Amnesia/psicología , Adulto , Narración , Anciano , Pruebas Neuropsicológicas , Factores de Tiempo , Corteza Prefrontal/patología , Corteza Prefrontal/fisiopatología , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/lesionesRESUMEN
The prefrontal cortex (PFC) has justifiably become a significant focus of chronic pain research. Collectively, decades of rodent and human research have provided strong rationale for studying the dysfunction of the PFC as a contributing factor in the development and persistence of chronic pain and as a key supraspinal mechanism for pain-induced comorbidities such as anxiety, depression, and cognitive decline. Chronic pain alters the structure, chemistry, and connectivity of PFC in both humans and rodents. In this review, we broadly summarize the complexities of reported changes within both rodent and human PFC caused by pain and offer insight into potential pharmacological and nonpharmacological approaches for targeting PFC to treat chronic pain and pain-associated comorbidities. SIGNIFICANCE STATEMENT: Chronic pain is a significant unresolved medical problem causing detrimental changes to physiological, psychological, and behavioral aspects of life. Drawbacks of currently approved pain therapeutics include incomplete efficacy and potential for abuse producing a critical need for novel approaches to treat pain and comorbid disorders. This review provides insight into how manipulation of prefrontal cortex circuits could address this unmet need of more efficacious and safer pain therapeutics.
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Corteza Prefrontal , Corteza Prefrontal/fisiopatología , Corteza Prefrontal/metabolismo , Humanos , Animales , Dolor Crónico/fisiopatología , Dolor Crónico/terapia , Dolor/fisiopatología , Dolor/tratamiento farmacológicoRESUMEN
BACKGROUND: Fatigue is one of the most common neurological symptoms reported post coronavirus disease 2019 (COVID-19) infection. In order to establish effective early intervention strategies, more emphasis should be placed on the correlation between fatigue and cortical neurophysiological changes, especially in healthcare workers, who are at a heightened risk of COVID-19 infection. METHODS: A prospective cohort study was conducted involving 29 COVID-19 medical workers and 24 healthy controls. The assessment included fatigue, sleep and health quality, psychological status, and physical capacity. Functional near-infrared spectroscopy (fNIRS) was employed to detect activation of brain regions. Bilateral primary motor cortex (M1) excitabilities were measured using single- and paired-pulse transcranial magnetic stimulation. Outcomes were assessed at 1, 3, and 6 months into the disease course. RESULTS: At 1-month post-COVID-19 infection, 37.9% of patients experienced severe fatigue symptoms, dropping to 10.3% at 3 months. Interestingly, the remarkable decreased activation/excitability of bilateral prefrontal lobe (PFC) and M1 were closely linked to fatigue symptoms after COVID-19. Notably, greater increase in M1 region excitability correlated with more significant fatigue improvement. Re-infected patients exhibited lower levels of brain activation and excitability compared to single-infection patients. CONCLUSIONS: Both single infection and reinfection of COVID-19 lead to decreased activation and excitability of the PFC and M1. The degree of excitability improvement in the M1 region correlates with a greater recovery in fatigue. Based on these findings, targeted interventions to enhance and regulate the excitability of M1 may represent a novel strategy for COVID-19 early rehabilitation. TRIAL REGISTRATION: The Ethics Review Committee of Xijing Hospital, No. KY20232051-F-1; www.chictr.org.cn , ChiCTR2300068444.
Asunto(s)
COVID-19 , Fatiga , Personal de Salud , Corteza Motora , Corteza Prefrontal , Estimulación Magnética Transcraneal , Humanos , COVID-19/fisiopatología , Fatiga/fisiopatología , Masculino , Femenino , Estudios Longitudinales , Adulto , Corteza Prefrontal/fisiopatología , Corteza Prefrontal/diagnóstico por imagen , Corteza Motora/fisiopatología , Persona de Mediana Edad , SARS-CoV-2/aislamiento & purificación , Estudios Prospectivos , Espectroscopía Infrarroja Corta , Estudios de CohortesRESUMEN
BACKGROUND: Progressive supranuclear palsy (PSP) is a rare 4R-tauopathy. Transcranial direct current stimulation (tDCS) may improve specific symptoms. OBJECTIVES: This randomized, double-blinded, sham-controlled trial aimed at verifying the short-, mid-, and long-term effect of multiple sessions of anodal tDCS over the left dorsolateral prefrontal cortex (DLPFC) cortex in PSP. METHODS: Twenty-five patients were randomly assigned to active or sham stimulation (2 mA for 20 minute) for 5 days/week for 2 weeks. Participants underwent assessments at baseline, after the 2-week stimulation protocol, then after 45 days and 3 months from baseline. Primary outcomes were verbal and semantic fluency. The efficacy was verified with analysis of covariance. RESULTS: We failed to detect a significant effect of active stimulation on primary outcomes. Stimulation was associated to worsening of specific behavioral complaints. CONCLUSIONS: A 2-week protocol of anodal left DLPFC tDCS is not effective in PSP. Specific challenges in running symptomatic clinical trials with classic design are highlighted. © 2024 International Parkinson and Movement Disorder Society.
Asunto(s)
Corteza Prefrontal , Parálisis Supranuclear Progresiva , Estimulación Transcraneal de Corriente Directa , Humanos , Parálisis Supranuclear Progresiva/terapia , Parálisis Supranuclear Progresiva/fisiopatología , Masculino , Femenino , Estimulación Transcraneal de Corriente Directa/métodos , Anciano , Persona de Mediana Edad , Método Doble Ciego , Corteza Prefrontal/fisiopatología , Resultado del Tratamiento , Corteza Prefontal Dorsolateral/fisiologíaRESUMEN
BACKGROUND: Previous evidence suggests that early life complications (ELCs) interact with polygenic risk for schizophrenia (SCZ) in increasing risk for the disease. However, no studies have investigated this interaction on neurobiological phenotypes. Among those, anomalous emotion-related brain activity has been reported in SCZ, even if evidence of its link with SCZ-related genetic risk is not solid. Indeed, it is possible this relationship is influenced by non-genetic risk factors. Thus, this study investigated the interaction between SCZ-related polygenic risk and ELCs on emotion-related brain activity. METHODS: 169 healthy participants (HP) in a discovery and 113 HP in a replication sample underwent functional magnetic resonance imaging (fMRI) during emotion processing, were categorized for history of ELCs and genome-wide genotyped. Polygenic risk scores (PRSs) were computed using SCZ-associated variants considering the most recent genome-wide association study. Furthermore, 75 patients with SCZ also underwent fMRI during emotion processing to verify consistency of their brain activity patterns with those associated with risk factors for SCZ in HP. RESULTS: Results in the discovery and replication samples indicated no effect of PRSs, but an interaction between PRS and ELCs in left ventrolateral prefrontal cortex (VLPFC), where the greater the activity, the greater PRS only in presence of ELCs. Moreover, SCZ had greater VLPFC response than HP. CONCLUSIONS: These results suggest that emotion-related VLPFC response lies in the path from genetic and non-genetic risk factors to the clinical presentation of SCZ, and may implicate an updated concept of intermediate phenotype considering early non-genetic factors of risk for SCZ.
Asunto(s)
Emociones , Imagen por Resonancia Magnética , Herencia Multifactorial , Esquizofrenia , Humanos , Esquizofrenia/fisiopatología , Esquizofrenia/genética , Esquizofrenia/diagnóstico por imagen , Masculino , Femenino , Adulto , Emociones/fisiología , Adulto Joven , Estudio de Asociación del Genoma Completo , Factores de Riesgo , Predisposición Genética a la Enfermedad , Corteza Prefrontal/fisiopatología , Corteza Prefrontal/diagnóstico por imagen , Encéfalo/fisiopatología , Encéfalo/diagnóstico por imagen , Voluntarios Sanos , Persona de Mediana Edad , Puntuación de Riesgo GenéticoRESUMEN
Individuals with attention deficit-hyperactivity disorder (ADHD) struggle with the interaction of attention and emotion. The ventromedial prefrontal cortex (vmPFC) and dorsolateral prefrontal cortex (dlPFC) are assumed to be involved in this interaction. In the present study, we aimed to explore the effect of stimulation applied over the dlPFC and vmPFC on attention bias in individuals with ADHD. Twenty-three children with ADHD performed the emotional Stroop and dot probe tasks during transcranial direct current stimulation (tDCS) in 3 conditions: anodal dlPFC (F3)/cathodal vmPFC (Fp2), anodal vmPFC (Fp2)/cathodal dlPFC (F3), and sham stimulation. Findings suggest reduction of attention bias in both real conditions based on emotional Stroop task and not dot probe task. These results were independent of emotional states. The dlPFC and vmPFC are involved in attention bias in ADHD. tDCS can be used for attention bias modification in children with ADHD.