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Depression is highly comorbid among individuals with Parkinson's Disease (PD), who often experience unique challenges to accessing and benefitting from empirically supported interventions like Cognitive Behavioral Therapy (CBT). Given the role of reward processing in both depression and PD, this study analyzed a subset (N = 25) of participants who participated in a pilot telemedicine intervention of PD-informed CBT, and also completed a Reward- and Punishment-Learning Task (RPLT) at baseline. At the conclusion of CBT, participants were categorized into treatment responders (n = 14) and non-responders (n = 11). Responders learned more optimally from negative rather than positive feedback on the RPLT, while this pattern was reversed in non-responders. Computational modeling suggested group differences in learning rate to negative feedback may drive the observed differences. Overall, the results suggest that a within-subject bias for punishment-based learning might help to predict response to CBT intervention for depression in those with PD.Plain Language Summary Performance on a Computerized Task may predict which Parkinson's Disease Patients benefit from Cognitive Behavioral Treatment of Clinical DepressionWhy was the study done? Clinical depression regularly arises in individuals with Parkinson's Disease (PD) due to the neurobiological changes with the onset and progression of the disease as well as the unique psychosocial difficulties associated with living with a chronic condition. Nonetheless, psychiatric disorders among individuals with PD are often underdiagnosed and likewise undertreated for a variety of reasons. The results of our study have implications about how to improve the accuracy and specificity of mental health treatment recommendations in the future to maximize benefits for individuals with PD, who often face additional barriers to accessing quality mental health treatment.What did the researchers do? We explored whether performance on a computerized task called the Reward- and Punishment-Learning Task (RPLT) helped to predict response to Cognitive Behavioral Therapy (CBT) for depression better than other predictors identified in previous studies. Twenty-five individuals with PD and clinical depression that completed a 10-week telehealth CBT program were assessed for: Demographics (Age, gender, etc.); Clinical information (PD duration, mental health diagnoses, levels of anxiety/depression, etc.); Neurocognitive performance (Memory, processing speed, impulse control, etc.); and RPLT performance.What did the researchers find? A total of 14 participants significantly benefitted from CBT treatment while 11 did not significantly benefit from treatment.There were no differences before treatment in the demographics, clinical information, and neurocognitive performance of those participants who ended up benefitting from the treatment versus those who did not.There were, however, differences before treatment in RPLT performance so that those individuals that benefitted from CBT seemed to learn better from negative feedback.What do the findings mean? Our results suggest that the CBT program benefitted those PD patients with clinical depression that seemed to overall learn best from avoiding punishment rather than obtaining reward which was targeted in CBT by focusing on increasing engagement in rewarding activities. The Reward- and Punishment-Learning Task hence may be a useful tool to help predict treatment response and provide more individualized recommendations on how to best maximize the benefits of psychotherapy for individuals with PD that may struggle to connect to mental health care. Caution is recommended about interpretating these results beyond this study as the overall number of participants was small and the data for this study were collected as part of a previous study so there was no opportunity to include additional measurements of interest.
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Terapia Cognitivo-Conductual , Enfermedad de Parkinson , Castigo , Recompensa , Humanos , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/psicología , Enfermedad de Parkinson/complicaciones , Masculino , Femenino , Terapia Cognitivo-Conductual/métodos , Anciano , Persona de Mediana Edad , Comorbilidad , Depresión/terapia , Depresión/psicología , Aprendizaje , Telemedicina/métodos , Resultado del Tratamiento , Trastorno Depresivo/terapia , Trastorno Depresivo/psicologíaRESUMEN
The cognitive impact of psychological trauma can manifest as a range of post-traumatic stress symptoms that are often attributed to impairments in learning from positive and negative outcomes, aka reinforcement learning. Research on the impact of trauma on reinforcement learning has mainly been inconclusive. This study aimed to circumscribe the impact of psychological trauma on reinforcement learning in the context of neural response in time and frequency domains. Two groups of participants were tested - those who had experienced psychological trauma and a control group who had not - while they performed a probabilistic classification task that dissociates learning from positive and negative feedback during a magnetoencephalography (MEG) examination. While the exposure to trauma did not exhibit any effects on learning accuracy or response time for positive or negative feedback, MEG cortical activity was modulated in response to positive feedback. In particular, the medial and lateral orbitofrontal cortices (mOFC and lOFC) exhibited increased activity, while the insular and supramarginal cortices showed decreased activity during positive feedback presentation. Furthermore, when receiving negative feedback, the trauma group displayed higher activity in the medial portion of the superior frontal cortex. The timing of these activity changes occurred between 160 and 600 ms post feedback presentation. Analysis of the time-frequency domain revealed heightened activity in theta and alpha frequency bands (4-10 Hz) in the lOFC in the trauma group. Moreover, dividing the two groups according to their learning performance, the activity for the non-learner subgroup was found to be lower in lOFC and higher in the supramarginal cortex. These differences were found in the trauma group only. The results highlight the localization and neural dynamics of feedback processing that could be affected by exposure to psychological trauma. This approach and associated findings provide a novel framework for understanding the cognitive correlates of psychological trauma in relation to neural dynamics in the space, time, and frequency domains. Subsequent work will focus on the stratification of cognitive and neural correlates as a function of various symptoms of psychological trauma. Clinically, the study findings and approach open the possibility for neuromodulation interventions that synchronize cognitive and psychological constructs for individualized treatment.
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Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental problems with various genetic and environmental components. The ASD diagnosis is based on symptom expression without reliance on any biomarkers. The genetic contributions in ASD remain elusive. Various studies have linked ASD with iron. Since iron plays a crucial role in brain development, neurotransmitter synthesis, neuronal myelination and mitochondrial function, we hypothesized that iron dysregulation in the brain could play a role and contribute to the pathogenesis of ASD. In this study, we investigated single nucleotide polymorphisms in ASD in various iron metabolism genes, including the Transferrin Receptor (TFRC) gene (rs11915082), the Solute Carrier Family 11 Member 2 (SLC11A2) gene (rs1048230 and rs224589), the Solute Carrier Family 40 Member 1 (SLC40A1) gene (rs1439816), and hepcidin antimicrobial peptide (HAMP) gene (rs10421768). We recruited 48 patients with ASD and 88 matched non-ASD controls. Our results revealed a significant difference between ASD and controls in the G allele of the TFRC gene rs11915082, and in the C allele of the SLC40A1 gene rs1439816. In silico analysis demonstrated potential positive role of the indicated genetic variations in ASD development and pathogenesis. These results suggest that specific genetic variations in iron metabolism genes may represent part of early genetic markers for early diagnosis of ASD. A significant effect of SNPs, groups (ASD/control) as well as interaction between SNPs and groups was revealed. Follow-up post hoc tests showed a significant difference between the ASD and control groups in rs11915082 (TFRC gene) and rs1439816 (SLC40A1 gene). Backward conditional logistic regression using both the genotype and allele data showed similar ability in detecting ASD using allel model (Nagelkerke R2 = 0.350 p = 0.967; Variables: rs1439816, rs11915082) compared to genotype model (Nagelkerke R2 = 0.347, p = 0.430; Variables: rs1439816 G, rs1439816 C, rs10421768 A). ROC curve showed 54% sensitivity in detecting ASD compared to 47% for the genotype model. Both models differentiated controls with high accuracy; the allele model had a specificity of 91% compared to 92% for the genotype model. In conclusion, our findings suggest that specific genetic variations in iron metabolism may represent early biomarkers for a diagnosis of ASD. Further research is needed to correlate these markers with specific blood iron indicators and their contribution to brain development and behavior.
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Trastorno del Espectro Autista , Humanos , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/diagnóstico , Polimorfismo de Nucleótido Simple/genética , Genotipo , Hierro/metabolismo , Biomarcadores , Predisposición Genética a la EnfermedadRESUMEN
Foraging entails a complex balance between approach and avoidance alongside sensorimotor and homeostatic processes under the control of multiple cortical and subcortical areas. Recently, it has become clear that several thalamic nuclei located near the midline regulate motivated behaviors. However, one midline thalamic nucleus that project to key nodes in the foraging network, the central medial (CMT) nucleus, has received little attention so far. Therefore, the present study examined CMT contributions to foraging behavior using inactivation and unit recording techniques in male rats. Inactivation of CMT or the basolateral amygdala (BLA) with muscimol abolished the rats' normally cautious behavior in the foraging task. Moreover, CMT neurons showed large but heterogeneous activity changes during the foraging task, with many neurons decreasing or increasing their discharge rates, with a modest bias for the latter. A generalized linear model revealed that the nature (inhibitory vs. excitatory) and relative magnitude of the activity modulations seen in CMT neurons differed markedly from those of principal BLA cells but were very similar to those of fast-spiking BLA interneurons. Together, these findings suggest that CMT is an important regulator of foraging behavior. In the Discussion, we consider how CMT is integrated in the network of structures that regulate foraging.SIGNIFICANCE STATEMENTForaging entails a complex balance between approach and avoidance alongside sensorimotor and homeostatic processes under the control of multiple cortical and subcortical areas. Although the central medial thalamic (CMT) nucleus is connected to many nodes in this network, its role in the regulation of foraging behavior has not been investigated so far. Here, we examined CMT contributions to foraging behavior using inactivation and unit recording techniques. We found that CMT inactivation abolishes the rats' normally cautious foraging behavior and that CMT neurons show large but heterogeneous changes in firing rates during the foraging task. Together, these results suggest that CMT is an important regulator of foraging behavior.
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Objective: Subanesthetic ketamine rapidly reduces depressive symptoms and suicidal ideation in some depressed patients. Its effects on neurocognitive functioning in such individuals with significant suicidal ideation is not well understood, even though certain neurocognitive deficits are associated with suicide behavior beyond clinical symptoms.Methods: In this study, depressed patients with clinically significant suicidal ideation (n = 78) underwent neuropsychological testing before and 1 day after double-blind treatment with intravenous ketamine (n = 39) or midazolam (n = 39). A subgroup randomized to midazolam whose ideation did not remit after initial infusion received open ketamine and additional neurocognitive testing a day after this treatment. The primary outcome was change in performance on this neurocognitive battery. The study was conducted between November 2012 and January 2017.Results: Blinded ketamine produced rapid improvement in suicidal ideation and mood in comparison to midazolam, as we had reported previously. Ketamine, relative to midazolam, was also associated with specific improvement in reaction time (Choice RT) and interference processing/cognitive control (computerized Stroop task)-the latter a measure that has been associated with past suicide attempt in depression. In midazolam nonremitters later treated with open ketamine and retested, reaction time and interference processing/cognitive control also improved relative to both of their prior assessments. Neurocognitive improvement, however, was not correlated with changes in depression, suicidal thinking, or general mood.Conclusions: Overall, ketamine was found to have a positive therapeutic effect on neurocognition 1 day after treatment on at least 1 measure associated with suicidal behavior in the context of depression. Results suggest additional independent therapeutic effects for ketamine in the treatment of depressed patients at risk for suicidal behavior.Trial Registration: ClinicalTrials.gov identifier: NCT01700829.
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Cognición/efectos de los fármacos , Depresión , Ketamina , Midazolam , Tiempo de Reacción/efectos de los fármacos , Ideación Suicida , Adulto , Anestésicos Intravenosos/administración & dosificación , Anestésicos Intravenosos/efectos adversos , Depresión/diagnóstico , Depresión/tratamiento farmacológico , Depresión/fisiopatología , Depresión/psicología , Femenino , Humanos , Ketamina/administración & dosificación , Ketamina/efectos adversos , Masculino , Midazolam/administración & dosificación , Midazolam/efectos adversos , Trastornos Neurocognitivos/inducido químicamente , Trastornos Neurocognitivos/diagnóstico , Pruebas Neuropsicológicas , Gravedad del Paciente , Resultado del TratamientoRESUMEN
Anxiety spectrum disorders are characterized by excessive and uncontrollable worrying about potential negative events in the short- and long-term future. Various reports linked anxiety spectrum disorders with working memory (WM) deficits despite conflicting results stemming from different study approaches. It remains unclear, however, how different anxiety spectrum disorders such as generalized anxiety disorder (GAD), social anxiety disorder (SAD), and panic disorder (PD), differ in WM function. In this study, we utilized verbal, numerical, and sequential evaluations of WM to cover most possible facets of the WM data space. We used principal component analysis to extract the uncorrelated/whitened components of WM based on these measures. We evaluated medication-free patients with GAD, SAD, and PD patients as well as matched healthy individuals using a battery that measures WM duration and load. We found that patients with GAD and SAD, but not PD, exhibited poor performance only in the WM principal component that represents maintenance. There were no other significant differences between the four groups. Further, different WM components significantly predicted the severity of anxiety symptoms in the groups. We explored the clinical utility of WM components for differentiating patients with anxiety spectrum disorders from healthy individuals. By only using the WM components that represent maintenance and encoding, we managed to differentiate patients from controls in 84% of cases. For the first time, we present multiple novel approaches to examine cognitive function and design cognitive screening, and potentially diagnostics, for psychiatric disorders.
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Dysregulation of habit formation has been recently proposed as pivotal to eating disorders. Here, we report that a subset of patients suffering from restrictive anorexia nervosa have enhanced habit formation compared with healthy controls. Habit formation is modulated by striatal cholinergic interneurons. These interneurons express vesicular transporters for acetylcholine (VAChT) and glutamate (VGLUT3) and use acetylcholine/glutamate cotransmission to regulate striatal functions. Using mice with genetically silenced VAChT (VAChT conditional KO, VAChTcKO) or VGLUT3 (VGLUT3cKO), we investigated the roles that acetylcholine and glutamate released by cholinergic interneurons play in habit formation and maladaptive eating. Silencing glutamate favored goal-directed behaviors and had no impact on eating behavior. In contrast, VAChTcKO mice were more prone to habits and maladaptive eating. Specific deletion of VAChT in the dorsomedial striatum of adult mice was sufficient to phenocopy maladaptive eating behaviors of VAChTcKO mice. Interestingly, VAChTcKO mice had reduced dopamine release in the dorsomedial striatum but not in the dorsolateral striatum. The dysfunctional eating behavior of VAChTcKO mice was alleviated by donepezil and by l-DOPA, confirming an acetylcholine/dopamine deficit. Our study reveals that loss of acetylcholine leads to a dopamine imbalance in striatal compartments, thereby promoting habits and vulnerability to maladaptive eating in mice.
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Acetilcolina/metabolismo , Cuerpo Estriado , Trastornos de Alimentación y de la Ingestión de Alimentos/metabolismo , Ácido Glutámico/metabolismo , Interneuronas/metabolismo , Adulto , Animales , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiopatología , Donepezilo/farmacología , Conducta Alimentaria/efectos de los fármacos , Trastornos de Alimentación y de la Ingestión de Alimentos/tratamiento farmacológico , Trastornos de Alimentación y de la Ingestión de Alimentos/genética , Trastornos de Alimentación y de la Ingestión de Alimentos/fisiopatología , Femenino , Humanos , Levodopa/farmacología , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Proteínas de Transporte Vesicular de Acetilcolina/genética , Proteínas de Transporte Vesicular de Acetilcolina/metabolismoRESUMEN
Depression can occur due to common major life transitions, such as giving birth, menopause, retirement, empty-nest transition, and midlife crisis. Although some of these transitions are perceived as positive (e.g., giving birth), they may still lead to depression. We conducted a systematic literature review of the factors underlying the occurrence of depression following major life transition in some individuals. This review shows that major common life transitions can cause depression if they are sudden, major, and lead to loss (or change) of life roles (e.g., no longer doing motherly or fatherly chores after children leave family home). Accordingly, we provide a theoretical framework that explains depression caused by transitions in women. One of the most potential therapeutic methods of ameliorating depression associated with life transitions is either helping individuals accept their new roles (e.g., accepting new role as a mother to ameliorate postpartum depression symptoms) or providing them with novel life roles (e.g., volunteering after retirement or children leave family home) may help them overcome their illness.
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Depresión/epidemiología , Depresión/etiología , Rol de Género , Acontecimientos que Cambian la Vida , Modelos Psicológicos , Adaptación Psicológica , Depresión/psicología , Depresión Posparto/epidemiología , Depresión Posparto/etiología , Depresión Posparto/psicología , Femenino , Humanos , Embarazo , Jubilación/psicologíaAsunto(s)
Salud Global/tendencias , Trastornos Mentales/terapia , Salud Mental/tendencias , Desarrollo Sostenible/tendencias , Objetivos , Financiación de la Atención de la Salud , Humanos , Cooperación Internacional , Trastornos Mentales/economía , Trastornos Mentales/epidemiología , Servicios de Salud Mental/economíaRESUMEN
Neuropathic pain is a subset of chronic pain that is caused by neurons that are damaged or firing aberrantly in the peripheral or central nervous systems. The treatment guidelines for neuropathic pain include antidepressants, calcium channel α2 delta ligands, topical therapy, and opioids as a second-line option. Pharmacotherapy has not been effective in the treatment of neuropathic pain except in the treatment of trigeminal neuralgia with carbamazepine. The inability to properly treat neuropathic pain causes frustration in both the patients and their treating physicians. Venoms, which are classically believed to be causes of pain and death, have peptide components that have been implicated in pain relief. Although some venoms are efficacious and have shown benefits in patients, their side-effect profile precludes their more widespread use. This review identifies and explores the use of venoms in neuropathic pain relief. This treatment can open doors to potential therapeutic targets. We believe that further research into the mechanisms of action of these receptors as well as their functions in nature will provide alternative therapies as well as a window into how they affect neuropathic pain.
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Analgésicos no Narcóticos/uso terapéutico , Neuralgia/tratamiento farmacológico , Péptidos/uso terapéutico , Toxinas Biológicas/uso terapéutico , Ponzoñas/uso terapéutico , Analgésicos no Narcóticos/aislamiento & purificación , Analgésicos no Narcóticos/farmacología , Animales , Humanos , Neuralgia/diagnóstico , Neuralgia/epidemiología , Manejo del Dolor/métodos , Péptidos/aislamiento & purificación , Péptidos/farmacología , Toxinas Biológicas/aislamiento & purificación , Toxinas Biológicas/farmacología , Ponzoñas/aislamiento & purificación , Ponzoñas/farmacología , omega-Conotoxinas/aislamiento & purificación , omega-Conotoxinas/farmacología , omega-Conotoxinas/uso terapéuticoRESUMEN
In this review, we discuss the genetic etiologies of Alzheimer's disease (AD). Furthermore, we review genetic links to protein signaling pathways as novel pharmacological targets to treat AD. Moreover, we also discuss the clumps of AD-m ediated genes according to their single nucleotide polymorphism mutations. Rigorous data mining approaches justified the significant role of genes in AD prevalence. Pedigree analysis and twin studies suggest that genetic components are part of the etiology, rather than only being risk factors for AD. The first autosomal dominant mutation in the amyloid precursor protein (APP) gene was described in 1991. Later, AD was also associated with mutated early-onset (presenilin 1/2, PSEN1/2 and APP) and late-onset (apolipoprotein E, ApoE) genes. Genome-wide association and linkage analysis studies with identified multiple genomic areas have implications for the treatment of AD. We conclude this review with future directions and clinical implications of genetic research in AD.
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Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple , Presenilina-1/genética , Estudio de Asociación del Genoma Completo , HumanosRESUMEN
BACKGROUND AND OBJECTIVES: Asymmetric onset of motor symptoms in PD can affect cognitive function. We examined whether motor-symptom laterality could affect feedback-based associative learning and explored its underlying neural mechanism by functional magnetic resonance imaging in PD patients. METHODS: We recruited 63 early-stage medication-naïve PD patients (29 left-onset medication-naïve patients, 34 right-onset medication-naïve patients) and 38 matched normal controls. Subjects completed an acquired equivalence task (including acquisition, retention, and generalization) and resting-state functional magnetic resonance imaging scans. Learning accuracy and response time in each phase of the task were recorded for behavioral measures. Regional homogeneity was used to analyze resting-state functional magnetic resonance imaging data, with regional homogeneity lateralization to evaluate hemispheric functional asymmetry in the striatum. RESULTS: Left-onset patients made significantly more errors in acquisition (feedback-based associative learning) than right-onset patients and normal controls, whereas right-onset patients performed as well as normal controls. There was no significant difference among these three groups in the accuracy of either retention or generalization phase. The three groups did not show significant differences in response time. In the left-onset group, there was an inverse relationship between acquisition errors and regional homogeneity in the right dorsal rostral putamen. There were no significant regional homogeneity changes in either the left or the right dorsal rostral putamen in right-onset patients when compared to controls. CONCLUSIONS: Motor-symptom laterality could affect feedback-based associative learning in PD, with left-onset medication-naïve patients being selectively impaired. Dysfunction in the right dorsal rostral putamen may underlie the observed deficit in associative learning in patients with left-sided onset.© 2016 International Parkinson and Movement Disorder Society.
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Aprendizaje por Asociación/fisiología , Disfunción Cognitiva/fisiopatología , Lateralidad Funcional/fisiología , Neuroimagen Funcional/métodos , Enfermedad de Parkinson/fisiopatología , Putamen/fisiopatología , Anciano , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Retroalimentación Psicológica/fisiología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico por imagen , Putamen/diagnóstico por imagenRESUMEN
Major depressive disorder (MDD) is the most common non-motor manifestation of Parkinson's disease (PD) affecting 50% of patients. However, little is known about the cognitive correlates of MDD in PD. Using a computer-based cognitive task that dissociates learning from positive and negative feedback, we tested four groups of subjects: (1) patients with PD with comorbid MDD, (2) patients with PD without comorbid MDD, (3) matched patients with MDD alone (without PD), and (4) matched healthy control subjects. Furthermore, we used a mathematical model of decision-making to fit both choice and response time data, allowing us to detect and characterize differences between the groups that are not revealed by cognitive results. The groups did not differ in learning accuracy from negative feedback, but the MDD groups (PD patients with MDD and patients with MDD alone) exhibited a selective impairment in learning accuracy from positive feedback when compared to the non-MDD groups (PD patients without MDD and healthy subjects). However, response time in positive feedback trials in the PD groups (both with and without MDD) was significantly slower than the non-PD groups (MDD and healthy groups). While faster response time usually correlates with poor learning accuracy, it was paradoxical in PD groups, with PD patients with MDD having impaired learning accuracy and PD patients without MDD having intact learning accuracy. Mathematical modeling showed that both MDD groups (PD with MDD and MDD alone) were significantly slower than non-MDD groups in the rate of accumulation of information for stimuli trained by positive feedback, which can lead to lower response accuracy. Conversely, modeling revealed that both PD groups (PD with MDD and PD alone) required more evidence than other groups to make responses, thus leading to slower response times. These results suggest that PD patients with MDD exhibit cognitive profiles with mixed traits characteristic of both MDD and PD, furthering our understanding of both PD and MDD and their often-complex comorbidity. To the best of our knowledge, this is the first study to examine feedback-based learning in PD with MDD while controlling for the effects of PD and MDD.
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Anxiety disorders, including generalized anxiety disorder (GAD), social anxiety disorder (SAD), and panic anxiety disorder (PAD), are a group of common psychiatric conditions. They are characterized by excessive worrying, uneasiness, and fear of future events, such that they affect social and occupational functioning. Anxiety disorders can alter behavior and cognition as well, yet little is known about the particular domains they affect. In this study, we tested the cognitive correlates of medication-free patients with GAD, SAD, and PAD, along with matched healthy participants using a probabilistic category-learning task that allows the dissociation between positive and negative feedback learning. We also fitted all participants' data to a Q-learning model and various actor-critic models that examine learning rate parameters from positive and negative feedback to investigate effects of valence vs. action on performance. SAD and GAD patients were more sensitive to negative feedback than either PAD patients or healthy participants. PAD, SAD, and GAD patients did not differ in positive-feedback learning compared to healthy participants. We found that Q-learning models provide the simplest fit of the data in comparison to other models. However, computational analysis revealed that groups did not differ in terms of learning rate or exploration values. These findings argue that (a) not all anxiety spectrum disorders share similar cognitive correlates, but are rather different in ways that do not link them to the hallmark of anxiety (higher sensitivity to negative feedback); and (b) perception of negative consequences is the core feature of GAD and SAD, but not PAD. Further research is needed to examine the similarities and differences between anxiety spectrum disorders in other cognitive domains and potential implementation of behavioral therapy to remediate cognitive deficits.
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Lithium remains the gold standard in treating bipolar disorder but has unwanted toxicity and side effects. We previously reported that ebselen inhibits inositol monophosphatase (IMPase) and exhibits lithium-like effects in animal models through lowering of inositol. Ebselen has been tested in clinical trials for other disorders, enabling us to determine for the first time the effect of a blood-brain barrier-penetrant IMPase inhibitor on human central nervous system (CNS) function. We now report that in a double-blind, placebo-controlled trial with healthy participants, acute oral ebselen reduced brain myo-inositol in the anterior cingulate cortex, consistent with CNS target engagement. Ebselen decreased slow-wave sleep and affected emotional processing by increasing recognition of some emotions, decreasing latency time in the acoustic startle paradigm, and decreasing the reinforcement of rewarding stimuli. In summary, ebselen affects the phosphoinositide cycle and has CNS effects on surrogate markers that may be relevant to the treatment of bipolar disorder that can be tested in future clinical trials.
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Antioxidantes/farmacología , Azoles/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Inositol/metabolismo , Litio/farmacología , Compuestos de Organoselenio/farmacología , Adulto , Estudios Cruzados , Método Doble Ciego , Emociones/efectos de los fármacos , Femenino , Voluntarios Sanos , Humanos , Isoindoles , Aprendizaje/efectos de los fármacos , Masculino , Refuerzo en Psicología , Sueño/efectos de los fármacos , Encuestas y Cuestionarios , Factores de Tiempo , Adulto JovenRESUMEN
We recorded basolateral amygdala (BL) neurons in a seminaturalistic foraging task. Rats had to leave their nest to retrieve food in an elongated arena inhabited by a mechanical predator. There were marked trial-to-trial variations in behavior. After poking their head into the foraging arena and waiting there for a while, rats either retreated to their nest or initiated foraging. Before initiating foraging, rats waited longer on trials that followed failed than successful trials indicating that prior experience influenced behavior. Upon foraging initiation, most principal cells (Type-1) reduced their firing rate, while in a minority (Type-2) it increased. When rats aborted foraging, Type-1 cells increased their firing rates, whereas in Type-2 cells it did not change. Surprisingly, the opposite activity profiles of Type-1 and Type-2 units were also seen in control tasks devoid of explicit threats or rewards. The common correlate of BL activity across these tasks was movement velocity, although an influence of position was also observed. Thus depending on whether rats initiated movement or not, the activity of BL neurons decreased or increased, regardless of whether threat or rewards were present. Therefore, BL activity not only encodes threats or rewards, but is closely related to behavioral output. We propose that higher order cortical areas determine task-related changes in BL activity as a function of reward/threat expectations and internal states. Because Type-1 and Type-2 cells likely form differential connections with the central amygdala (controlling freezing), this process would determine whether movement aimed at attaining food or exploration is suppressed or facilitated. Significance statement: For decades, amygdala research has been dominated by pavlovian and operant conditioning paradigms. This work has led to the view that amygdala neurons signal threats or rewards, in turn causing defensive or approach behaviors. However, the artificial circumstances of conditioning studies bear little resemblance to normal life. In natural conditions, subjects are simultaneously presented with potential threats and rewards, forcing them to engage in a form of risk assessment. We examined this process using a seminaturalistic foraging task. In constant conditions of threats and rewards, amygdala activity could be high or low, depending on the rats' decisions on a given trial. Therefore, amygdala activity does not only encode threats or rewards but is also closely related to behavioral output.
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Amígdala del Cerebelo/fisiología , Condicionamiento Operante/fisiología , Ambiente , Miedo/psicología , Conducta Alimentaria/fisiología , Potenciales de Acción/fisiología , Amígdala del Cerebelo/citología , Animales , Conducta de Elección/fisiología , Conducta Exploratoria , Neuronas/clasificación , Neuronas/fisiología , Ratas , Ratas Sprague-Dawley , Recompensa , RobóticaRESUMEN
Previous research has shown that trial ordering affects cognitive performance, but this has not been tested using category-learning tasks that differentiate learning from reward and punishment. Here, we tested two groups of healthy young adults using a probabilistic category learning task of reward and punishment in which there are two types of trials (reward, punishment) and three possible outcomes: (1) positive feedback for correct responses in reward trials; (2) negative feedback for incorrect responses in punishment trials; and (3) no feedback for incorrect answers in reward trials and correct answers in punishment trials. Hence, trials without feedback are ambiguous, and may represent either successful avoidance of punishment or failure to obtain reward. In Experiment 1, the first group of subjects received an intermixed task in which reward and punishment trials were presented in the same block, as a standard baseline task. In Experiment 2, a second group completed the separated task, in which reward and punishment trials were presented in separate blocks. Additionally, in order to understand the mechanisms underlying performance in the experimental conditions, we fit individual data using a Q-learning model. Results from Experiment 1 show that subjects who completed the intermixed task paradoxically valued the no-feedback outcome as a reinforcer when it occurred on reinforcement-based trials, and as a punisher when it occurred on punishment-based trials. This is supported by patterns of empirical responding, where subjects showed more win-stay behavior following an explicit reward than following an omission of punishment, and more lose-shift behavior following an explicit punisher than following an omission of reward. In Experiment 2, results showed similar performance whether subjects received reward-based or punishment-based trials first. However, when the Q-learning model was applied to these data, there were differences between subjects in the reward-first and punishment-first conditions on the relative weighting of neutral feedback. Specifically, early training on reward-based trials led to omission of reward being treated as similar to punishment, but prior training on punishment-based trials led to omission of reward being treated more neutrally. This suggests that early training on one type of trials, specifically reward-based trials, can create a bias in how neutral feedback is processed, relative to those receiving early punishment-based training or training that mixes positive and negative outcomes.
RESUMEN
To test a prediction of our previous computational model of cortico-hippocampal interaction (Gluck and Myers [1993, 2001]) for characterizing individual differences in category learning, we studied young healthy subjects using an fMRI-adapted category-learning task that has two phases, an initial phase in which associations are learned through trial-and-error feedback followed by a generalization phase in which previously learned rules can be applied to novel associations (Myers et al. [2003]). As expected by our model, we found a negative correlation between learning-related hippocampal responses and accuracy during transfer, demonstrating that hippocampal adaptation during learning is associated with better behavioral scores during transfer generalization. In addition, we found an inverse relationship between Blood Oxygenation Level Dependent (BOLD) activity in the striatum and that in the hippocampal formation and the orbitofrontal cortex during the initial learning phase. Conversely, activity in the dorsolateral prefrontal cortex, orbitofrontal cortex and parietal lobes dominated over that of the hippocampal formation during the generalization phase. These findings provide evidence in support of theories of the neural substrates of category learning which argue that the hippocampal region plays a critical role during learning for appropriately encoding and representing newly learned information so that that this learning can be successfully applied and generalized to subsequent novel task demands.
Asunto(s)
Discriminación en Psicología/fisiología , Generalización Psicológica/fisiología , Hipocampo/irrigación sanguínea , Transferencia de Experiencia en Psicología/fisiología , Adulto , Femenino , Hipocampo/fisiología , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Oxígeno/sangre , Valor Predictivo de las Pruebas , Tiempo de Reacción , Adulto JovenRESUMEN
One barrier to interpreting past studies of cognition and major depressive disorder (MDD) has been the failure in many studies to adequately dissociate the effects of MDD from the potential cognitive side effects of selective serotonin reuptake inhibitors (SSRIs) use. To better understand how remediation of depressive symptoms affects cognitive function in MDD, we evaluated three groups of subjects: medication-naïve patients with MDD, medicated patients with MDD receiving the SSRI paroxetine, and healthy control (HC) subjects. All were administered a category-learning task that allows for dissociation between learning from positive feedback (reward) vs. learning from negative feedback (punishment). Healthy subjects learned significantly better from positive feedback than medication-naïve and medicated MDD groups, whose learning accuracy did not differ significantly. In contrast, medicated patients with MDD learned significantly less from negative feedback than medication-naïve patients with MDD and healthy subjects, whose learning accuracy was comparable. A comparison of subject's relative sensitivity to positive vs. negative feedback showed that both the medicated MDD and HC groups conform to Kahneman and Tversky's (1979) Prospect Theory, which expects losses (negative feedback) to loom psychologically slightly larger than gains (positive feedback). However, medicated MDD and HC profiles are not similar, which indicates that the state of medicated MDD is not "normal" when compared to HC, but rather balanced with less learning from both positive and negative feedback. On the other hand, medication-naïve patients with MDD violate Prospect Theory by having significantly exaggerated learning from negative feedback. This suggests that SSRI antidepressants impair learning from negative feedback, while having negligible effect on learning from positive feedback. Overall, these findings shed light on the importance of dissociating the cognitive consequences of MDD from those of SSRI treatment, and from cognitive evaluation of MDD subjects in a medication-naïve state before the administration of antidepressants. Future research is needed to correlate the mood-elevating effects and the cognitive balance between reward- and punishment-based learning related to SSRIs.