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A 10-Hz repetitive transcranial magnetic stimulation to the left dorsal lateral prefrontal cortex has been shown to increase dopaminergic activity in the dorsal striatum, a region strongly implicated in reinforcement learning. However, the behavioural influence of this effect remains largely unknown. We tested the causal effects of 10-Hz stimulation on behavioural and computational characteristics of reinforcement learning. A total of 40 healthy individuals were randomized into active and sham (placebo) stimulation groups. Each participant underwent one stimulation session (1500 pulses) in which stimulation was applied over the left dorsal lateral prefrontal cortex using a robotic arm. Participants then completed a reinforcement learning task sensitive to striatal dopamine functioning. Participants' choices were modelled using a reinforcement learning model (Q-learning) that calculates separate learning rates associated with positive and negative reward prediction errors. Subjects receiving active stimulation exhibited increased reward rate (number of correct responses per second of task activity) compared with those in sham. Computationally, although no group differences were observed, the active group displayed a higher learning rate for correct trials (αG) compared with incorrect trials (αL). Finally, when tested with novel pairs of stimuli, the active group displayed extremely fast reaction times, and a trend towards a higher reward rate. This study provided specific behavioural and computational accounts of altered striatal-mediated behaviour, particularly response vigour, induced by a proposed increase of dopamine activity by 10-Hz stimulation to the left dorsal lateral prefrontal cortex. Together, these findings bolster the use of repetitive transcranial magnetic stimulation to target neurocognitive disturbances attributed to the dysregulation of dopaminergic-striatal circuits.

Korsakoff’s syndrome (KS) is characterized by episodic memory impairment due to damage to the medial diencephalic structures. Although commonly associated with chronic alcoholism, starvation due to the hunger strike is one of its nonalcoholic causes. Learning the stimulus-response associations and transferring the just-learned associations to novel combinations were previously tested by specific tasks in memory-impaired patients with hippocampal, basal forebrain, and basal ganglia damage. To add to this previous research, we aimed to use the same tasks in a group of patients with hunger strike-related KS presenting a stable isolated amnestic profile. Twelve patients with hunger strike-related KS and matched healthy controls were tested in two tasks varying in task complexity. Each task included two phases: the initial phase is feedback-based learning of (simple vs. complex) stimulus-response associations, and the following phase is transfer generalization (in the presence vs. absence of feedback). On a task involving simple associations, five patients with KS failed to learn the associations, while the other seven patients showed intact learning and transfer. On the other task involving more complex associations, seven patients showed slower learning and failed at transfer generalization, whereas the other five patients failed even at the acquisition phase. These findings of a task-complexity-related impairment on associative learning and transfer represent a distinct pattern from the spared learning but impaired transfer previously observed on these tasks in patients with medial temporal lobe amnesia.

AIM: Traumatic brain injury (TBI) was associated with increased plasma serotonin 2A receptor (5-HT2AR) autoantibodies in adults who experienced neurodegenerative complications. We tested whether the baseline presence of plasma serotonin 2A receptor (5-HT2AR) autoantibodies was a significant predictor of the two-year rate of cognitive decline in middle-aged and older adult TBI. METHODS: Plasma from thirty-five middle-aged and older adult veterans (mean 65 years old) who had suffered traumatic brain injury was subjected to protein-A affinity chromatography. One-fortieth dilution of the resulting immunoglobulin (Ig) G fraction was tested for binding (in ELISA) to a linear synthetic peptide corresponding to the second extracellular loop region of the human 5-HT2A receptor. All available patients completed baseline and two-year follow-up neurocognitive tests of memory (St Louis University Mental Status), processing speed (Digit Symbol Substitution Test) and executive function (Trails-making Test, Part B). Change in cognitive performance was computed as (two-year – baseline) raw test score. RESULTS: Eighteen patients completed both baseline and two-year follow up neurocognitive tests. TBI patients harboring plasma 5-HT2AR autoantibodies at the baseline examination (n=13) did not differ significantly in their baseline clinical characteristics (age, education level) compared to TBI patients lacking baseline plasma autoantibodies (n=5). Plasma serotonin 2AR antibody-positive patients experienced a significantly greater post-baseline decline in performance on the St Louis University Mental Status test (P=0.0118) and in the Digit Symbol Substitution Test (P=0.011), but not in Trails-making Part B (P=0.129) compared to serotonin 2AR antibody-negative patients. In multivariable linear regression analyses that adjusted for age, baseline presence of plasma 5-HT2AR autoantibody was a significant predictor of the two-year rate of decline in memory, and processing speed. Binding of plasma autoantibody to the serotonin 2A receptor peptide in the enzyme linked immunosorbent assay was also significantly higher (at 1/160th titer of the protein-A eluate= 1 μg/mL IgG) in TBI patients harboring vs. those not harboring baseline plasma 5-HT2AR autoantibodies. CONCLUSION: These data suggest that plasma 5-hydroxytryptamine 2A receptor autoantibodies which were increased in approximately two-thirds of middle-aged and older adults following traumatic brain injury predicts rapid and substantial declines in cognitive function (memory and processing speed), independent of age.

Background10-Hz repetitive transcranial magnetic stimulation (rTMS) to the left dorsal lateral prefrontal cortex (DLPFC) has been shown to increase dopaminergic activity in the dorsal striatum, a region strongly implicated in reinforcement learning. However, the behavioural influence of this effect remains largely unknown.ObjectiveHere, we tested the causal effects of rTMS on behavioral and computational characteristics of reinforcement learning.Methods40 healthy individuals were randomized into Active and Sham rTMS groups. Each participant underwent one 10-Hz rTMS session (1500 pulses) in which stimulation was applied over the left DLPFC using a robotic arm. Participants then completed a reinforcement learning task sensitive to striatal dopamine functioning. Participants’ trial-to-trial training choices were modelled using a reinforcement learning model (Q-learning) that calculates separate learning rates associated with positive and negative reward prediction errors.ResultsSubjects receiving Active TMS exhibited an increased reward rate (number of correct responses per second of task activity) compared to the Sham rTMS group. Computationally, the Active rTMS group displayed a higher learning rate for correct trials (αG) compared to incorrect trials (αL). Finally, when tested with novel pairs of stimuli, the Active group displayed extremely fast reaction times, and a trend towards a higher reward rate.ConclusionsThe present study provided specific behavioral and computational accounts of altered striatal-mediated reinforcement learning induced by a proposed increase of dopamine activity by 10-Hz rTMS to the left DLPFC. Together, these findings bolster the use of TMS to target neurocognitive disturbances attributed to the dysregulation of dopaminergic-striatal circuits.

Alcohol-dependent individuals are often reported to use behavioral strategies both to escape from and avoid negative affective states, and also to approach positive affective states. However, there has been little examination of how these individuals acquire and express these types of behaviors. In this study, male adults meeting the International Classification of Diseases-10th Revision (ICD-10) criteria for alcohol dependence recruited from an outpatient treatment clinic and healthy male controls were given a computer-based task to assess learning and performance of escape, avoidance, and approach behaviors. In this task, participants control a spaceship and can either gain points by shooting an enemy spaceship or hide in safe areas to escape or avoid on-screen aversive events. We found that patients with alcohol dependence exhibited greater escape and approach behaviors, tended to show greater avoidance behavior, and achieved higher total score on the computer task than healthy controls. This is the first demonstration of such behavioral differences in this population, supporting the overactivation of both positive and negative reinforcement systems in alcohol dependence, and suggesting that such behavioral biases are not limited to alcohol-related cues. The contribution of this work to behavioral assessment and therapeutic approaches, as well as possible future directions, are discussed.

Objective To test whether Mindfulness-Based Cognitive Therapy to Prevent Suicide (MBCT-S) is associated with improvement in attentional control, an objective marker of suicide attempt. Method In the context of a randomized clinical trial targeting suicide risk in Veterans, computerized Stroop and emotion Stroop (E-Stroop) tasks were administered 3 times over 6-months follow-up to 135 high suicide risk Veterans. Seventy were randomized to receive MBCT-S in addition to enhanced treatment as usual (eTAU), and 65 were randomized to eTAU only. E-Stroop word types included positively- and negatively-valenced emotion, suicide, and combat-related words. Interference scores and mixed effects linear regression analyses were used. Results Veterans receiving MBCT-S showed a more favorable trajectory of attentional control over time, as indicated by performance on two E-Stroop tasks. Combat-stress interference scores improved over time among Veterans in MBCT-S. Interference processing time for negative affective words deteriorated over time among Veterans receiving eTAU only. Conclusions MBCT-S may effectively target attentional control, and in particular reduce processing time during affective interference, in high suicide risk Veterans. Future studies to replicate these findings are warranted.

Researchers have exerted tremendous efforts to empirically study how habits form and dominate at the expense of deliberation, yet we know very little about breaking these rigid habits to restore goal-directed control. In a three-experiment study, we first illustrate a novel approach of studying well-learned habits, in order to effectively demonstrate habit disruption. In Experiment 1, we use a Go/NoGo task with familiar color-response associations to demonstrate outcome-insensitivity when compared to novel, more flexible associations. Specifically, subjects perform more accurately when the required mapping is the familiar association of green–Go/red–NoGo than when it is red–Go/green–NoGo, confirming outcome-insensitive, habitual control. As a control condition, subjects show equivalent performance with unfamiliar color-response mappings (using the colors blue and purple mapped to Go and NoGo responses). Next, in Experiments 2 and 3, we test a motivation-based feedback manipulation in varying magnitudes (i.e., performance feedback with and without monetary incentives) to break the well-established habits elicited by our familiar stimuli. We find that although performance feedback prior to the contingency reversal test is insufficient to disrupt outcome-insensitivity in Experiment 2, a combination of performance feedback and monetary incentive is able to restore goal-directed control in Experiment 3, effectively breaking the habits. As the first successful demonstration of well-learned habit disruption in the laboratory, these findings provide new insights into how we execute and modify habits, while fostering new and translational research avenues that may be applicable to treating habit-based pathologies.

Studies of partial reinforcement in eyeblink conditioning have typically shown slower learning of a CS-US association when paired CS-US trials are interleaved with CS-alone trials. However, recent work has shown that CS-US learning is not slowed by interleaved US-alone trials. This discrepancy is surprising since both partial reinforcement protocols reduce the total number of paired CS-US trials. Previously, Kimble et al. (1955) reported that inserting a block of US-alone trials during CS-US training did not disrupt eyeblink acquisition. Here, we sought to replicate and extend these findings by comparing interleaved vs. blocked US-alone trials during CS-US paired training. Ninety-seven undergraduates volunteered for this experiment for research credit. Participants received 60 acquisition trials, consisting of either 100% CS-US paired trials, 50% US-alone trials intermixed with CS-US paired trials, or a block of 20 US-alone trials inserted between blocks of 20 CS-US trials. We also utilized a previously published computational model of hippocampal and cerebellar learning to test the effects of these US-alone protocols. Both empirical and computational results supported the finding that US-alone trials, either intermixed or inserted as a block of trials, do not disrupt acquisition of conditioned eyeblinks. Possible neural substrates of these US-alone effects are discussed.

Substance dependence is thought to be mediated by abnormalities in cognitive abilities, but how this impacts decision-making remains unclear. This study aimed to test whether people who are opiate dependent differed from never-dependent controls in learning from reward and punishment or in the generalization of learning to novel conditions. Participants with opiate dependency consisted of 21 people who were outpatients in a methadone maintenance program; the control group consisted of 21 healthy participants with no histories of substance abuse. Subjects completed a computer-based task that involved two phases: the training phase involved participants being presented with compound stimulus (a shape and color) in each trial, with the goal of learning which compounds to 'pick' for rewards or 'skip' to avoid punishment. The test phase involved a transfer test, where stimuli from the first phase were combined together to form novel compounds without feedback. The control group demonstrated fewer errors compared to opiate-dependent individuals during the training phase. In the test phase, controls used prior knowledge of both shapes and colors in responding; however, opiate-dependent individuals used shapes but did not use their knowledge of color to modulate responding. When performance during training was equated in the groups using a learning threshold, this difference between groups on the generalization test remained. A deficit in learning generalization might be indicative of group differences in learning strategies in operation during training; however, future work is necessary to uncover the specific neural substrates in action during transfer tasks, and to determine the effects of acute methadone dosage on decision-making.

Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder, characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta. Given that dopamine is critically involved in learning and other cognitive processes, such as working memory, dopamine loss in PD has been linked both to learning abnormalities and to cognitive dysfunction more generally in the disease. It is unclear, however, whether avoidance behavior is impacted in PD. This is significant, as this type of instrumental behavior plays an important role in both decision-making and emotional (dys)function. Consequently, the aim of the present study was to examine avoidance learning and operant extinction in PD using a computer-based task. On this task, participants control a spaceship and attempt to shoot an enemy spaceship to gain points. They also learn to hide in safe areas to protect from (i.e., avoid) aversive events (on-screen explosions and point loss). The results showed that patients with PD (N = 25) acquired an avoidance response during aversive periods to the same extent as healthy age- and education-matched controls (N = 19); however, patients demonstrated greater hiding during safe periods not associated with aversive events, which could represent maladaptive generalization of the avoidance response. Furthermore, this impairment was more pronounced during the extinction phase, and in patients who reported higher levels of depression. These results demonstrate for the first time that PD is associated with maladaptive avoidance patterns, which could possibly contribute to the emergence of depression in the disease.

AIMS: To evaluate temporal trends in racial/ethnic groups in rates of serious hypoglycemia among higher risk patients dually enrolled in Veterans Health Administration and Medicare fee-for-service and assess the relationship(s) between hypoglycemia rates, insulin/secretagogues and comorbid conditions. METHODS: Retrospective observational serial cross-sectional design. Patients were ≥ 65 years receiving insulin and/or secretagogues. The primary outcome was the annual (period prevalence) rates (2004–2015), per 1,000 patient years, of serious hypoglycemic events, defined as hypoglycemic-related emergency department visits or hospitalizations. RESULTS: Subjects were 77–83% White, 7–10% Black, 4–5% Hispanic

Neurocognitive detection of suicidal states has the potential to significantly advance objective risk assessment. This goal requires establishing that neurocognitive deficits fluctuate around the time of a suicide attempt. The current study therefore evaluated whether neurocognitive performance is temporally related to suicide attempt, in a sample at highrisk for suicide (n = 141). Evaluations consisted of a clinician-administered interview, self-report questionnaires, and neurocognitive tasks assessing response inhibition, attentional control, and memory recognition. Analyses examined whether neurocognitive scores significantly differed according to the following temporal suicide attempt categories: (a) past-week attempt; (b) past-year attempt (not in past week); and (c) no past-year attempt. Univariate results showed that response inhibition and memory recognition were significantly related to suicide attempt recency. Post-hoc pairwise tests showed that participants with a past-week suicide attempt showed greater impairments than those without a past-year attempt. Multivariate tests showed the same pattern of results, adjusting for age, suicide attempts prior to past year, mood disturbance, and suicidal ideation. These results show that neurocognitive assessment of response inhibition and memory recognition shows sensitivity to the recency of a suicide attempt. While future prospective studies are needed, results suggest that phasic neurocognitive deficits may serve as objective markers of short-term suicide risk.

Using high-resolution resting state functional magnetic resonance imaging (fMRI), the present study tested the hypothesis that ABCA7 genetic risk differentially affects intra-medial temporal lobe (MTL) functional connectivity between MTL subfields, versus internetwork connectivity of the MTL with the medial prefrontal cortex (mPFC), in nondemented older African Americans. Although the association of ABCA7 risk variants with Alzheimer's disease (AD) has been confirmed worldwide, its effect size on the relative odds of being diagnosed with AD is significantly higher in African Americans. However, little is known about the neural correlates of cognitive function in older African Americans and how they relate to AD risk conferred by ABCA7. In a case-control fMRI study of 36 healthy African Americans, we observed ABCA7 related impairments in behavioral generalization that was mediated by dissociation in entorhinal cortex (EC) resting state functional connectivity. Specifically, ABCA7 risk variant was associated with EC-hippocampus hyper-synchronization and EC-mPFC hypo-synchronization. Carriers of the risk genotype also had a significantly smaller anterolateral EC, despite our finding no group differences on standardized neuropsychological tests. Our findings suggest a model where impaired cortical connectivity leads to a more functionally isolated EC at rest, which translates into aberrant EC-hippocampus hyper-synchronization resulting in generalization deficits. While we cannot identify the exact mechanism underlying the observed alterations in EC structure and network function, considering the relevance of Aβ in ABCA7 related AD pathogenesis, the results of our study may reflect the synergistic reinforcement between amyloid and tau pathology in the EC, which significantly increases tau-induced neuronal loss and accelerates synaptic alterations. Finally, our results add to a growing literature suggesting that generalization of learning may be a useful tool for assessing the mild cognitive deficits seen in the earliest phases of prodromal AD, even before the more commonly reported deficits in episodic memory arise.

Annual rates of emergency department visits or hospitalizations for hypoglycemia (HYPO) were evaluated using a serial cross-sectional study design (2004-2015) of VHA/Medicare enrolled patients. Subjects were ≥65 years receiving secretagogues only (Secr), or insulin with or without Secr (Ins), and who had HbA1c value(s). Separately for Secr/Ins groups and by race/ethnicity, we assessed age/sex adjusted HYPO rates (per 1000 patients) and A1c values (from prior to an event or end of year for those without an event). In 2015, subjects were 99% men, 10% [B]lack, 6% [H]ispanic, and 75% [W]hite; 75% had major comorbidity categories; 24% had cardiovascular conditions only, and 9% advanced diabetes only. Ins use increased by 88%, similar among B/H/W. HYPO rates markedly declined for Ins and Secr in all races but remained higher for B. The percent of patients with A1c 9% also increased: 11.9%/15.8%% [B], 6.4/12.2%[W], and 12.0/17.6%[H]. Mean A1c values also increased in B/H/W, and were similar (difference ≤0.2%) between patients with and without HYPO. Guideline recommendations (post 2008) for individualized A1c goals may have mediated reductions in racial disparities for HYPO rates. Disclosure C. Tseng: None. O. Soroka: None. C.E. Myers: None. D.C. Aron: None. L.M. Pogach: None. Funding U.S. Department of Veterans Affairs (IIR14-082)

OBJECTIVE Generalization is the application of existing knowledge to novel situations. Questions remain about the precise role of the hippocampus in this facet of learning, but a connectionist model by Gluck and Myers (1993) predicts that generalization should be enhanced following hippocampal damage. METHOD In a two-category learning task, a group of amnesic patients (n = 9) learned the training items to a similar level of accuracy as matched controls (n = 9). Both groups then classified new items at various levels of distortion. RESULTS The amnesic group showed significantly more accurate generalization to high-distortion novel items, a difference also present compared to a larger group of unmatched controls (n = 33). CONCLUSIONS The model prediction of a broadening of generalization gradients in amnesia, at least for items near category boundaries, was supported by the results. Our study shows for the first time that amnesia can sometimes improve generalization. (PsycINFO Database Record

Objective Addiction is often conceptualized as a behavioral strategy for avoiding negative experiences. In rodents, opioid intake has been associated with abnormal acquisition and extinction of avoidance behavior. Here, we tested the hypothesis that these findings would generalize to human opioid-dependent subjects. Method Adults meeting DSM-IV criteria for heroin dependence and treated with opioid medication (n = 27) and healthy controls (n = 26) were recruited between March 2013 and October 2013 and given a computer-based task to assess avoidance behavior. For this task, subjects controlled a spaceship and could either gain points by shooting an enemy spaceship or hide in safe areas to avoid on-screen aversive events. Hiding duration during different periods of the task was used to measure avoidance behavior. Results While groups did not differ on escape responding (hiding) during the aversive event, heroin-dependent men (but not women) made more avoidance responses during a warning signal that predicted the aversive event (analysis of variance, sex × group interaction, P = .007). Heroin-dependent men were also slower to extinguish the avoidance response when the aversive event no longer followed the warning signal (P = .011). This behavioral pattern resulted in reduced opportunity to obtain reward without reducing risk of punishment. Results suggest that, in male patients, differences in avoidance behavior cannot be easily explained by impaired task performance or by exaggerated motor activity. Conclusions This study provides evidence for abnormal acquisition and extinction of avoidance behavior in opioid-dependent patients. Interestingly, data suggest that abnormal avoidance is demonstrated only by male patients. Findings shed light on cognitive and behavioral manifestations of opioid addiction and may facilitate development of therapeutic approaches to help affected individuals.

The dentate gyrus (DG) and area CA3 of the hippocampus are highly organized lamellar structures which have been implicated in specific cognitive functions such as pattern separation and pattern completion. Here we describe how the anatomical organization and physiology of the DG and CA3 are consistent with structures that perform pattern separation and completion. We then raise a new idea related to the complex circuitry of the DG and CA3 where CA3 pyramidal cell ‘backprojections’ play a potentially important role in the sparse firing of granule cells (GCs), considered important in pattern separation. We also propose that GC axons, the mossy fibers, already known for their highly specialized structure, have a dynamic function that imparts variance – ‘mossy fiber variance’ – which is important to pattern separation and completion. Computational modeling is used to show that when a subset of GCs become ‘dominant,’ one consequence is loss of variance in the activity of mossy fiber axons and a reduction in pattern separation and completion in the model. Empirical data are then provided using an example of ‘dominant’ GCs – subsets of GCs that develop abnormally and have increased excitability. Notably, these abnormal GCs have been identified in animal models of disease where DG-dependent behaviors are impaired. Together these data provide insight into pattern separation and completion, and suggest that behavioral impairment could arise from dominance of a subset of GCs in the DG-CA3 network.

Avoidance behavior is a typically adaptive response performed by an organism to avert harmful situations. Individuals differ remarkably in their tendency to acquire and perform new avoidance behaviors, as seen in anxiety disorders where avoidance becomes pervasive and inappropriate. In rodent models of avoidance, the inbred Wistar-Kyoto (WKY) rat demonstrates increased learning and expression of avoidance compared to the outbred Sprague Dawley (SD) rat. However, underlying mechanisms that contribute to these differences are unclear. Computational modeling techniques can help identify factors that may not be easily decipherable from behavioral data alone. Here, we utilize a reinforcement learning (RL) model approach to better understand strain differences in avoidance behavior. An actor-critic model, with separate learning rates for action selection (in the actor) and state evaluation (in the critic), was applied to individual data of avoidance acquisition from a large cohort of WKY and SD rats. Latent parameters were extracted, such as learning rate and subjective reinforcement value of foot shock, that were then compared across groups. The RL model was able to accurately represent WKY and SD avoidance behavior, demonstrating that the model could simulate individual performance. The model determined that the perceived negative value of foot shock was significantly higher in WKY than SD rats, whereas learning rate in the actor was lower in WKY than SD rats. These findings demonstrate the utility of computational modeling in identifying underlying processes that could promote strain differences in behavioral performance.

Many individuals with posttraumatic stress disorder (PTSD) report experiencing frequent intrusive memories of the original traumatic event (e.g., flashbacks). These memories can be triggered by situations or stimuli that reflect aspects of the trauma and may reflect basic processes in learning and memory, such as generalization. It is possible that, through increased generalization, non-threatening stimuli that once evoked normal memories become associated with traumatic memories. Previous research has reported increased generalization in PTSD, but the role of visual discrimination processes has not been examined. To investigate visual discrimination in PTSD, 143 participants (Veterans and civilians) self-assessed for symptom severity were grouped according to the presence of severe PTSD symptoms (PTSS) vs. few/no symptoms (noPTSS). Participants were given a visual match-to-sample pattern separation task that varied trials by spatial separation (Low, Medium, High) and temporal delays (5, 10, 20, 30 s). Unexpectedly, the PTSS group demonstrated better discrimination performance than the noPTSS group at the most difficult spatial trials (Low spatial separation). Further assessment of accuracy and reaction time using diffusion drift modeling indicated that the better performance by the PTSS group on the hardest trials was not explained by slower reaction times, but rather a faster accumulation of evidence during decision making in conjunction with a reduced threshold, indicating a tendency in the PTSS group to decide quickly rather than waiting for additional evidence to support the decision. This result supports the need for future studies examining the precise role of discrimination and generalization in PTSD, and how these cognitive processes might contribute to expression and maintenance of PTSD symptoms.

Addiction is the continuation of a habit in spite of negative consequences. A vast literature gives evidence that this poor decision-making behavior in individuals addicted to drugs also generalizes to laboratory decision making tasks, suggesting that the impairment in decision-making is not limited to decisions about taking drugs. In the current experiment, opioid-addicted individuals and matched controls with no history of illicit drug use were administered a probabilistic classification task that embeds both reward-based and punishment-based learning trials, and a computational model of decision making was applied to understand the mechanisms describing individuals' performance on the task. Although behavioral results showed that opioid-addicted individuals performed as well as controls on both reward- and punishment-based learning, the modeling results suggested subtle differences in how decisions were made between the two groups. Specifically, the opioid-addicted group showed decreased tendency to repeat prior responses, meaning that they were more likely to "chase reward" when expectancies were violated, whereas controls were more likely to stick with a previously-successful response rule, despite occasional expectancy violations. This tendency to chase short-term reward, potentially at the expense of developing rules that maximize reward over the long term, may be a contributing factor to opioid addiction. Further work is indicated to better understand whether this tendency arises as a result of brain changes in the wake of continued opioid use/abuse, or might be a pre-existing factor that may contribute to risk for addiction.

Elevated β-amyloid and impaired synaptic function in hippocampus are among the earliest manifestations of Alzheimer's disease (AD). Most cognitive assessments employed in both humans and animal models, however, are insensitive to this early disease pathology. One critical aspect of hippocampal function is its role in episodic memory, which involves the binding of temporally coincident sensory information (e.g., sights, smells, and sounds) to create a representation of a specific learning epoch. Flexible associations can be formed among these distinct sensory stimuli that enable the "transfer" of new learning across a wide variety of contexts. The current studies employed a mouse analog of an associative "transfer learning" task that has previously been used to identify risk for prodromal AD in humans. The rodent version of the task assesses the transfer of learning about stimulus features relevant to a food reward across a series of compound discrimination problems. The relevant feature that predicts the food reward is unchanged across problems, but an irrelevant feature (i.e., the context) is altered. Experiment 1 demonstrated that C57BL6/J mice with bilateral ibotenic acid lesions of hippocampus were able to discriminate between two stimuli on par with control mice; however, lesioned mice were unable to transfer or apply this learning to new problem configurations. Experiment 2 used the APPswe PS1 mouse model of amyloidosis to show that robust impairments in transfer learning are evident in mice with subtle β-amyloid-induced synaptic deficits in the hippocampus. Finally, Experiment 3 confirmed that the same transfer learning impairments observed in APPswePS1 mice were also evident in the Tg-SwDI mouse, a second model of amyloidosis. Together, these data show that the ability to generalize learned associations to new contexts is disrupted even in the presence of subtle hippocampal dysfunction and suggest that, across species, this aspect of hippocampal-dependent learning may be useful for early identification of AD-like pathology.

Exaggerated avoidance behavior is a predominant symptom in all anxiety disorders and its degree often parallels the development and persistence of these conditions. Both human and non-human animal studies suggest that individual differences as well as various contextual cues may impact avoidance behavior. Specifically, we have recently shown that female sex and inhibited temperament, two anxiety vulnerability factors, are associated with greater duration and rate of the avoidance behavior, as demonstrated on a computer-based task closely related to common rodent avoidance paradigms. We have also demonstrated that avoidance is attenuated by the administration of explicit visual signals during "non-threat" periods (i.e., safety signals). Here, we use a reinforcement-learning network model to investigate the underlying mechanisms of these empirical findings, with a special focus on distinct reward and punishment sensitivities. Model simulations suggest that sex and inhibited temperament are associated with specific aspects of these sensitivities. Specifically, differences in relative sensitivity to reward and punishment might underlie the longer avoidance duration demonstrated by females, whereas higher sensitivity to punishment might underlie the higher avoidance rate demonstrated by inhibited individuals. Simulations also suggest that safety signals attenuate avoidance behavior by strengthening the competing approach response. Lastly, several predictions generated by the model suggest that extinction-based cognitive-behavioral therapies might benefit from the use of safety signals, especially if given to individuals with high reward sensitivity and during longer safe periods. Overall, this study is the first to suggest cognitive mechanisms underlying the greater avoidance behavior observed in healthy individuals with different anxiety vulnerabilities.

Fast, inexpensive, and noninvasive identification of Alzheimer's disease (AD) before clinical symptoms emerge would augment our ability to intervene early in the disease. Individuals with fully penetrant genetic mutations causing autosomal dominant Alzheimer's disease (ADAD) are essentially certain to develop the disease, providing a unique opportunity to examine biomarkers during the preclinical stage. Using a generalization task that has previously shown to be sensitive to medial temporal lobe pathology, we compared preclinical individuals carrying ADAD mutations to noncarrying kin to determine whether generalization (the ability to transfer previous learning to novel but familiar recombinations) is vulnerable early, before overt cognitive decline. As predicted, results revealed that preclinical ADAD mutation carriers made significantly more errors during generalization than noncarrying kin, despite no differences between groups during learning or retention. This impairment correlated with the left hippocampal volume, particularly in mutation carriers. Such identification of generalization deficits in early ADAD may provide an easily implementable and potentially linguistically and culturally neutral way to identify and track cognition in ADAD.

While avoidance is a core symptom of PTSD, little is known about whether individuals with PTSD show a general cognitive bias to acquire and express avoidance, in situations not related to trauma or fear. Here, we used a computer-based task to examine operant acquisition and extinction of avoidance in participants with and without severe self-reported PTSD symptoms. A total of 119 participants (77 male, 42 female; 74 veteran, 45 civilian) with symptoms (PTSS; n = 63) or with few/no symptoms (noPTSS; n = 56) performed a task, in which they controlled a spaceship and could shoot a target to gain points or hide in "safe areas" to escape or avoid on-screen aversive events. Results show that participants with PTSS exhibited more avoidance across trials than noPTSS participants, particularly due to more avoidance behavior in PTSS females compared to noPTSS females. Avoidance behavior decreased across extinction trials but interactions with PTSS and gender fell short of significance. Overall, PTSD symptoms were associated with propensity to acquire and express avoidance behavior, in both civilians and veterans, and even in a cognitive task that does not explicitly involve trauma or fear. This effect was more pronounced in females, highlighting the role of gender differences in PTSD symptomatology. Importantly, this study also demonstrates the potential of an objective assessment of avoidance behavior, which could be used to supplement the common but limited self-report tools.

The severity and number of reexperiencing symptoms (e.g., flashbacks) show considerable variability across individuals with posttraumatic stress disorder (PTSD). One interpretation of reexperiencing symptoms invokes generalization: Specifically, the traumatic memory may be stored in such a way that neutral stimuli that only vaguely resemble some feature of the traumatic event are sufficient to trigger the memory. If this is the case, then individuals with higher levels of reexperiencing symptoms might show greater generalization, even in contexts unrelated to trauma. In the current study, an acquired equivalence test was used to assess associative learning and generalization in 114 U.S. veterans who were also given a test of declarative memory. PTSD symptoms were rated by the veteran. After adjusting for demographic variables, psychoactive medication use, and initial learning, regression analyses showed that the number of PTSD reexperiencing symptoms significantly improved the model for generalization (β = -.23, R(2) = .34) but not associative learning or declarative memory. The results support the idea that generalization is linked to reexperiencing symptoms, is not limited to learning about traumatic events, and can emerge even in a relatively innocuous computer-based learning task.

Acquisition and maintenance of avoidance behaviour is a key feature of all human anxiety disorders. Animal models have been useful in understanding how anxiety vulnerability could translate into avoidance learning. For example, behaviourally-inhibited temperament and female sex, two vulnerability factors for clinical anxiety, are associated with faster acquisition of avoidance responses in rodents. However, to date, the translation of such empirical data to human populations has been limited since many features of animal avoidance paradigms are not typically captured in human research. Here, using a computer-based task that captures many features of rodent escape-avoidance learning paradigms, we investigated whether avoidance learning would be faster in humans with inhibited temperament and/or female sex and, if so, whether this facilitation would take the same form. Results showed that, as in rats, both vulnerability factors were associated with facilitated acquisition of avoidance behaviour in humans. Specifically, inhibited temperament was specifically associated with higher rate of avoidance responding, while female sex was associated with longer avoidance duration. These findings strengthen the direct link between animal avoidance work and human anxiety vulnerability, further motivating the study of animal models while also providing a simple testbed for a direct human testing.

Aspects of stimulus-response (S-R) learning, mediated by striatal dopamine signaling, have been found to be altered in cocaine users relative to healthy controls. However, the influence of cocaine users’ marijuana and alcohol use has not been accounted for. This study evaluated S-R learning and other neurocognitive functions in cocaine users while controlling for the relative influences of marijuana and alcohol use. Twenty-five long-term cocaine users and 2 control groups (25 moderate marijuana and alcohol users and 23 healthy controls) completed a computerized assessment of probabilistic category learning (the Weather Prediction task), as well as measures of equivalence learning, declarative learning, and executive, attentional, and motor function. Cocaine users exhibited decreased performance on the Weather Prediction task, as well as measures of declarative learning, attention, and motor function (p 0.05), relative to both control groups. Cocaine users exhibited decrements in probabilistic category learning, declarative recall, and attentional and motor function, compared with both marijuana and alcohol users and nondrug users. Therefore, these decrements appear to be specifically related to the cocaine use, but not the moderate marijuana and alcohol use, of long-term cocaine users.

To better understand how medication status and task demands affect cognition in major depressive disorder (MDD), we evaluated medication-naïve patients with MDD, medicated patients with MDD receiving the selective serotonin reuptake inhibitors (SSRI) paroxetine, and healthy controls. All three groups were administered a computer-based cognitive task with two phases, an initial phase in which a sequence is learned through reward-based feedback (which our prior studies suggest is striatal-dependent), followed by a generalization phase that involves a change in the context where learned rules are to be applied (which our prior studies suggest is hippocampal-region dependent). Medication-naïve MDD patients were slow to learn the initial sequence but were normal on subsequent generalization of that learning. In contrast, medicated patients learned the initial sequence normally, but were impaired at the generalization phase. We argue that these data suggest (i) an MDD-related impairment in striatal-dependent sequence learning which can be remediated by SSRIs and (ii) an SSRI-induced impairment in hippocampal-dependent generalization of past learning to novel contexts, not otherwise seen in the medication-naïve MDD group. Thus, SSRIs might have a beneficial effect on striatal function required for sequence learning, but a detrimental effect on the hippocampus and other medial temporal lobe structures is critical for generalization.

To test a prediction of our previous computational model of cortico-hippocampal interaction (Gluck and Myers (1993, 2001)) for characterizing individual differences in category learn- ing, 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 adap- tation 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 cor- tex 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 appropri- ately encoding and representing newly learned information so that that this learning can be success- fully applied and generalized to subsequent novel task demands. Hum Brain Mapp 35:3122-3131, 2014. V C 2013 Wiley Periodicals, Inc.

Post-traumatic stress disorder (PTSD) can develop following exposure to a traumatic event. Re-experiencing, which includes intrusive memories or flashbacks of the trauma, is a core symptom cluster of PTSD. From an associative learning perspective, this cluster may be attributed to cues associated with the trauma, which have come to elicit symptoms in a variety of situations encountered in daily life due to a tendency to overgeneralize. Consistent with this, prior studies have indicated that both individuals with clinically diagnosed with PTSD, and those with self-reported symptoms who may not meet full diagnostic criteria, show changes in generalization. Building on prior research, the current study examined whether PTSD symptom burden, but also gender, veteran status, and combat experience–all associated with PTSD vulnerability–modulate learning and generalization in a computer-based task. Participants were presented with stimulus compounds consisting of a foreground and background that could be predictive of reward, punishment or no outcome. Learning was followed by a generalization test where these components were recombined to form novel configurations. An interaction between PTSD symptom burden and gender was found where females with more severe PTSD symptoms showed no evidence of sensitivity to the background. This result is consistent with increased generalization, and may indicate a decrease in the ability to process cue configurations leading to re-experiencing in a variety of situations. Further work is indicated to help elucidate the cognitive processes driving gender differences that may confer vulnerability to PTSD.