Rewarded Extinction Increases Amygdalar Connectivity and Stabilizes Long-Term Memory Traces in the vmPFC.

Neurobiological evidence in rodents indicates that threat extinction incorporates reward neurocircuitry. Consequently, incorporating reward associations with an extinction memory may be an effective strategy to persistently attenuate threat responses. Moreover, while there is considerable research on the short-term effects of extinction strategies in humans, the long-term effects of extinction are rarely considered. In a within-subjects fMRI study with both female and male participants, we compared counterconditioning (CC; a form of rewarded-extinction) to standard extinction at recent (24 h) and remote (approximately one month) retrieval tests. Relative to standard extinction, rewarded extinction diminished 24-h relapse of arousal and threat expectancy, and reduced activity in brain regions associated with the appraisal and expression of threat (e.g., thalamus, insula, periaqueductal gray). The retrieval of reward-associated extinction memory was accompanied by functional connectivity between the amygdala and the ventral striatum, whereas the retrieval of standard-extinction memories was associated with connectivity between the amygdala and ventromedial prefrontal cortex (vmPFC). One month later, the retrieval of both standard-extinction and rewarded-extinction was associated with amygdala-vmPFC connectivity. However, only rewarded extinction created a stable memory trace in the vmPFC, identified through overlapping multivariate patterns of fMRI activity from extinction to 24-h and one-month retrieval. These findings provide new evidence that reward may generate a more stable and enduring memory trace of attenuated threat in humans.SIGNIFICANCE STATEMENT Prevalent treatments for pathologic fear and anxiety are based on the principles of Pavlovian extinction. Unfortunately, extinction forms weak memories that only temporarily inhibit the retrieval of threat associations. Thus, to increase the translational relevance of extinction research, it is critical to investigate whether extinction can be augmented to form a more enduring memory, especially after long intervals. Here, we used a multiday fMRI paradigm in humans to compare the short-term and long-term neurobehavioral effects of aversive-to-appetitive counterconditioning (CC), a form of augmented extinction. Our results provide novel evidence that including an appetitive stimulus during extinction can reduce short-term threat relapse and stabilize the memory trace of extinction in the ventromedial prefrontal cortex (vmPFC), for at least one month after learning.

Episodic retrieval involves early and sustained effects of reactivating information from encoding.

Several fMRI studies have shown a correspondence between the brain regions activated during encoding and retrieval, consistent with the view that memory retrieval involves hippocampally-mediated reinstatement of cortical activity. With the limited temporal resolution of fMRI, the precise timing of such reactivation is unclear, calling into question the functional significance of these effects. Whereas reactivation influencing retrieval should emerge with neural correlates of retrieval success, that signifying post-retrieval monitoring would trail retrieval. The present study employed EEG to provide a temporal landmark of retrieval success from which we could investigate the sub-trial time course of reactivation. Pattern-classification analyses revealed that early-onsetting reactivation differentiated the outcome of recognition-memory judgments and was associated with individual differences in behavioral accuracy, while reactivation was also evident in a sustained form later in the trial. The EEG findings suggest that, whereas prior fMRI findings could be interpreted as reflecting the contribution of reinstatement to retrieval success, they could also indicate the maintenance of episodic information in service of post-retrieval evaluation.

States of epistemic curiosity interfere with memory for incidental scholastic facts.

Curiosity can be a powerful motivator to learn and retain new information. Evidence shows that high states of curiosity elicited by a specific source (i.e., a trivia question) can promote memory for incidental stimuli (non-target) presented close in time. The spreading effect of curiosity states on memory for other information has potential for educational applications. Specifically, it could provide techniques to improve learning for information that did not spark a sense of curiosity on its own. Here, we investigated how high states of curiosity induced through trivia questions affect memory performance for unrelated scholastic facts (e.g., scientific, English, or historical facts) presented in close temporal proximity to the trivia question. Across three task versions, participants viewed trivia questions closely followed in time by a scholastic fact unrelated to the trivia question, either just prior to or immediately following the answer to the trivia question. Participants then completed a surprise multiple-choice memory test (akin to a pop quiz) for the scholastic material. In all three task versions, memory performance was poorer for scholastic facts presented after trivia questions that had elicited high versus low levels of curiosity. These results contradict previous findings showing curiosity-enhanced memory for incidentally presented visual stimuli and suggest that target information that generates a high-curiosity state interferes with encoding complex and unrelated scholastic facts presented close in time.

Recall of Autobiographical Memories Following Odor vs Verbal Cues Among Adults With Major Depressive Disorder.

Importance: Major depressive disorder (MDD) is associated with deficits in autobiographical memory (AM) recall, which is thought to stem from disruptions in effortful recall. Understanding whether these deficits are mitigated when recall is stimulated more directly, such as by odor cues, could inform therapeutic interventions for MDD. Objective: To evaluate whether deficits in specific AM recall in MDD are mitigated when odor cues vs word cues are used to prompt memory. Design, Setting, and Participants: This cross-sectional study assessed recall of specific AMs in response to both odor cues and word cues (in a randomized, counterbalanced order) in a repeated measures design. Data were collected between September 2021 and November 2022. The study took place at the University of Pittsburgh School of Medicine in Pennsylvania and included adults with a primary diagnosis of MDD, according to the Mini International Neuropsychiatric Interview. Data were analyzed from January to June 2023. Main Outcomes and Measures: The primary outcome measure was the percentage of specific AMs recalled in response to odor-cued memories vs word-cued memories. Additional outcome measures included ratings of arousal, vividness, repetition, and recall response time for odor-cued memories vs word-cued memories. Results: Thirty-two adults (mean [SD] age, 30.0 [10.1] years; 26 [81.3%] female; 6 [18.8%] male) with a primary diagnosis of MDD completed the study. Participants recalled more specific AMs for odor cues than word cues (mean [SD], 68.4% [20.4%] vs 52.1% [23.3%]; Cohen d, 0.78; P < .001). Additionally, odor-cued recall was rated more arousing (mean [SD], 3.0 [0.8] vs 2.6 [0.7]; Cohen d, 1.28; P < .001) and vivid (mean [SD], 3.3 [0.7] vs 3.0 [0.7]; Cohen d, 0.67; P < .001), and was slower than word-cued recall (mean [SD], 14.5 [3.6] vs 8.9 [3.4] seconds; Cohen d, 1.18; P < .001). When compared with the population mean for word cues in healthy controls (80%), participants recalled fewer specific memories in response to words (Cohen d, 1.18; P < .001), supporting the presence of overgenerality. Notably, the percentage of specific memories recalled in response to odor cues did not differ from the healthy control population mean (Cohen d, 0.26; P = .15). Conclusions and Relevance: In this cross-sectional study, adults with MDD recalled more specific AMs in response to odor cues compared with word cues. This study suggests that AM deficits may only be observed when verbal cues are used and provides a potential new method for increasing specific AM recall in patients with MDD.

The Effect of Dopaminergic Replacement Therapy on Creative Thinking and Insight Problem-Solving in Parkinson's Disease Patients.

Parkinson's disease (PD) patients receiving dopaminergic treatment may experience bursts of creativity. Although this phenomenon is sometimes recognized among patients and their clinicians, the association between dopamine replacement therapy (DRT) in PD patients and creativity remains underexplored. It is unclear, for instance, whether DRT affects creativity through convergent or divergent thinking, idea generation, or a general lack of inhibition. It is also unclear whether DRT only augments pre-existing creative attributes or generates creativity de novo. Here, we tested a group of PD patients when "on" and "off" dopaminergic treatment on a series of tests of creative problem-solving (Alternative Uses Task, Compound Remote Associates, Rebus Puzzles), and related their performance to a group of matched healthy controls as well as to their pre-PD creative skills and measures of inhibition/impulsivity. Results did not provide strong evidence that DRT improved creative thinking in PD patients. Rather, PD patients "on" medication showed less flexibility in divergent thinking, generated fewer ideas via insight, and showed worse performance in convergent thinking overall (by making more errors) than healthy controls. Pre-PD creative skills predicted enhanced flexibility and fluency in divergent thinking when PD patients were "on" medication. However, results on convergent thinking were mixed. Finally, PD patients who exhibited deficits in a measure of inhibitory control showed weaker convergent thinking while "on" medication, supporting previous evidence on the importance of inhibitory control in creative problem-solving. Altogether, results do not support the hypothesis that DRT promotes creative thinking in PD. We speculate that bursts of artistic production in PD are perhaps conflated with creativity due to lay conceptions of creativity (i.e., an art-bias).

Threat Responsiveness as a Function of Cannabis and Alcohol Use Disorder Severity.

Objective: Two of the most commonly abused substances by adolescents in the United States are alcohol and cannabis, both of which are associated with adverse medical and psychiatric outcomes throughout the lifespan. Both are assumed to impact the development of emotional processing although findings on the direction of this impact have been mixed. Preclinical animal work and some functional magnetic resonance imaging (fMRI) work with humans have suggested cannabis use disorder (CUD) and alcohol use disorder (AUD) are associated with increased threat responsiveness. However, other fMRI work has indicated CUD/AUD are associated with diminished threat responsiveness. In this study, we report on a study examining the relationship of severity of CUD/AUD and threat responsiveness in an adolescent population. Methods: The study involved 87 (43 male) adolescents with varying levels of CUD/AUD symptomatology (N = 45 above clinical cutoffs for CUD or AUD). They were scanned with fMRI during a looming threat task that involved images of threatening and neutral human faces or animals that appeared to be either looming or receding. Results: Increasing levels of CUD symptomatology were associated with decreased responding to looming stimuli within regions, including rostral frontal and fusiform gyrus as well as the amygdala. There were no relationships with AUD symptomatology. Conclusions: These data indicate that CUD in particular is associated with a decrease in responsiveness to the looming threat cue possibly relating to the putative neurotoxic impact of cannabis abuse.

Alcohol use disorder and cannabis use disorder symptomatology in adolescents are differentially related to dysfunction in brain regions supporting face processing.

Despite extensive behavioral evidence of impairments in face processing and expression recognition in adults with alcohol or cannabis use disorders (AUD/CUD), neuroimaging findings have been inconsistent. Moreover, relatively little work has examined the relationship of AUD or CUD symptoms with face or expression processing within adolescents. Given the high prevalence of alcohol and cannabis use during adolescence, understanding how these usage behaviors interact with neural mechanisms supporting face and expression processing could have important implications for youth social and emotional functioning. In this study, adolescents (N = 104) responded to morphed fearful and happy expressions during fMRI and their level of AUD and/or CUD symptoms were related to the BOLD response data. We found that AUD and CUD symptom severity were both negatively related to responses to faces generally. However, whereas this relationship was shown for AUD within ventromedial prefrontal cortex and lingual gyrus, it was shown for CUD within rostromedial prefrontal cortex including anterior cingulate cortex. Additionally, AUD symptom levels were associated with differential responses within medial temporal pole and inferior parietal lobule as a function of expression. These results have potential implications for understanding the social and emotional functioning of adolescents with AUD and CUD symptoms.

Association of Different Types of Childhood Maltreatment With Emotional Responding and Response Control Among Youths.

Importance: Childhood maltreatment is associated with serious developmental consequences that may be different depending on the form of maltreatment. However, relatively little research has investigated this issue despite implications for understanding the development of psychiatric disorders after maltreatment. Objective: To determine the association of childhood maltreatment and potential differential associations of childhood abuse or neglect with neural responsiveness within regions of the brain implicated in emotional responding and response control. Design, Setting, and Participants: In this cross-sectional study, participants aged 10 to 18 years with varying levels of prior maltreatment as indexed by the Childhood Trauma Questionnaire (CTQ) were recruited from a residential care facility and the surrounding community. Blood oxygen level-dependent response data were analyzed via 2 analyses of covariance that examined 2 (sex) × 3 (task condition [view, congruent, incongruent]) × 3 (valence [negative, neutral, positive]) with Blom-transformed covariates: (1) total CTQ score; and (2) abuse and neglect subscores. Data were collected from April 1, 2016, to June 30, 2018. Data analyses occurred from June 10, 2018, to October 31, 2018. Main Outcomes and Measures: Blood oxygenation level-dependent signals in response to an Affective Stroop task were measured via functional magnetic resonance imaging. Results: The sample included 116 youths (mean [SD] age, 15.0 [2.2] years; 70 [60.3%] male). Fifteen participants reported no prior maltreatment. The remaining 101 participants (87.1%) reported at least some prior maltreatment, and 55 (54.5%) reported significant maltreatment, ie, total CTQ scores were greater than the validated CTQ score threshold of 40. There were significant total CTQ score × task condition associations within the bilateral postcentral gyrus, left precentral gyrus, midcingulate cortex, middle temporal gyrus, and superior temporal gyrus (left postcentral gyrus: F = 11.73; partial η2 = 0.14; right postcentral and precentral gyrus: F = 9.81; partial η2 = 0.10; midcingulate cortex: F = 12.76; partial η2 = 0.12; middle temporal gyrus: F = 13.24; partial η2 = 0.10; superior temporal gyrus: F = 10.33; partial η2 = 0.11). In all examined regions of the brain, increased maltreatment was associated with decreased differential responsiveness to incongruent task trials compared with view trials (left postcentral gyrus: r = -0.34; 95% CI, -0.17 to -0.51; right postcentral and precentral gyrus: r = -0.31; 95% CI, -0.14 to -0.49; midcingulate cortex: r = -0.36; 95% CI, -0.18 to -0.53; middle temporal gyrus: r = -0.35; 95% CI, -0.17 to -0.52; superior temporal gyrus: r = -0.37; 95% CI, -0.20 to -0.55). These interactions were particularly associated with level of abuse rather than neglect. A second analysis of covariance revealed significant abuse × task condition (but not neglect × task) interactions within the midcingulate cortex (F = 13.96; partial η2 = 0.11), right postcentral gyrus and inferior parietal lobule (F = 15.21; partial η2 = 0.12), left postcentral and precentral gyri (F = 11.16; partial η2 = 0.12), and rostromedial frontal cortex (F = 10.36; partial η2 = 0.08)). In all examined regions of the brain, increased abuse was associated with decreased differential responsiveness to incongruent task trials compared with view trials (midcingulate cortex: partial r = -0.33; P < .001; right postcentral gyrus and inferior parietal lobule: partial r = -0.41; P < .001; left postcentral and precentral gyri: partial r = -0.40; P < .001; and rostromedial frontal cortex: partial r = -0.40; P < .001). Conclusions and Relevance: These data document associations of different forms of childhood maltreatment with atypical neural response. This suggests that forms of maltreatment may differentially influence the development of psychiatric pathology.

Pattern reactivation co-varies with activity in the core recollection network during source memory.

Neuroimaging studies of episodic memory have consistently demonstrated that memory retrieval involves reactivating patterns of neural activity that were present during encoding, and these effects are thought to reflect the qualitative retrieval (recollection) of information that is specific to the content of an episode. By contrast, recollection is also accompanied by other neural correlates that generalize across episodic content and are consequently referred to as the "core recollection network". The neural mechanism by which these specific and core effects interact to give rise to episodic memory retrieval is largely unknown. The current study addressed this issue by testing for correlations (connectivity) between pattern reactivation and activity in the core recollection network. Subjects encoded a series of words with different tasks and then completed a two-step source memory test, whereby they identified the task (source) previously associated with the word and the confidence of that judgment. Multivariate pattern analysis (MVPA) was used in combination with fMRI to first identify encoding-related neural patterns and then test for their reactivation during retrieval. Consistent with prior findings, the magnitude of reactivation increased with source-memory confidence. Moreover, individual-trial measures of reactivation exhibited positive correlations with activity in multiple regions of the core recollection network. Importantly, evidence of functional connectivity between pattern reactivation and a region of left posterior parietal cortex supports the role of this region in tracking the retrieval of episodic information in service of making subjective memory decisions.

Neural reinstatement and the amount of information recollected.

Recent functional neuroimaging studies have attempted to understand the cognitive and neural bases of episodic memory retrieval, as well as the extent to which different retrieval judgments reflect qualitative as opposed to continuous changes in neural signals. The present study addressed this issue by investigating the reinstatement of episodic content according to the amount of information available at retrieval. Subjects encoded a series of words in the context of three distinct tasks, while a manipulation of presentation duration (4 or 8s) was also employed. A later recognition memory test was used to segregate trials according to whether or not they were accompanied by the recollection of details from encoding. Functional MRI data acquired during both the encoding and retrieval phases were used in conjunction with multi-voxel pattern-analysis (MVPA) to provide a measure of the degree to which encoding-related patterns of brain activity were later reactivated (reinstated) at the time of retrieval. Critically, the magnitude of reinstatement differed with respect to the encoding manipulation, such that reinstatement was stronger for items associated with the longer presentation duration. Together with duration-related differences in retrieval activity in left posterior parietal cortex, the results provide neural evidence for the reinstatement of different amounts of episodic information, consistent with the idea that recollection is based on a continuous neural signal.