Ventromedial Prefrontal Research Articles

A cross-cultural comparison of intrinsic and extrinsic motivational drives for learning.

Intrinsic motivational drives, like the autonomous feeling of control, and extrinsic motivational drives, like monetary reward, can benefit learning. Extensive research has focused on neurobiological and psychological factors that affect these drives, but our understanding of the sociocultural factors is limited. Here, we compared the effects of autonomy and rewards on episodic recognition memory between students from Dutch and Chinese universities. In an exploratory learning task, participants viewed partially obscured objects that they needed to subsequently remember. We independently manipulated autonomy, as volitional control over an exploration trajectory, as well as the chance to receive monetary rewards. The learning task was followed by memory tests for objects and locations. For both cultural groups, we found that participants learned better in autonomous than non-autonomous conditions. However, the beneficial effect of reward on memory performance was stronger for Chinese than for Dutch participants. By incorporating the sociocultural brain perspective, we discuss how differences in norms and values between Eastern and Western cultures can be integrated with the neurocognitive framework about dorsal lateral and ventral medial prefrontal cortex and dopaminergic reward modulations on learning and memory. These findings have important implications for understanding the neurocognitive mechanisms in which both autonomy and extrinsic rewards are commonly used to motivate students in the realm of education and urge more attention to investigate cultural differences in learning.

Functional connectivity in complex regional pain syndrome: A bicentric study

Brain imaging studies in complex regional pain syndrome (CRPS) have found mixed evidence for functional and structural changes in CRPS. In this cross-sectional study, we evaluated two patient cohorts from different centers and examined functional connectivity (rsFC) in 51 CRPS patients and 50 matched controls. rsFC was compared in predefined ROI pairs, but also in non-hypothesis driven analyses. Resting state (rs)fMRI changes in default mode network (DMN) and the degree rank order disruption index (kD) were additionally evaluated. Finally, imaging parameters were correlated with clinical severity and somatosensory function. Among predefined pairs, we found only weakly to moderately lower functional connectivity between the right nucleus accumbens and bilateral ventromedial prefrontal cortex in the infra-slow oscillations (ISO) band. The unconstrained ROI-to-ROI analysis revealed lower rsFC between the periaqueductal gray matter (PAG) and left anterior insula, and higher rsFC between the right sensorimotor thalamus and nucleus accumbens. In the correlation analysis, pain was positively associated with insulo-prefrontal rsFC, whereas sensorimotor thalamo-cortical rsFC was positively associated with tactile spatial resolution of the affected side. In contrast to previous reports, we found no group differences for kD or rsFC in the DMN, but detected overall lower data quality in patients. In summary, while some of the previous results were not replicated despite the larger sample size, novel findings from two independent cohorts point to potential down-regulated antinociceptive modulation by the PAG and increased connectivity within the reward system as pathophysiological mechanisms in CRPS. However, in light of the detected systematic differences in data quality between patients and healthy subjects, validity of rsFC abnormalities in CRPS should be carefully scrutinized in future replication studies.

Proximity Within Adolescent Peer Networks Predicts Neural Similarity During Affective Experience.

Individuals befriend others who are similar to them. One important source of similarity in relationships is similarity in felt emotion. In the present study, we used novel methods to assess whether greater similarity in the multivoxel brain representation of affective stimuli was associated with adolescents' proximity within real-world school-based social networks. We examined dyad-level neural similarity within a set of brain regions associated with the representation of affect including the ventromedial prefrontal cortex (vmPFC), amygdala, insula, and temporal pole. Greater proximity was associated with greater vmPFC neural similarity during pleasant and neutral experiences. Moreover, we used unsupervised clustering on social networks to identify groups of friends and observed that individuals from the same (verses different) friend groups were more likely to have greater vmPFC neural similarity during pleasant and negative experiences. These findings suggest that similarity in the multivoxel brain representation of affect may play an important role in adolescent friendships.

Distinct Roles of Medial Prefrontal Cortex Subregions in the Consolidation and Recall of Remote Spatial Memories.

It is a common belief that memories, over time, become progressively independent of the hippocampus and are gradually stored in cortical areas. This view is mainly based on evidence showing that prefrontal cortex (PFC) manipulations impair the retrieval of remote memories, while hippocampal inhibition does not. More controversial is whether activity in the medial PFC is required immediately after learning to initiate consolidation. Another question concerns functional differences among PFC subregions in forming and storing remote memories. To address these issues, we directly contrasted the effects of loss-of-function manipulations of the anterior cingulate cortex (aCC) and the ventromedial PFC, which includes the infralimbic (IL) and prelimbic (PL) cortices, before testing and immediately after training on the ability of CD1 mice to recall the hidden platform location in the Morris water maze. We injected an AAV carrying the hM4Di receptor into the PL-IL or aCC. Interestingly, pretest administrations of clozapine-N-oxide (CNO; 3 mg/kg) revealed that the aCC, but not the PL-IL, was necessary to recall remote spatial information. Furthermore, systemic post-training administration of CNO impaired memory recall at remote, but not recent, time points in both groups. These findings revealed a functional dissociation between the two prefrontal areas, demonstrating that both the PL-IL and the aCC are involved in early consolidation of remote spatial memories, but only the aCC is engaged in their recall.

Patterns of abnormal activations in severe mental disorders a transdiagnostic data-driven meta-analysis of task-based fMRI studies.

Studies suggest severe mental disorders (SMDs), such as schizophrenia, major depressive disorder and bipolar disorder, are associated with common alterations in brain activity, albeit with a graded level of impairment. However, discrepancies between study findings likely to results from both small sample sizes and the use of different functional magnetic resonance imaging (fMRI) tasks. To address these issues, data-driven meta-analytic approach designed to identify homogeneous brain co-activity patterns across tasks was conducted to better characterize the common and distinct alterations between these disorders. A hierarchical clustering analysis was conducted to identify groups of studies reporting similar neuroimaging results, independent of task type and psychiatric diagnosis. A traditional meta-analysis (activation likelihood estimation) was then performed within each of these groups of studies to extract their aberrant activation maps. A total of 762 fMRI study contrasts were targeted, comprising 13 991 patients with SMDs. Hierarchical clustering analysis identified 5 groups of studies (meta-analytic groupings; MAGs) being characterized by distinct aberrant activation patterns across SMDs: (1) emotion processing; (2) cognitive processing; (3) motor processes, (4) reward processing, and (5) visual processing. While MAG1 was mostly commonly impaired, MAG2 was more impaired in schizophrenia, while MAG3 and MAG5 revealed no differences between disorder. MAG4 showed the strongest between-diagnoses differences, particularly in the striatum, posterior cingulate cortex, and ventromedial prefrontal cortex. SMDs are characterized mostly by common deficits in brain networks, although differences between disorders are also present. This study highlights the importance of studying SMDs simultaneously rather than independently.

Value construction through sequential sampling explains serial dependencies in decision making.

Many decisions are expressed as a preference for one item over another. When these items are familiar, it is often assumed that the decision maker assigns a value to each of the items and chooses the item with the highest value. These values may be imperfectly recalled, but are assumed to be stable over the course of an interview or psychological experiment. Choices that are inconsistent with a stated valuation are thought to occur because of unspecified noise that corrupts the neural representation of value. Assuming that the noise is uncorrelated over time, the pattern of choices and response times in value-based decisions are modeled within the framework of Bounded Evidence Accumulation (BEA), similar to that used in perceptual decision-making. In BEA, noisy evidence samples accumulate over time until the accumulated evidence for one of the options reaches a threshold. Here, we argue that the assumption of temporally uncorrelated noise, while reasonable for perceptual decisions, is not reasonable for value-based decisions. Subjective values depend on the internal state of the decision maker, including their desires, needs, priorities, attentional state, and goals. These internal states may change over time, or undergo revaluation, as will the subjective values. We reasoned that these hypothetical value changes should be detectable in the pattern of choices made over a sequence of decisions. We reanalyzed data from a well-studied task in which participants were presented with pairs of snacks and asked to choose the one they preferred. Using a novel algorithm ( Reval ), we show that the subjective value of the items changes significantly during a short experimental session (about 1 hour). Values derived with Reval explain choice and response time better than explicitly stated values. They also better explain the BOLD signal in the ventromedial prefrontal cortex, known to represent the value of decision alternatives. Revaluation is also observed in a BEA model in which successive evidence samples are not assumed to be independent. We argue that revaluation is a consequence of the process by which values are constructed during deliberation to resolve preference choices.

How distributed subcortical integration of reward and threat may inform subsequent approach-avoidance decisions.

Healthy and successful living involves carefully navigating rewarding and threatening situations by balancing approach and avoidance behaviours. Excessive avoidance to evade potential threats often leads to forfeiting potential rewards. However, little is known about how reward and threat information is integrated neurally to inform approach or avoidance decisions. In this preregistered study, participants (Nbehaviour=31, 17F; NMRI=28, 15F) made approach-avoidance decisions under varying reward (monetary gains) and threat (electrical stimulations) prospects during functional MRI scanning. In contrast to theorized parallel subcortical processing of reward and threat information before cortical integration, Bayesian Multivariate Multilevel analyses revealed subcortical reward and threat integration prior to indicating approach-avoidance decisions. This integration occurred in the ventral striatum, thalamus, and bed nucleus of the stria terminalis (BNST). When reward was low, risk-diminishing avoidance decisions dominated, which was linked to more positive tracking of threat magnitude prior to indicating avoidance than approach decisions across these regions. In contrast, the amygdala exhibited dual sensitivity to reward and threat. While anticipating outcomes of risky approach decisions, we observed positive tracking of threat magnitude within the salience network (dorsal anterior cingulate cortex, thalamus, periaqueductal gray, BNST). Conversely, after risk-diminishing avoidance, characterized by reduced reward prospects, we observed more negative tracking of reward magnitude in the ventromedial prefrontal cortex and ventral striatum. These findings shed light on the temporal dynamics of approach-avoidance decision-making. Importantly, they demonstrate the role of subcortical integration of reward and threat information in balancing approach and avoidance, challenging theories positing predominantly separate subcortical processing prior to cortical integration.Significance statement When deciding whether to approach or avoid situations, our decision-making involves balancing potential rewards and threats. Widespread theories of decision-making in humans propose parallel processing of reward and threat information in subcortical regions, followed by cortical integration. Challenging these notions, we found evidence for dual and integrated processing of reward and threat in subcortical regions during decision-making. In contrast, after decision-making, we observed the expected parallel processing while anticipating decision outcomes. These findings advance our understanding of approach-avoidance decision-making processes, opposing traditional views that segregate brain regions as predominantly reward-sensitive or threat-sensitive, thereby paving the way for a more nuanced perspective that takes into account the stage of decision-making.

Thalamus and its functional connections with cortical regions contribute to complexity-dependent cognitive reasoning

The thalamus is crucial for supporting various cognitive behaviors due to its extensive connectivity with multiple cortical regions. However, the role of the thalamus and its functional connections with cortical regions in cognitive reasoning remains unclear, since previous research has mainly focused on cortical regions when studying the neural mechanisms underlying cognitive reasoning. To fill this knowledge gap, we utilized 7 T functional magnetic resonance imaging (fMRI) to study the activation patterns of the thalamus and its functional connections with cortical regions during cognitive reasoning task, while also examining how the complexity of reasoning tasks affects thalamic activation and functional connections with cortical regions. Our findings showed that cognitive reasoning processes are related to increased activation of the thalamus and its functional connections with a specific set of cortical regions, consisting of dorsolateral prefrontal cortex, inferior frontal sulcus, intraparietal sulcus, anterior cingulate cortex/presupplementary motor area, precuneus, and ventral medial prefrontal cortex. Moreover, the increase in relational complexity of the reasoning tasks led to a corresponding increase in thalamic activation and functional connectivity with cortical regions. Given the complex thalamus structure, including multiple distinct nuclei exhibiting specific functional connections with particular cortical regions, we used an atlas defined thalamic subdivisions based on its structural connectivity with different cortical regions. Our findings indicated that these different thalamic subregions not only exhibited distinct connectivity patterns with specific cortical regions during performance of cognitive reasoning, but also showed distinct connectivity patterns varied with task complexity. Overall, our study presents evidence of the thalamus’s role and its connections with cortical regions in supporting increasingly complex cognitive reasoning behavior, illuminating its contribution to higher-order cognitive functions, such as reasoning.

Contextual memory bias in emotional events: neurobiological correlates and depression risk

BackgroundContextual memory loss of emotional events plays a critical role in depression psychopathology. Individuals with depression, clinical or subclinical, exhibit enhanced and impaired memory for emotionally negative stimuli and context in an event, respectively. This suggests that contextual encoding may fail because of attentional interference caused by concurrent negative stimuli, possibly leading to contextual memory loss as a depression risk. Amygdala–prefrontal connectivity and cortisol may underlie the mechanism; however, the relationships remain unknown. MethodsOne hundred twenty participants, including 34 with subclinical depression, underwent behavioral tasks, functional magnetic resonance imaging (fMRI) scans, and saliva collection. Encoding and 24h later recollection performance of visuoperceptual/spatial/temporal context in a series of events, where fearful (vs. neutral) faces appeared, were measured via contextual memory tasks. Overgeneral autobiographical memory (OGM), a more remote form of contextual memory loss, was also assessed via the Autobiographical Memory Test. Amygdala connectivity was measured by fMRI during attentional interference by fearful (vs. neutral) faces to differentiate selective attention from encoding. Basal cortisol levels were assayed through saliva collected at encoding during the visit day and across 2 consecutive days in the following week (12 time points in total). We explored whether contextual memory encoding failure would explain depressive symptoms through OGM under possible moderation of amygdala connectivity and cortisol. ResultsIn individuals with subclinical depression compared to those without, fearful faces disturbed memory encoding of the visuoperceptual context rather than 24h later recollection, while neutral faces in their temporal proximity contrastingly augmented it. The more the contextual memory encoding bias (fearful vs. neutral) intensified, the more the amygdala’s functional connectivity with the ventromedial prefrontal cortex (vmPFC) weakened. Higher total cortisol output was correlated with poorer 24-h later recollection of the temporal context, although at a trend level. Moderated mediation effects of the amygdala-vmPFC connectivity and cortisol were non-significant; however, contextual encoding bias explained depressive symptoms through negatively valenced OGM. ConclusionsNegative stimuli appearing in an event might impair memory encoding of the visuoperceptual context under attentional interference, represented as weakened amygdala-vmPFC connectivity implicated in emotion-related attentional dysregulation. Conversely, negative stimuli might enhance temporally proximal visuoperceptual encoding after their disappearance. Contextual encoding bias could explain the overgeneralization (or lower coherence) of autobiographical memory and increase the risk of depression. The possible role of cortisol in recollecting the context of emotional events warrants further investigation.

The unique contribution of uncertainty reduction during naturalistic language comprehension

Language comprehension is an incremental process with prediction. Delineating various mental states during such a process is critical to understanding the relationship between human cognition and the properties of language. Entropy reduction, which indicates the dynamic decrease of uncertainty as language input unfolds, has been recognized as effective in predicting neural responses during comprehension. According to the entropy reduction hypothesis (Hale, 2006), entropy reduction is related to the processing difficulty of a word, the effect of which may overlap with other well-documented information-theoretical metrics such as surprisal or next-word entropy. However, the processing difficulty was often confused with the information conveyed by a word, especially lacking neural differentiation. We propose that entropy reduction represents the cognitive neural process of information gain that can be dissociated from processing difficulty. This study characterized various information-theoretical metrics using GPT-2 and identified the unique effects of entropy reduction in predicting fMRI time series acquired during language comprehension. In addition to the effects of surprisal and entropy, entropy reduction was associated with activations in the left inferior frontal gyrus, bilateral ventromedial prefrontal cortex, insula, thalamus, basal ganglia, and middle cingulate cortex. The reduction of uncertainty, rather than its fluctuation, proved to be an effective factor in modeling neural responses. The neural substrates underlying the reduction in uncertainty might imply the brain’s desire for information regardless of processing difficulty.

Mapping lesion-related human aggression to a common brain network

BackgroundAggression exacts a significant toll on human societies and is highly prevalent among neuropsychiatric patients for which neural mechanisms are unclear and treatment options are limited. MethodsUsing recently validated lesion network mapping technique, we derived an aggression associated network by analyzing 182 patients who had suffered penetrating head injuries during their service in the Vietnam War. To test whether damage to this lesion-derived network would increase the risk of aggression related neuropsychiatric symptoms, we used the Harvard Lesion Repository (N = 928). To explore potential therapeutic relevance of this network, we used an independent Deep brain stimulation dataset of 25 patients with epilepsy, in which irritability and aggression are known potential side effects. ResultsWe found that lesions associated with aggression occurred in many different brain locations but were characterized by a specific brain network defined by functional connectivity to a hub region in the right prefrontal cortex (PFC). This network involves positive connectivity to the ventromedial PFC, dorsolateral PFC, frontal pole, posterior cingulate cortex, anterior cingulate cortex, temporal-parietal junction, and lateral temporal lobe and negative connectivity to the amygdala, hippocampus, insula, and visual cortex. Among all 25 neuropsychiatric symptoms included in the Harvard Lesion Repository, criminality demonstrated the most alignment with our aggression associated network. DBS site connectivity to this same network was associated with increased irritability. ConclusionsWe conclude that brain lesions associated with aggression map to a specific human brain circuit, and the functionally connected regions in this circuit provide testable targets for therapeutic neuromodulation.

Divergent subregional information processing in mouse prefrontal cortex during working memory

Working memory (WM) is a critical cognitive function allowing recent information to be temporarily held in mind to inform future action. This process depends on coordination between prefrontal cortex (PFC) subregions and other connected brain areas. However, few studies have examined the degree of functional specialization between these subregions throughout WM using electrophysiological recordings in freely-moving mice. Here we record single-units in three neighboring mouse medial PFC (mPFC) subregions—supplementary motor area (MOs), dorsomedial PFC (dmPFC), and ventromedial (vmPFC)—during a freely-behaving non-match-to-position WM task. The MOs is most active around task phase transitions, when it transiently represents the starting sample location. Dorsomedial PFC contains a stable population code, including persistent sample-location-specific firing during the delay period. Ventromedial PFC responds most strongly to reward-related information during choices. Our results reveal subregionally segregated WM computation in mPFC and motivate more precise consideration of the dynamic neural activity required for WM.

Action expectancy modulates activity in the mirror neuron system and mentalizing system

Action understanding involves two distinct processing levels that engage separate neural mechanisms: perception of concrete kinematic information and recognition of abstract action intentions. The mirror neuron system and the mentalizing system have both been linked to concrete action and abstract information processing, but their specific roles remain debatable. Here, we conducted a functional magnetic resonance imaging study with 26 participants who passively observed expected and unexpected actions. We performed whole-brain activation, region of interest, and effective connectivity analyses to investigate the neural correlates of these actions. Whole-brain activation analyses revealed that expected actions were associated with increased activation in the left medial superior frontal gyrus, while unexpected actions were linked to heightened activity in the left supramarginal gyrus, left superior parietal lobule, right inferior temporal gyrus, and left middle frontal gyrus. Region of interest analyses demonstrated that the left ventral premotor cortex exhibited greater activation during the observation of expected actions compared to unexpected actions, while the left inferior frontal gyrus, left superior parietal lobule, and left precuneus showed stronger activation during the observation of unexpected actions. Effective connectivity was observed between the left ventral premotor cortex and the left angular gyrus, left intraparietal sulcus, left dorsal premotor cortex, and left ventromedial prefrontal cortex with the middle frontal gyrus when observing unexpected, but not expected, actions. These findings suggest that expected actions are primarily processed by the mirror neuron system, whereas unexpected actions engage both the mirror neuron system and the mentalizing system, with these systems playing complementary roles in the understanding of unexpected actions.

Metabotropic Glutamate Receptor 5 as a Potential Biomarker of the Intersection of Trauma and Cannabis Use.

Metabotropic glutamate receptor 5 (mGlu5) dysregulation has been implicated in the pathophysiology of trauma-related psychopathology, and there are direct interactions between the endocannabinoid and glutamatergic systems. However, relationships between cannabis use (CU) and mGlu5 have not been directly investigated in trauma-related psychopathology. Using positron emission tomography with [18F]FPEB, we examined relationships between CU status and mGlu5 availability in vivo in a cross-diagnostic sample of individuals with trauma-related psychopathology (n = 55). Specifically, we tested whether mGlu5 availability in frontolimbic regions of interest (ROIs; dorsolateral prefrontal cortex, orbitofrontal cortex, ventromedial prefrontal cortex, amygdala, hippocampus) differed as a function of CU status. Past-year CU (n = 22) was associated with 18.62%-19.12% higher mGlu5 availability in frontal and 14.24%-16.55% higher mGlu5 in limbic ROIs relative to participants with no recent CU. Similarly, past-month or monthly CU (n = 16) was associated with higher mGlu5 availability in frontal (18.05%-20.62%) and limbic (15.53%-16.83%) ROIs. mGlu5 availability in the orbitofrontal cortex and amygdala was negatively associated with depressive symptoms in the past-year CU group. In both CU groups, exploratory analyses showed negative correlations between mGlu5 availability and sadness across all ROIs and with perceptions of worthlessness and past failures (r's = -.47 to .66, P's = .006-.033) in the ventromedial prefrontal cortex. Participants with CU reported lower mean depressive symptoms (P's = .006-.037) relative to those without CU. These findings have substantial implications for our understanding of interactions between CU and glutamatergic neurotransmission in trauma-related psychopathology, underscoring the need for treatment development efforts to consider the effects of CU in this population.

Cross-species striatal hubs: Linking anatomy to resting-state connectivity

Corticostriatal connections are essential for motivation, cognition, and behavioral flexibility. There is broad interest in using resting-state functional magnetic resonance imaging (rs-fMRI) to link circuit dysfunction in these connections with neuropsychiatric disorders. In this paper, we used tract-tracing data from non-human primates (NHPs) to assess the likelihood of monosynaptic connections being represented in rs-fMRI data of NHPs and humans. We also demonstrated that existing hub locations in the anatomical data can be identified in the rs-fMRI data from both species. To characterize this in detail, we mapped the complete striatal projection zones from 27 tract-tracer injections located in the orbitofrontal cortex (OFC), dorsal anterior cingulate cortex (dACC), ventromedial prefrontal cortex (vmPFC), ventrolateral PFC (vlPFC), and dorsal PFC (dPFC) of macaque monkeys. Rs-fMRI seeds at the same regions of NHP and homologous regions of human brains showed connectivity maps in the striatum mostly consistent with those observed in the tracer data. We then examined the location of overlap in striatal projection zones. The medial rostral dorsal caudate connected with all five frontocortical regions evaluated in this study in both modalities (tract-tracing and rs-fMRI) and species (NHP and human). Other locations in the caudate also presented an overlap of four frontocortical regions, suggesting the existence of different locations with lower levels of input diversity. Small retrograde tracer injections and rs-fMRI seeds in the striatum confirmed these cortical input patterns. This study sets the ground for future studies evaluating rs-fMRI in clinical samples to measure anatomical corticostriatal circuit dysfunction and identify connectional hubs to provide more specific treatment targets for neurological and psychiatric disorders.

Cortico-hippocampal interactions underlie schema-supported memory encoding in older adults.

Although episodic memory is typically impaired in older adults (OAs) compared to young adults (YAs), this deficit is attenuated when OAs can leverage their rich semantic knowledge, such as their knowledge of schemas. Memory is better for items consistent with pre-existing schemas and this effect is larger in OAs. Neuroimaging studies have associated schema use with the ventromedial prefrontal cortex (vmPFC) and hippocampus (HPC), but most of this research has been limited to YAs. This fMRI study investigated the neural mechanisms underlying how schemas boost episodic memory in OAs. Participants encoded scene-object pairs with varying congruency, and memory for the objects was tested the following day. Congruency with schemas enhanced object memory for YAs and, more substantially, for OAs. FMRI analyses examined how cortical modulation of HPC predicted subsequent memory. Congruency-related vmPFC modulation of left HPC enhanced subsequent memory in both age groups, while congruency-related modulation from angular gyrus (AG) boosted subsequent memory only in OAs. Individual differences in cortico-hippocampal modulations indicated that OAs preferentially used their semantic knowledge to facilitate encoding via an AG-HPC interaction, suggesting a compensatory mechanism. Collectively, our findings illustrate age-related differences in how schemas influence episodic memory encoding via distinct routes of cortico-hippocampal interactions.

Neural processing of audiovisual and painful analogue trauma and its relationship with subsequent audiovisual and pain intrusions

ABSTRACT Background: Posttraumatic stress disorder and medically unexplained pain frequently co-occur. While pain is common during traumatic events, the processing of pain during trauma and its relation to audiovisual and pain intrusions is poorly understood. Objective: Here we investigate neural activations during painful analogue trauma, focusing on areas that have been related to threat and pain processing, and how they predict intrusion formation. We also examine the moderating role of cumulative lifetime adversity. Methods: Sixty-five healthy women were assessed using functional magnetic resonance imaging. An analogue trauma was induced by an adaptation of the trauma-film paradigm extended by painful electrical stimulation in a 2 (film: aversive, neutral) x 2 (pain: pain, no-pain) design, followed by 7-day audiovisual and pain intrusion assessment using event-based ecological momentary assessment. Intrusions were fitted with Bayesian multilevel regression and a hurdle lognormal distribution. Results: Conjunction analysis confirmed a wide network including anterior insula (AI) and dorsal anterior cingulate cortex (dACC) being active both, during aversive films and pain. Pain resulted in activation in areas amongst posterior insula and deactivation in a network around ventromedial prefrontal cortex (VMPFC). Higher AI and dACC activity during aversive>neutral film predicted greater audiovisual intrusion probability over time and predicted greater audiovisual intrusion frequency particularly for participants with high lifetime adversity. Lower AI, dACC, hippocampus, and VMPFC activity during pain>no-pain predicted greater pain intrusion probability particularly for participants with high lifetime adversity. Weak regulatory VMPFC activation was associated with both increased audiovisual and pain intrusion frequency. Conclusions: Enhanced AI and dACC processing during aversive films, poor pain vs. no-pain discrimination in AI and dACC, as well as weak regulatory VMPFC processing may be driving factors for intrusion formation, particularly in combination with high lifetime adversity. Results shed light on a potential path for the etiology of PTSD and medically unexplained pain.

Circadian Rhythms in Conditioned Threat Extinction Reflect Time-of-Day Differences in Ventromedial Prefrontal Cortex Neural Processing.

Circadian rhythms in conditioned threat extinction emerge from a tissue-level circadian timekeeper, or local clock, in the ventromedial prefrontal cortex (vmPFC). Yet it remains unclear how this local clock contributes to extinction-dependent adaptations. Here we used single-unit and local field potential analyses to interrogate neural activity in the male rat vmPFC during repeated extinction sessions at different times of day. In association with superior recall of a remote extinction memory during the circadian active phase, vmPFC putative principal neurons exhibited phasic firing that was amplified for cue presentations and diminished at transitions in freezing behavior. Coupling of vmPFC gamma amplitude to the phase of low-frequency oscillations was greater during freezing than mobility, and this difference was augmented during the active phase, highlighting a time-of-day dependence in the organization of freezing- versus mobility-associated cell assemblies. Additionally, a greater proportion of vmPFC neurons were phase-locked to low-frequency oscillations during the active phase, consistent with heightened neural excitability at this time of day. Our results suggest that daily fluctuations in vmPFC excitability precipitate enhanced neural recruitment into extinction-based cell assemblies during the active phase, providing a potential mechanism by which the vmPFC local clock modulates circuit and behavioral plasticity during conditioned threat extinction.

Starting the pill during adolescence: Age of onset and duration of use influence morphology of the hippocampus and ventromedial prefrontal cortex.

From adolescence, women become more likely to experience fear dysregulation. Oral contraceptives (OCs) can modulate the brain regions involved in fear processes. OCs are generally used for years and often initiated during adolescence, a sensitive period where certain brain regions involved in the fear circuitry are still undergoing important reorganization. It remains unknown whether OC use during adolescence may induce long-lasting changes in the fear circuitry. This study aimed to examine whether age of onset moderated the relationship between duration of use and fear-related brain structures. We collected structural MRI data in 98 healthy adult women (61 current users, 37 past users) and extracted grey matter volumes (GMV) and cortical thickness (CT) of key regions of the fear circuitry. Non-linear multiple regressions revealed interaction effects between age of onset and quadratic duration of use on GMV of the right hippocampus and right ventromedial prefrontal cortex (vmPFC). Among women who initiated OCs earlier in adolescence, a short duration of use was associated with smaller hippocampal GMV and thicker vmPFC compared to a longer duration of use. For both GMV and CT of the right vmPFC, women with an early OC onset had more grey matter at a short duration of use than those with a later onset. Our results suggest that OC use earlier in adolescence may induce lasting effects on structural correlates of fear learning and its regulation. These findings support further investigation into the timing of OC use to better comprehend how OCs could disrupt normal brain development processes.

Functional connectivity of the amygdala in relation to high stress and low mindfulness

BackgroundHigh psychological stress has been associated with several brain functional changes, including functional connectivity (FC) alterations in regions such as the prefrontal cortex and the amygdala. This study explored FC alterations associated with high perceived stress, and also investigated whether these neuroimaging features were correlated with low levels of mindfulness. MethodsThis study included 29 adults (12 males and 17 females; mean age: 27.6 ± 3.2) who complained of moderate or higher perceived stress and 31 adults (17 males and 14 females; mean age: 29.2 ± 7.2) who complained of low-level stress on the questionnaire scale. Seed-based resting-state FC analysis was conducted to compare between high and low stress groups. The dorsolateral prefrontal cortex (DLPFC), the ventromedial prefrontal cortex (VMPFC) and the amygdala were selected as seeds. ResultsHigh stress group showed weaker left amygdala-based FC in the left cerebellum crus II and the left orbitofrontal cortex compared with low stress group. High stress group had weaker FC between the left DLPFC and the left inferior parietal lobule. On the contrary, high stress group had stronger FC between the left VMPFC and the left caudate compared with low stress group. Weaker FC between the amygdala and the cerebellum crus II was correlated with lower level of awareness facet of mindfulness. ConclusionsThose with high perceived stress showed low levels of mindfulness and several FC alterations centered on the prefrontal cortex and amygdala. Our findings also suggest that weak amygdala-based FC alterations associated with high psychological stress are related to low-level awareness facet of mindfulness.