Nucleus reuniens transiently synchronizes memory networks at beta frequencies.

Episodic memory-based decision-making requires top-down medial prefrontal cortex and hippocampal interactions. This integrated prefrontal-hippocampal memory state is thought to be organized by synchronized network oscillations and mediated by connectivity with the thalamic nucleus reuniens (RE). Whether and how the RE synchronizes prefrontal-hippocampal networks in memory, however, remains unknown. Here, we recorded local field potentials from the prefrontal-RE-hippocampal network while rats engaged in a nonspatial sequence memory task, thereby isolating memory-related activity from running-related oscillations. We found that synchronous prefrontal-hippocampal beta bursts (15-30 Hz) dominated during memory trials, whereas synchronous theta activity (6-12 Hz) dominated during non-memory-related running. Moreover, RE beta activity appeared first, followed by prefrontal and hippocampal synchronized beta, suggesting that prefrontal-hippocampal beta could be driven by the RE. To test whether the RE is capable of driving prefrontal-hippocampal beta synchrony, we used an optogenetic approach (retroAAV-ChR2). RE activation induced prefrontal-hippocampal beta coherence and reduced theta coherence, matching the observed memory-driven network state in the sequence task. These findings are the first to demonstrate that the RE contributes to memory by driving transient synchronized beta in the prefrontal-hippocampal system, thereby facilitating interactions that underlie memory-based decision-making.

The Dark Side of Mentalizing: Learning Signals in the Default Network During Social Exchanges Support Cooperation and Exploitation.

The evolution of human social cognitive capacities such as mentalizing was associated with the expansion of frontoparietal cortical networks, particularly the default network. Mentalizing supports prosocial behaviors, but recent evidence indicates it may also serve a darker side of human social behavior. Using a computational reinforcement learning model of decision-making on a social exchange task, we examined how individuals optimized their approach to social interactions based on a counterpart's behavior and prior reputation. We found that learning signals encoded in the default network scaled with reciprocal cooperation and were stronger in individuals who were more exploitative and manipulative, but weaker in those who were more callous and less empathic. These learning signals, which help to update predictions about others' behavior, accounted for associations between exploitativeness, callousness, and social reciprocity. Separately, we found that callousness, but not exploitativeness, was associated with a behavioral insensitivity to prior reputation effects. While the entire default network was involved in reciprocal cooperation, sensitivity to reputation was selectively related to the activity of the medial temporal subsystem. Overall, our findings suggest that the emergence of social cognitive capacities associated with the expansion of the default network likely enabled humans to not only cooperate effectively with others, but to exploit and manipulate others as well.

Resting-state EEG delta and alpha power predict response to cognitive behavioral therapy in depression: a Canadian biomarker integration network for depression study.

Cognitive behavioral therapy (CBT) is often recommended as a first-line treatment in depression. However, access to CBT remains limited, and up to 50% of patients do not benefit from this therapy. Identifying biomarkers that can predict which patients will respond to CBT may assist in designing optimal treatment allocation strategies. In a Canadian Biomarker Integration Network for Depression (CAN-BIND) study, forty-one adults with depression were recruited to undergo a 16-week course of CBT with thirty having resting-state electroencephalography (EEG) recorded at baseline and week 2 of therapy. Successful clinical response to CBT was defined as a 50% or greater reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to post-treatment completion. EEG relative power spectral measures were analyzed at baseline, week 2, and as early changes from baseline to week 2. At baseline, lower relative delta (0.5-4 Hz) power was observed in responders. This difference was predictive of successful clinical response to CBT. Furthermore, responders exhibited an early increase in relative delta power and a decrease in relative alpha (8-12 Hz) power compared to non-responders. These changes were also found to be good predictors of response to the therapy. These findings showed the potential utility of resting-state EEG in predicting CBT outcomes. They also further reinforce the promise of an EEG-based clinical decision-making tool to support treatment decisions for each patient.

Identifying the midline thalamus in humans in vivo.

The midline thalamus is critical for flexible cognition, memory, and stress regulation in humans and its dysfunction is associated with several neurological and psychiatric disorders, including Alzheimer's disease, schizophrenia, and depression. Despite the pervasive role of the midline thalamus in cognition and disease, there is a limited understanding of its function in humans, likely due to the absence of a rigorous noninvasive neuroimaging methodology to identify its location. Here, we introduce a new method for identifying the midline thalamus in vivo using probabilistic tractography and k-means clustering with diffusion weighted imaging data. This approach clusters thalamic voxels based on data-driven cortical and subcortical connectivity profiles and then segments the midline thalamus according to anatomical connectivity tracer studies in rodents and macaques. Results from two different diffusion weighted imaging sets, including adult data (22-35 years) from the Human Connectome Project (n = 127) and adolescent data (9-14 years) collected at Florida International University (n = 34) showed that this approach reliably classifies midline thalamic clusters. As expected, these clusters were most evident along the dorsal/ventral extent of the third ventricle and were primarily connected to the agranular medial prefrontal cortex (e.g., anterior cingulate cortex), nucleus accumbens, and medial temporal lobe regions. The midline thalamus was then bisected based on a human brain atlas into a dorsal midline thalamic cluster (paraventricular and paratenial nuclei) and a ventral midline thalamic cluster (rhomboid and reuniens nuclei). This anatomical connectivity-based identification of the midline thalamus offers the opportunity for necessary investigation of this region in vivo in the human brain and how it relates to cognitive functions in humans, and to psychiatric and neurological disorders.

Response Inhibition and Predicting Response to Pharmacological and Cognitive Behavioral Therapy Treatments for Major Depressive Disorder: A Canadian Biomarker Integration Network for Depression Study.

BACKGROUND: Major depressive disorder (MDD) is associated with various cognitive impairments, including response inhibition. Deficits in response inhibition may also underlie poor antidepressant treatment response. Recent studies revealed that the neurobiological correlates of response inhibition can predict response to pharmacological treatments. However, the generalizability of this finding to first-line nonpharmacological treatments, particularly cognitive behavioral therapy, remains to be investigated. METHODS: Data from two independent treatment protocols were combined, one in which 65 patients with MDD underwent treatment with escitalopram, and the other in which 41 patients with MDD underwent a course of cognitive behavioral therapy. A total of 25 healthy control subjects were also recruited. Neural correlates of response inhibition were captured by participants completing a Go/NoGo task during electroencephalography recording. Response inhibition-related measures of interest included the amplitudes of the N2 and P3 event-related potentials. RESULTS: Pretreatment P3 amplitude, which has been linked to both the motor and cognitive aspects of response inhibition, was a significant predictor of change in depressive symptoms following escitalopram and cognitive behavioral therapy treatment. A greater pretreatment P3 amplitude was associated with a greater reduction in depressive severity. In addition, the pretreatment P3 amplitude was found to be significantly greater at baseline in remitters than in nonremitters and healthy control subjects. CONCLUSIONS: The integrity of response inhibition may be critical for a successful course of pharmacological or psychological treatment for MDD. Electrophysiological correlates of response inhibition may have utility as a general prognostic marker of treatment response in MDD. Future studies may investigate the benefit of preceding first-line treatments with interventions that improve response inhibition in MDD.

Negative affectivity and disinhibition as moderators of an interpersonal pathway to suicidal behavior in borderline personality disorder.

This longitudinal study examined whether personality traits moderate the link between interpersonal dysfunction and suicidal behavior in a high-risk sample of 458 individuals diagnosed with borderline personality disorder (BPD). Participants were assessed annually for up to 30 years (mean number of follow-ups = 7.82). Using multilevel structural equation modeling, we examined i) longitudinal, within-person relationships among interpersonal dysfunction, suicidal ideation, and suicide attempts; and ii) moderation of these relationships by negative affectivity and disinhibition. Negative affectivity predicted a stronger within-person coupling between interpersonal dysfunction and suicidal ideation. Disinhibition predicted a stronger coupling between ideation and suicide attempts. Assessing negative affectivity and disinhibition in a treatment setting may guide clinician vigilance toward those at highest risk for interpersonally triggered suicidal behaviors.

Dual medial prefrontal cortex and hippocampus projecting neurons in the paraventricular nucleus of the thalamus.

The paraventricular nucleus (PVT) of the midline thalamus is a critical higher-order cortico-thalamo-cortical integration site that plays a critical role in various behaviors including reward seeking, cue saliency, and emotional memory. Anatomical studies have shown that PVT projects to both medial prefrontal cortex (mPFC) and hippocampus (HC). However, dual mPFC-HC projecting neurons which could serve a role in synchronizing mPFC and HC activity during PVT-dependent behaviors, have not been explored. Here we used a dual retrograde adenoassociated virus (AAV) tracing approach to characterize the location and proportion of different projection populations that send collaterals to mPFC and/or ventral hippocampus (vHC) in rats. Additionally, we examined the distribution of calcium binding proteins calretinin (CR) and calbindin (CB) with respect to these projection populations in PVT. We found that PVT contains separate populations of cells that project to mPFC, vHC, and those that innervate both regions. Interestingly, dual mPFC-HC projecting cells expressed neither CR nor CB. Topographically, CB+ and CR+ containing cells clustered around dual projecting neurons in PVT. These results are consistent with the features of dual mPFC-vHC projecting cells in the nucleus reuniens (RE) and suggestive of a functional mPFC-PVT-vHC system that may support mPFC-vHC interactions in PVT-dependent behaviors.

Explanatory personality science in the neuroimaging era: The map is not the territory.

The recent rise of magnetic resonance imaging (MRI) has led to a proliferation of studies that seek to link individual differences in personality directly to their neural correlates. These studies function to describe personality at a lower level of analysis, but they do little to advance the field's understanding of the causal mechanisms that give rise to personality traits. To transition to a more explanatory personality neuroscience, researchers should strive to conduct theory-driven empirical studies that bridge multiple levels of analysis. Effectively doing so will require a continued reliance on rich description, strong theories, large samples, and careful behavioral experimentation. Integrating these components will lead to more robust and informative studies of personality neuroscience that help to move the field closer to explaining the causal sources of individual differences.

Dual projecting cells linking thalamic and cortical communication routes between the medial prefrontal cortex and hippocampus.

The interactions between the medial prefrontal cortex (mPFC) and the hippocampus (HC) are critical for memory and decision making and have been specifically implicated in several neurological disorders including schizophrenia, epilepsy, frontotemporal dementia, and Alzheimer's disease. The ventral midline thalamus (vmThal), and lateral entorhinal cortex and perirhinal cortex (LEC/PER) constitute major communication pathways that facilitate mPFC-HC interactions in memory. Although vmThal and LEC/PER circuits have been delineated separately we sought to determine whether these two regions share cell-specific inputs that could influence both routes simultaneously. To do this we used a dual fluorescent retrograde tracing approach using cholera toxin subunit-B (CTB-488 and CTB-594) with injections targeting vmThal and the LEC/PER in rats. Retrograde cell body labeling was examined in key regions of interest within the mPFC-HC system including: (1) mPFC, specifically anterior cingulate cortex (ACC), dorsal and ventral prelimbic cortex (dPL, vPL), and infralimbic cortex (IL); (2) medial and lateral septum (MS, LS); (3) subiculum (Sub) along the dorsal-ventral and proximal-distal axes; and (4) LEC and medial entorhinal cortex (MEC). Results showed that dual vmThal-LEC/PER-projecting cell populations are found in MS, vSub, and the shallow layers II/III of LEC and MEC. We did not find any dual projecting cells in mPFC or in the cornu ammonis (CA) subfields of the HC. Thus, mPFC and HC activity is sent to vmThal and LEC/PER via non-overlapping projection cell populations. Importantly, the dual projecting cell populations in MS, vSub, and EC are in a unique position to simultaneously influence both cortical and thalamic mPFC-HC pathways critical to memory. SIGNIFICANCE STATEMENT: The interactions between mPFC and HC are critical for learning and memory, and dysfunction within this circuit is implicated in various neurodegenerative and psychiatric diseases. mPFC-HC interactions are mediated through multiple communication pathways including a thalamic hub through the vmThal and a cortical hub through lateral entorhinal cortex and perirhinal cortex. Our data highlight newly identified dual projecting cell populations in the septum, Sub, and EC of the rat brain. These dual projecting cells may have the ability to modify the information flow within the mPFC-HC circuit through synchronous activity, and thus offer new cell-specific circuit targets for basic and translational studies in memory.

Borderline personality disorder: stress reactivity or stress generation? A prospective dimensional study.

BACKGROUND: Individuals diagnosed with borderline personality disorder (BPD) often describe their lives as stressful and unpredictable. However, it is unclear whether the adversity faced by those with BPD is a product of stress reactivity or stress generation. Here, we examined the dynamic, prospective associations between BPD and stressful life events over 3 years. Given the heterogeneity present in BPD, we sought to understand which empirically derived dimensions of this heterogeneous disorder explain stress reactivity v. stress generation. METHODS: Participants included 355 individuals diagnosed with BPD and followed longitudinally at three annual assessments. Auto-regressive cross-lagged panel models were used to examine prospective associations between stressful life events and three latent dimensions implicated in BPD: negative affect, disinhibition, and antagonism. RESULTS: Antagonism and disinhibition, but not negative affect, prospectively predicted dependent stressful life events (events the individual may have some role in). Evidence for decompensation under stress was more tenuous, with independent stressful life events (those presumably outside the individual's control) predicting increases in negative affect. CONCLUSIONS: Our longitudinal study of a well-characterized clinical sample found more evidence for stress generation than for stress-induced decompensation in BPD. Stress generation in BPD is driven by externalizing dimensions: antagonism and disinhibition. These results highlight the utility of empirically derived dimensions for parsing heterogeneity present in BPD, leading to improvements in diagnostic evaluation, clinical prediction, and individualized approaches to treatment planning.

Interactions between neuroticism and stressful life events predict response to pharmacotherapy for major depression: A CAN-BIND 1 report.

Exposure to stressful life events and individual differences in the personality trait neuroticism are important risk factors that interact to predict major depressive disorder (MDD). Less is known about their effect on treatment response in depression. Here, we examine whether stressful life events experienced prior to and during treatment interact with neuroticism to predict response to 16-week pharmacotherapy for MDD. Participants included 159 outpatients with MDD who were initially treated with 8 weeks of escitalopram. Those who responded to the initial treatment continued on escitalopram monotherapy, whereas non-responders received 8 weeks of adjunctive aripiprazole. Personality was assessed using the NEO-Five Factor Inventory, and stressful life events were assessed using the Life Events and Difficulties Schedule, a rigorous contextual interview that includes independent ratings of threatening life events. High baseline neuroticism was associated with a lower likelihood of response when patients experienced one or more negative life events before treatment. Secondary analyses indicated that this effect was specific to neuroticism, and not better accounted for by its self-criticism or negative affect facets. Our results suggest that assessing personality and stressful life events at baseline can help clinicians assess which patients will respond to antidepressant therapy and which may need treatment augmentation.

Medial prefrontal cortex and hippocampal activity differentially contribute to ordinal and temporal context retrieval during sequence memory.

Remembering sequences of events defines episodic memory, but retrieval can be driven by both ordinality and temporal contexts. Whether these modes of retrieval operate at the same time or not remains unclear. Theoretically, medial prefrontal cortex (mPFC) confers ordinality, while the hippocampus (HC) associates events in gradually changing temporal contexts. Here, we looked for evidence of each with BOLD fMRI in a sequence task that taxes both retrieval modes. To test ordinal modes, items were transferred between sequences but retained their position (e.g., AB3). Ordinal modes activated mPFC, but not HC. To test temporal contexts, we examined items that skipped ahead across lag distances (e.g., ABD). HC, but not mPFC, tracked temporal contexts. There was a mPFC and HC by retrieval mode interaction. These current results suggest that the mPFC and HC are concurrently engaged in different retrieval modes in support of remembering when an event occurred.

Disentangling cognitive processes in externalizing psychopathology using drift diffusion modeling: Antagonism, but not disinhibition, is associated with poor cognitive control.

Although externalizing psychopathology has been linked to deficits in cognitive control, the cognitive processes underlying this association are unclear. Here, we provide a theoretical account of how research on cognitive processes can help to integrate and distinguish personality and psychopathology. We then apply this account to connect the two major subcomponents of externalizing, Antagonism and Disinhibition, with specific control processes using a battery of inhibitory control tasks and corresponding computational modeling. Participants (final N = 104) completed the flanker, go/no-go, and recent probes tasks, as well as normal and maladaptive personality inventories and measures of psychological distress. We fit participants' task behavior using a hierarchical drift diffusion model (DDM) to decompose their responses into specific cognitive processes. Using multilevel structural equation models, we found that Antagonism was associated with faster RTs on the flanker task and lower accuracy on flanker and go/no-go tasks. These results were complemented by DDM parameter associations: Antagonism was linked to decreased threshold and drift rate parameter estimates in the flanker task and a decreased drift rate on no-go trials. Altogether, our findings indicate that Antagonism is associated with specific impairments in fast (sub-second) inhibitory control processes involved in withholding prepared/prepotent responses and filtering distracting information. Disinhibition and momentary distress, however, were not associated with task performance.

Calretinin and calbindin architecture of the midline thalamus associated with prefrontal-hippocampal circuitry.

The midline thalamus bidirectionally connects the medial prefrontal cortex (mPFC) and hippocampus (HC) creating a unique cortico-thalamo-cortical circuit fundamental to memory and executive function. While the anatomical connectivity of midline thalamus has been thoroughly investigated, little is known about its cellular organization within each nucleus. Here we used immunohistological techniques to examine cellular distributions in the midline thalamus based on the calcium binding proteins parvalbumin (PV), calretinin (CR), and calbindin (CB). We also examined these calcium binding proteins in a population of reuniens cells known to project to both mPFC and HC using a dual fluorescence retrograde adenoassociated virus-based tracing approach. These dual reuniens mPFC-HC projecting cells, in particular, are thought to be important for synchronizing mPFC and HC activity. First, we confirmed the absence of PV+ neurons in the midline thalamus. Second, we found a common pattern of CR+ and CB+ cells throughout midline thalamus with CR+ cells running along the nearby third ventricle (3V) and penetrating the midline. CB+ cells were consistently more lateral and toward the middle of the dorsal-ventral extent of the midline thalamus. Notably, single-labeled CR+ and CB+ zones were partially overlapping and included dual-labeled CR+ /CB+ cells. Within RE, we also observed a CR and CB subzone specific diversity. Interestingly, dual mPFC-HC projecting neurons in RE expressed none of the calcium binding proteins examined, but were contained in nests of CR+ and CB+ cells. Overall, the midline thalamus was well organized into CR+ and CB+ rich zones distributed throughout the region, with dual mPFC-HC projecting cells in reuniens representing a unique cell population. These results provide a cytoarchitectural organization in the midline thalamus based on calcium binding protein expression, and set the stage for future cell-type specific interrogations of the functional role of these different cell populations in mPFC-HC interactions.

From Description to Explanation: Integrating Across Multiple Levels of Analysis to Inform Neuroscientific Accounts of Dimensional Personality Pathology.

Dimensional approaches to psychiatric nosology are rapidly transforming the way researchers and clinicians conceptualize personality pathology, leading to a growing interest in describing how individuals differ from one another. Yet, in order to successfully prevent and treat personality pathology, it is also necessary to explain the sources of these individual differences. The emerging field of personality neuroscience is well-positioned to guide the transition from description to explanation within personality pathology research. However, establishing comprehensive, mechanistic accounts of personality pathology will require personality neuroscientists to move beyond atheoretical studies that link trait differences to neural correlates without considering the algorithmic processes that are carried out by those correlates. We highlight some of the dangers we see in overpopulating personality neuroscience with brain-trait associational studies and offer a series of recommendations for personality neuroscientists seeking to build explanatory theories of personality pathology.

Disinhibition and Detachment in Adolescence: A Developmental Cognitive Neuroscience Perspective on the Alternative Model for Personality Disorders.

Personality pathology often emerges during adolescence, but attempts to understand its neurocognitive basis have traditionally been undermined by problems associated with the categorical classification of personality disorders. In contrast, dimensional models of personality pathology, such as the Alternative Model for Personality Disorders (AMPD) in DSM-5, may provide a stronger foundation for neurobiological investigations of maladaptive individual differences in personality. As an example, we review studies of the adolescent development of reward processing and cognitive control and connect these systems to the normal personality hierarchy and to two dimensions included in the AMPD - Detachment and Disinhibition. We argue that by linking developmental changes in these systems to the AMPD, researchers will be better positioned to understand the relationship between neurocognitive development and the expression of personality pathology in adolescence and early adulthood.

Awake delta and theta-rhythmic hippocampal network modes during intermittent locomotor behaviors in the rat.

Delta-frequency network activity is commonly associated with sleep or behavioral disengagement accompanied by a dearth of cortical spiking, but delta in awake behaving animals is not well understood. We show that hippocampal (HC) synchronization in the delta frequency band (1-4 Hz) is related to animals' locomotor behavior using detailed analyses of the HC local field potential (LFP) and simultaneous head- and body-tracking data. In contrast to running-speed modulation of the theta rhythm (6-10 Hz), delta was most prominent when animals were stationary or moving slowly, that is, when theta and fast gamma (65-120 Hz) were weak, and often developed rapidly when animals paused briefly between runs. We next combined time-frequency decomposition of the LFP with hierarchical clustering algorithms to categorize momentary estimations of the power spectral density (PSD) into putative modes of HC activity. Delta and theta power were strikingly orthogonal across spectral modes, as well as across bouts of precisely defined running and stationary behavior. Delta-band and theta-band coherences between HC recording sites were monotonically related to theta-delta ratios across modes; and whereas theta coherence between HC and medial prefrontal cortex (mPFC) increased during running, delta-band coherence between mPFC and HC increased during stationary bouts. Taken together, our findings suggest that delta-dominated network modes (and corresponding mPFC-HC couplings) represent functionally distinct circuit dynamics that are temporally and behaviorally interspersed among theta-dominated modes during navigation. As such, delta modes could play a fundamental role in coordinating encoding and retrieval mechanisms or decision-making processes at a timescale that segments event sequences within behavioral episodes. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

RatHat: A Self-Targeting Printable Brain Implant System.

There has not been a major change in how neuroscientists approach stereotaxic methods in decades. Here, we present a new stereotaxic method that provides an alternative approach to a traditional u-frame stereotaxic device and reduces costs, surgical time, and aids repeatability. The RatHat brain implantation system is a 3D-printable stereotaxic device for rats that is fabricated prior to surgery and fits to the shape of the skull. RatHat builds are directly implanted into the brain without the need for head-leveling or coordinate-mapping during surgery. The RatHat can be used in conjunction with the traditional u-frame stereotaxic device, but does not require the use of a micromanipulator for successful implantations. Each RatHat contains several primary components including the implant for mounting intracranial components, the surgical stencil for targeting drill sites, and the protective cap for preventing damage from impacts and debris. Each component serves a unique function and can be used together or separately. We demonstrate the feasibility of the RatHat in four different proof-of-principle experiments: (1) a three-pole cannula apparatus, (2) an optrode-electrode assembly, (3) a fixed-electrode array, and (4) a tetrode hyperdrive. Implants were successful, durable, and long-lasting (up to nine months). RatHat print files are easily created, can be modified in computer aided design (CAD) software for a variety of applications, and are easily shared, contributing to open science goals and replications. The RatHat has been adapted to multiple experimental paradigms in our lab and should be a useful new way to conduct stereotaxic implant surgeries in rodents.

The hippocampus, prefrontal cortex, and perirhinal cortex are critical to incidental order memory.

Considerable research in rodents and humans indicates the hippocampus and prefrontal cortex are essential for remembering temporal relationships among stimuli, and accumulating evidence suggests the perirhinal cortex may also be involved. However, experimental parameters differ substantially across studies, which limits our ability to fully understand the fundamental contributions of these structures. In fact, previous studies vary in the type of temporal memory they emphasize (e.g., order, sequence, or separation in time), the stimuli and responses they use (e.g., trial-unique or repeated sequences, and incidental or rewarded behavior), and the degree to which they control for potential confounding factors (e.g., primary and recency effects, or order memory deficits secondary to item memory impairments). To help integrate these findings, we developed a new paradigm testing incidental memory for trial-unique series of events, and concurrently assessed order and item memory in animals with damage to the hippocampus, prefrontal cortex, or perirhinal cortex. We found that this new approach led to robust order and item memory, and that hippocampal, prefrontal and perirhinal damage selectively impaired order memory. These findings suggest the hippocampus, prefrontal cortex and perirhinal cortex are part of a broad network of structures essential for incidentally learning the order of events in episodic memory.