Do hippocampal pyramidal cells respond to nonspatial stimuli?

There are currently a number of theories of rodent hippocampal function. They fall into two major groups that differ in the role they impute to space in hippocampal information processing. On one hand, the cognitive map theory sees space as crucial and central, with other types of nonspatial information embedded in a primary spatial framework. On the other hand, most other theories see the function of the hippocampal formation as broader, treating all types of information as equivalent and concentrating on the processes carried out irrespective of the specific material being represented, stored, and manipulated. One crucial difference, therefore, is the extent to which theories see hippocampal pyramidal cells as representing nonspatial information independently of a spatial framework. Studies have reported the existence of single hippocampal unit responses to nonspatial stimuli, both to simple sensory inputs as well as to more complex stimuli such as objects, conspecifics, rewards, and time, and these findings been interpreted as evidence in favor of a broader hippocampal function. Alternatively, these nonspatial responses might actually be feature-in-place signals where the spatial nature of the response has been masked by the fact that the objects or features were only presented in one location or one spatial context. In this article, we argue that when tested in multiple locations, the hippocampal response to nonspatial stimuli is almost invariably dependent on the animal's location. Looked at collectively, the data provide strong support for the cognitive map theory.

Hippocampal place cells have goal-oriented vector fields during navigation.

The hippocampal cognitive map supports navigation towards, or away from, salient locations in familiar environments1. Although much is known about how the hippocampus encodes location in world-centred coordinates, how it supports flexible navigation is less well understood. We recorded CA1 place cells while rats navigated to a goal on the honeycomb maze2. The maze tests navigation via direct and indirect paths to the goal and allows the directionality of place cells to be assessed at each choice point. Place fields showed strong directional polarization characterized by vector fields that converged to sinks distributed throughout the environment. The distribution of these 'convergence sinks' (ConSinks) was centred near the goal location and the population vector field converged on the goal, providing a strong navigational signal. Changing the goal location led to movement of ConSinks and vector fields towards the new goal. The honeycomb maze allows independent assessment of spatial representation and spatial action in place cell activity and shows how the latter relates to the former. The results suggest that the hippocampus creates a vector-based model to support flexible navigation, allowing animals to select optimal paths to destinations from any location in the environment.

Author Correction: The honeycomb maze provides a novel test to study hippocampal-dependent spatial navigation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The honeycomb maze provides a novel test to study hippocampal-dependent spatial navigation.

Here we describe the honeycomb maze, a behavioural paradigm for the study of spatial navigation in rats. The maze consists of 37 platforms that can be raised or lowered independently. Place navigation requires an animal to go to a goal platform from any of several start platforms via a series of sequential choices. For each, the animal is confined to a raised platform and allowed to choose between two of the six adjacent platforms, the correct one being the platform with the smallest angle to the goal-heading direction. Rats learn rapidly and their choices are influenced by three factors: the angle between the two choice platforms, the distance from the goal, and the angle between the correct platform and the direction of the goal. Rats with hippocampal damage are impaired in learning and their performance is affected by all three factors. The honeycomb maze represents a marked improvement over current spatial navigation tests, such as the Morris water maze, because it controls the choices of the animal at each point in the maze, provides the ability to assess knowledge of the goal direction from any location, enables the identification of factors influencing task performance and provides the possibility for concomitant single-cell recording.

Recommendations for Dynamic Treatment of Identity-Based Trauma: Opening the "I" to Reflection.

Current treatments for trauma are ineffective for many patients. For traumas involving violence that targets aspects of patients' identities, treatments that do not address systemic factors involved in the trauma (e.g., past and ongoing experiences of identity-based oppression and marginalization, developmental sequelae of invalidation or policing of identity, and identity-related patterns of transference and countertransference) may be ineffective. Psychodynamic approaches can flexibly address the identity-related dynamics between therapist and patient and incorporate patients' experiences of their various identities, in the context of trauma, into clinical formulation and treatment. The authors present concepts relevant to the dynamics of intersectional identities that may arise between therapist and patient and provide a case study illustrating how a patient's various identities affect their symptom manifestation and treatment course. The authors advocate for cultural humility and self-exploration of biases and assumptions among clinicians, because therapists do not hold expert knowledge of their patients' cultural experiences.

Minimally invasive Dorsal cheilectomy and Hallux metatarsophalangeal joint arthroscopy for the treatment of Hallux Rigidus.

BACKGROUND: Minimally invasive dorsal cheilectomy (MIDC) has become a popular alternative to an open approach for treating Hallux Rigidus (HR). To reduce some of the complications related to the MIDC approach, a first metatarsophalangeal (MTP) joint arthroscopy can be performed in addition to address the intra-articular pathology associated with Hallux Rigidus. This study aims to examine the effectiveness of MIDC with first MTP arthroscopy in patients with HR with a minimum 1-year follow-up. METHODS: This was a multicenter retrospective review for adult patients with Coughlin and Shurnass Grade 0-3 who were treated with MIDC and first MTP arthroscopy between 3/1/2020 and 8/1/2022, with at least one year of follow-up data. Demographic information, first MTP range of motion (ROM), visual analog scale (VAS), Manchester-Oxford Foot Questionnaire (MOXFQ), and EQ-5D-5 L scores were collected. Continuous data was expressed as a mean and standard deviation, categorical data was expressed as a percentage. Wilcoxon Rank Sum test was used to compare continuous variables. All P < 0.05 was considered significant. RESULTS: A total of 31 patients were included in the study. Average follow-up time was 16.5 months (range: 12 to 26.2). There was 1 (3.2%) undersurface EHL tendon tear, 2 (6.5%) conversions to an MTP fusion, and 1 (3.2%) revision cheilectomy and capsular release for MTP joint contracture. There was a significant improvement in patient's ROM in dorsiflexion (50 vs 89.6 degrees, P = 0.002), postoperative VAS pain scores (6.4 vs 2.1, P < 0.001), MOXFQ pain scores (58.1 vs 30.7, P = 0.001), MOXFQ Walking/Standing scores (56.6 vs 20.6, P = 0.001), MOXFQ Social Interaction scores (47.3 vs 19.36, P = 0.002), and MOXFQ Index scores (54.7 vs 22.4, P < 0.001). CONCLUSION: We found that MIDC with first MTP arthroscopy was effective at improving patient-reported outcomes at one year with low complication and revision rates. These results suggest that MIDC with first MTP arthroscopy is an effective treatment for early-stage HR. LEVEL OF EVIDENCE: IV.

Fully integrated silicon probes for high-density recording of neural activity.

Sensory, motor and cognitive operations involve the coordinated action of large neuronal populations across multiple brain regions in both superficial and deep structures. Existing extracellular probes record neural activity with excellent spatial and temporal (sub-millisecond) resolution, but from only a few dozen neurons per shank. Optical Ca2+ imaging offers more coverage but lacks the temporal resolution needed to distinguish individual spikes reliably and does not measure local field potentials. Until now, no technology compatible with use in unrestrained animals has combined high spatiotemporal resolution with large volume coverage. Here we design, fabricate and test a new silicon probe known as Neuropixels to meet this need. Each probe has 384 recording channels that can programmably address 960 complementary metal-oxide-semiconductor (CMOS) processing-compatible low-impedance TiN sites that tile a single 10-mm long, 70 × 20-µm cross-section shank. The 6 × 9-mm probe base is fabricated with the shank on a single chip. Voltage signals are filtered, amplified, multiplexed and digitized on the base, allowing the direct transmission of noise-free digital data from the probe. The combination of dense recording sites and high channel count yielded well-isolated spiking activity from hundreds of neurons per probe implanted in mice and rats. Using two probes, more than 700 well-isolated single neurons were recorded simultaneously from five brain structures in an awake mouse. The fully integrated functionality and small size of Neuropixels probes allowed large populations of neurons from several brain structures to be recorded in freely moving animals. This combination of high-performance electrode technology and scalable chip fabrication methods opens a path towards recording of brain-wide neural activity during behaviour.

Changes in Attachment Representation and Personality Organization in Transference-Focused Psychotherapy.

OBJECTIVE: The aim of this article was to construct an empirical bridge between object relations theory and attachment theory by investigating how researchers in both traditions have contributed to understanding and assessing identity diffusion (a keystone of personality pathology) and object relations in patients with borderline personality disorder during 1 year of transference-focused psychotherapy (TFP). METHODS: The Adult Attachment Interview (AAI) and the Structured Interview of Personality Organization (STIPO) were administered to patients (N=104, all women) before and after 1 year of treatment. This study was part of a randomized controlled trial in which 104 patients with borderline personality disorder were randomly assigned to receive either TFP (a manualized, structured psychodynamic treatment approach) or treatment by experienced community psychotherapists. Changes on the AAI in attachment representations, narrative coherence, and reflective function were examined for their associations with changes on the STIPO in identity, object relations, and aggression. RESULTS: Patients who shifted from disorganized (unresolved) to organized attachment on the AAI after 1 year of TFP (but not treatment by experienced community psychotherapists) showed hypothesized improvements in domains of personality organization on the STIPO, including identity, object relations, and aggression. Those who did not change from disorganized (unresolved) to organized attachment improved only in the domain of aggression. CONCLUSIONS: These findings highlight the centrality of identity diffusion to borderline personality disorder pathology and the importance of targeting it in treatment. Furthermore, the results suggest that identity may be indexed by measures of attachment security, narrative coherence, and personality organization.

Open Trial of Trauma-Focused Psychodynamic Psychotherapy for Posttraumatic Stress Disorder Among LGBTQ Individuals.

OBJECTIVE: Lesbian, gay, bisexual, transgender, and queer (LGBTQ) individuals report higher rates of exposure to traumatic events and posttraumatic stress disorder (PTSD) compared with heterosexual and cisgender individuals. No treatment outcomes research has focused on PTSD in the LGBTQ population. Trauma-focused psychodynamic psychotherapy (TFPP) is a brief, manualized, attachment- and affect-focused psychotherapy for PTSD. TFPP explicitly incorporates broad identity-related and societal factors into its conceptualization of trauma and its consequences, which may be especially helpful for LGBTQ patients with minority stress who seek affirmative care. METHODS: Fourteen LGBTQ patients with PTSD, assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), received 24 sessions of twice-weekly (12 weeks) TFPP via teletherapy provided by supervised early-career therapists inexperienced in the modality. Sessions were videotaped to monitor therapists' treatment adherence. Patients were assessed at baseline, week 5, termination (week 12), and 3 months posttreatment for PTSD symptoms (assessed with the CAPS-5) and secondary outcomes. RESULTS: TFPP was well tolerated by patients, with 12 (86%) completing the intervention. CAPS-5-measured PTSD symptoms, including dissociation, significantly improved during treatment (mean decrease=-21.8, d=-1.98), and treatment gains were maintained at follow-up. Most patients experienced PTSD clinical response (N=10, 71%) or diagnostic remission (N=7, 50%). Patients generally experienced significant, concomitant improvements in complex PTSD symptoms, general anxiety, depression, and psychosocial functioning. Adherence to the intervention among therapists was high, with 93% of rated sessions meeting adherence standards. CONCLUSIONS: TFPP shows promise in the treatment of PTSD among sexual and gender minority patients seeking LGBTQ-affirmative PTSD care.

Elucidating behavioral and functional connectivity markers of aberrant threat discrimination in PTSD.

BACKGROUND: Patients with posttraumatic stress disorder (PTSD) tend to overgeneralize threat to safe stimuli, potentially reflecting aberrant stimuli discrimination. Yet, it is not clear whether threat overgeneralization reflects general discrimination deficits, or rather a specific bias related to aversive stimuli. Here we tested this question and characterized the neural correlates of threat discrimination. METHODS: One-hundred and eight participants (33 PTSD; 43 trauma-exposed controls; 32 healthy controls) completed an emotionally neutral complex shape discrimination task involving identifying in 42 similar pairs the previously observed shape; and an emotionally aversive discrimination task, involving providing risk ratings for an aversive conditioned stimulus (CS+), and for several stimuli gradually differing in size from the original CS+. Resting state functional connectivity (rsFC) was collected before completing the tasks. RESULTS: No group differences emerged on the emotionally neutral task. Conversely, on the emotionally aversive task, individuals with PTSD had steeper linear risk rating slopes as the stimuli more resembled the conditioned stimulus. Finally, lower rsFC of amygdala-default mode network (DMN) and DMN-salience network (SN) were associated with steeper risk slopes, while for hippocampus-SN, lower rsFC was found only among participants with PTSD. CONCLUSIONS: Individuals with PTSD show deficits in discrimination only when presented with aversive stimuli. Dysregulated discrimination pattern may relate to a lack of input from regulatory brain areas (e.g., DMN/hippocampus) to threat-related brain areas (e.g., SN/amygdala).

Treatment selection in borderline personality disorder between dialectical behavior therapy and psychodynamic psychiatric management.

BACKGROUND: No evidence-based therapy for borderline personality disorder (BPD) exhibits a clear superiority. However, BPD is highly heterogeneous, and different patients may specifically benefit from the interventions of a particular treatment. METHODS: From a randomized trial comparing a year of dialectical behavior therapy (DBT) to general psychiatric management (GPM) for BPD, long-term (2-year-post) outcome data and patient baseline variables (n = 156) were used to examine individual and combined patient-level moderators of differential treatment response. A two-step bootstrapped and partially cross-validated moderator identification process was employed for 20 baseline variables. For identified moderators, 10-fold bootstrapped cross-validated models estimated response to each therapy, and long-term outcomes were compared for patients randomized to their model-predicted optimal v. non-optimal treatment. RESULTS: Significant moderators surviving the two-step process included psychiatric symptom severity, BPD impulsivity symptoms (both GPM > DBT), dependent personality traits, childhood emotional abuse, and social adjustment (all DBT > GPM). Patients randomized to their model-predicted optimal treatment had significantly better long-term outcomes (d = 0.36, p = 0.028), especially if the model had a relatively stronger (top 60%) prediction for that patient (d = 0.61, p = 0.004). Among patients with a stronger prediction, this advantage held even when applying a conservative statistical check (d = 0.46, p = 0.043). CONCLUSIONS: Patient characteristics influence the degree to which they respond to two treatments for BPD. Combining information from multiple moderators may help inform providers and patients as to which treatment is the most likely to lead to long-term symptom relief. Further research on personalized medicine in BPD is needed.

Precision medicine for long-term depression outcomes using the Personalized Advantage Index approach: cognitive therapy or interpersonal psychotherapy?

BACKGROUND: Psychotherapies for depression are equally effective on average, but individual responses vary widely. Outcomes can be improved by optimizing treatment selection using multivariate prediction models. A promising approach is the Personalized Advantage Index (PAI) that predicts the optimal treatment for a given individual and the magnitude of the advantage. The current study aimed to extend the PAI to long-term depression outcomes after acute-phase psychotherapy. METHODS: Data come from a randomized trial comparing cognitive therapy (CT, n = 76) and interpersonal psychotherapy (IPT, n = 75) for major depressive disorder (MDD). Primary outcome was depression severity, as assessed by the BDI-II, during 17-month follow-up. First, predictors and moderators were selected from 38 pre-treatment variables using a two-step machine learning approach. Second, predictors and moderators were combined into a final model, from which PAI predictions were computed with cross-validation. Long-term PAI predictions were then compared to actual follow-up outcomes and post-treatment PAI predictions. RESULTS: One predictor (parental alcohol abuse) and two moderators (recent life events; childhood maltreatment) were identified. Individuals assigned to their PAI-indicated treatment had lower follow-up depression severity compared to those assigned to their PAI-non-indicated treatment. This difference was significant in two subsets of the overall sample: those whose PAI score was in the upper 60%, and those whose PAI indicated CT, irrespective of magnitude. Long-term predictions did not overlap substantially with predictions for acute benefit. CONCLUSIONS: If replicated, long-term PAI predictions could enhance precision medicine by selecting the optimal treatment for a given depressed individual over the long term.

Grid cell symmetry is shaped by environmental geometry.

Grid cells represent an animal's location by firing in multiple fields arranged in a striking hexagonal array. Such an impressive and constant regularity prompted suggestions that grid cells represent a universal and environmental-invariant metric for navigation. Originally the properties of grid patterns were believed to be independent of the shape of the environment and this notion has dominated almost all theoretical grid cell models. However, several studies indicate that environmental boundaries influence grid firing, though the strength, nature and longevity of this effect is unclear. Here we show that grid orientation, scale, symmetry and homogeneity are strongly and permanently affected by environmental geometry. We found that grid patterns orient to the walls of polarized enclosures such as squares, but not circles. Furthermore, the hexagonal grid symmetry is permanently broken in highly polarized environments such as trapezoids, the pattern being more elliptical and less homogeneous. Our results provide compelling evidence for the idea that environmental boundaries compete with the internal organization of the grid cell system to drive grid firing. Notably, grid cell activity is more local than previously thought and as a consequence cannot provide a universal spatial metric in all environments.

Predictors and moderators of treatment dropout in cognitive-behavioral and psychodynamic therapies for panic disorder.

Introduction: Panic disorder patients who drop out of treatment typically do not remit from their disorder. How patient-level moderators influence dropping out of one panic-focused treatment over another has never been examined, nor in non-CBT treatments. Method: 200 patients with panic disorder with or without agoraphobia were randomized to receive cognitive-behavioral therapy (CBT), panic-focused psychodynamic psychotherapy (PFPP), or applied relaxation training (ART) across two sites. Therapy was twice a week for 12 weeks. A two-step variable search method was applied to identify potential prognostic predictors and moderators of patient dropout. Survival models predicting hazard of session-by-session dropout tested the resulting variables. Results: Across treatments, unemployment and higher psychosocial disability on the Sheehan Disability Scale predicted increased risk of dropout, while patients with higher anxiety sensitivity were more likely to complete treatment. Patients who reported experiencing childhood abuse had heightened dropout in ART, but not CBT or PFPP. Men were especially likely to complete PFPP. Session 2 expectancies and patient-rated alliance predicted lower dropout only in CBT. Conclusions: Patient-level factors may influence both whether patients will complete any treatment, and whether they continue in a particular panic-focused therapy. Moderators of dropout (e.g., abuse history) may inform treatment decisions for specific patients.Trial registration: ClinicalTrials.gov identifier: NCT00353470.

Increased flexor hallucis longus tension decreases ankle dorsiflexion.

BACKGROUND: Restricted excursion of the flexor hallucis longus (FHL) is associated with several clinical problems. An FHL excursion measurement device (EMD) was used to objectively assess differences between patients with clinically normal or tight FHL tendons. METHODS: 188 patients (356 feet) were enrolled. The EMD measured maximum ankle dorsiflexion with the great toe in 15°, 30°, and 45° of dorsiflexion. All had clinical assessment of FHL tightness by their provider independently of the EMD measurement. RESULTS: Increased hallux DF always caused decreased ankle DF. Patients with clinically tight FHLs demonstrated decreased ankle DF compared to normal subjects at all hallux positions (p<0.01). The EMD measurement was not sensitive enough for detection of FHL tightness in individuals. A clinically tight FHL was seen in almost 50% of feet. CONCLUSIONS: Tension in the FHL can limit ankle DF. Clinical tightness of the FHL is likely more common than currently recognized.

Separation anxiety in PTSD: A pilot study of mechanisms in patients undergoing IPT.

INTRODUCTION: Separation anxiety disorder (SAD) comprises one aspect of attachment dysregulation or insecurity. Although SAD aggravates posttraumatic stress disorder (PTSD) risk, no clinical research has tracked how many patients with PTSD have SAD, its clinical associations, or its response to PTSD treatment. Our open trial of interpersonal psychotherapy (IPT) for veterans with PTSD assessed these SAD domains. METHODS: Twenty-nine veterans diagnosed with chronic PTSD on the Clinician-Administered PTSD Scale were assessed for SAD using the Structured Clinical Interview for Separation Anxiety Symptoms (SCI-SAS), and for Symptom-Specific Reflective Function (SSRF), another dysregulated-attachment marker capturing patients' emotional understanding of their symptoms. Patients received 14 IPT sessions for PTSD with assessments at baseline, Week 4 (SCI-SAS and SSRF), and termination for SAD, PTSD, and depression. RESULTS: At baseline, 69% of patients met SAD criteria. Separation anxiety did not correlate with baseline PTSD severity, depressive severity, or age when traumatized; patients with and without SAD had comparable PTSD and depression severity. Patients with baseline comorbid SAD who completed IPT (N = 17) reported significantly improved adult separation anxiety (p = .009). Adult SAD improvements predicted depressive improvement (p = .049). Patients with SAD showed a stronger relationship between early SSRF gains and subsequent adult SAD improvement (p = .021) compared with patients without SAD. DISCUSSION: This first exploration of dysregulated/insecure attachment features among patients with PTSD found high SAD comorbidity and adult SAD improvement among patients with SAD following IPT. Highly impaired attachment patients normalized attachment posttreatment: 14-session IPT improved attachment dysregulation. This small study requires replication but begins to broaden clinical understanding of separation anxiety, attachment dysregulation, and PTSD.

A prognostic index for long-term outcome after successful acute phase cognitive therapy and interpersonal psychotherapy for major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) has a highly recurrent nature. After successful treatment, it is important to identify individuals who are at risk of an unfavorable long-term course. Despite extensive research, there is no consensus yet on the clinically relevant predictors of long-term outcome in MDD, and no prediction models are implemented in clinical practice. The aim of this study was to create a prognostic index (PI) to estimate long-term depression severity after successful and high quality acute treatment for MDD. METHODS: Data come from responders to cognitive therapy (CT) and interpersonal psychotherapy (IPT) in a randomized clinical trial (n = 85; CT = 45, IPT = 40). Primary outcome was depression severity, assessed with the Beck Depression Inventory II, measured throughout a 17-month follow-up phase. We examined 29 variables as potential predictors, using a model-based recursive partitioning method and bootstrap resampling in conjunction with backwards elimination. The selected predictors were combined into a PI. Individual PI scores were estimated using a cross-validation approach. RESULTS: A total of three post-treatment predictors were identified: depression severity, hopelessness, and self-esteem. Cross-validated PI scores evidenced a strong correlation (r = 0.60) with follow-up depression severity. CONCLUSION: Long-term predictions of MDD are multifactorial, involving a combination of variables that each has a small prognostic effect. If replicated and validated, the PI can be implemented to predict follow-up depression severity for each individual after acute treatment response, and to personalize long-term treatment strategies.

Changing character: A narrative review of personality change in psychotherapies for personality disorder.

Objective: Personality disorder (PD) is a negative prognostic indicator for treatment, and absolute improvements in functioning among these patients are often modest. This may be because personality features that give rise to dysfunction in PD are not targeted optimally during most treatments. Method: Attachment, mentalization, core beliefs, and personality organization/defense use were identified as personality constructs that have been pursued in treatment studies and that are proposed to underlie PD. Results: All constructs correlate with psychiatric symptoms, PD diagnosis, and functioning. Defense mechanisms and core beliefs further distinguish specific PDs, whereas personality organization separates more versus less severe PDs. Evidence from treatment and naturalistic studies indicate that maturation of defense mechanisms temporally precedes improvements in symptoms and functioning. Changes in attachment and mentalization correlate with some outcomes, but mediation of improvement has not been established. In psychodynamic therapy, transference interpretations may promote amelioration of personality dysfunction. With the exception of attachment, the experimental literature is lacking that could explicate the mechanisms by which these personality constructs maintain psychosocial dysfunction. Conclusions: Future research should aim to identify changes in these mechanisms that mediate positive outcomes in PD, as well as the specific therapeutic procedures that best promote positive change in PD.

Focus is key: Panic-focused interpretations are associated with symptomatic improvement in panic-focused psychodynamic psychotherapy.

Objective: This study examines whether, in panic-focused psychodynamic psychotherapy (PFPP), interpretations of conflicts that underlie anxiety (panic-focused or PF-interpretations) are specifically associated with subsequent panic disorder (PD) symptom improvement, over and above the provision of non-symptom-focused interpretations. Method: Technique use in Sessions 2 and 10 of a 24-session PFPP protocol was assessed for the 65 patients with complete outcome data randomized to PFPP in a two-site trial of psychotherapies for PD. Sessions were rated in 15-min segments for therapists' use of PF-interpretations, non-PF-interpretations, and PF-clarifications. Robust regressions were conducted to examine the relationship between these interventions and symptom change subsequent to the sampled session. Interpersonal problems were examined as a moderator of the relationship of PF-interpretations to symptom change. Results: At Session 10, but not at Session 2, patients who received a higher degree of PF-interpretations experienced greater subsequent improvement in panic symptoms. Non-PF-interpretations were not predictive. Patients with more interpersonal distress benefitted particularly from the use of PF-interpretations at Session 10. Conclusions: By the middle phase of PFPP, panic-focused interpretations may drive subsequent improvements in panic symptoms, especially among patients with higher interpersonal distress. Interpretations of conflict absent a panic focus may not be especially helpful.

A "Seleno Effect" Differentiates the Roles of Redox Active Cysteine Residues in Plasmodium falciparum Thioredoxin Reductase.

Here, we introduce the concept of the "seleno effect" in the study of oxidoreductases that catalyze thiol/disulfide exchange reactions. In these reactions, selenium can replace sulfur as a nucleophile, electrophile, or leaving group, and the resulting change in rate (the seleno effect) is defined as kS/ kSe. In solution, selenium accelerates the rate of thiol/disulfide exchange regardless of its chemical role (e.g., nucleophile or electrophile). Here we show that this is not the case for enzyme catalyzed reactions and that the magnitude of the seleno effect can differentiate the role of each sulfur atom of a disulfide bond between that of an electrophile or leaving group. We used selenium for sulfur substitution to study the thiol/disulfide exchange step that occurs between the N-terminal redox center and the C-terminal disulfide-containing ß-hairpin motif of Plasmodium falciparum thioredoxin reductase (PfTrxR), which has the sequence Gly-Cys535-Gly-Gly-Gly-Lys-Cys540-Gly. We assayed a truncated PfTrxR enzyme missing this C-terminal tail for disulfide-reductase activity using synthetic peptide substrates in which either Cys535 or Cys540 was replaced with selenocysteine (Sec). The results show that substitution of Cys535 with Sec resulted in a nearly 9-fold decrease in the rate of reduction, while substitution of Cys540 resulted in a 1.5-fold increase in the rate of reduction. We also produced full-length, semisynthetic enzymes in which Sec replaced either of these two Cys residues and observed similar results using E. coli thioredoxin as the substrate. In this assay, the observed seleno effect ( kS/ kSe) for the C535U mutant was 7.4, and that for the C540U mutant was 0.2.