Extinction and beyond: an expanded framework for exposure and response prevention for obsessive-compulsive disorder.

Exposure therapy is a first-line, empirically validated treatment for anxiety, obsessive-compulsive, and trauma-related disorders. Extinction learning is the predominant theoretical framework for exposure therapy, whereby repeated disconfirmation of a feared outcome yields fear reduction over time. Although this framework has strong empirical support and substantial translational utility, extinction learning is unlikely to be the sole process underlying the therapeutic effects of exposure therapy. In our clinic, we commonly treat obsessive-compulsive disorder (OCD) patients successfully with exposure therapy even when some or all of their feared outcomes are not amenable to disconfirmation and, by extension, to extinction learning. Herein, we present a generic clinical vignette illustrating a commonly encountered feared outcome in OCD that cannot be disconfirmed through exposure (damnation resulting from blasphemous thoughts). We describe two specific non-extinction-based strategies we commonly employ in such cases, and we associate these strategies with known change mechanisms that might account for their effectiveness: (1) non-associative habituation to aversive stimuli, and (2) fear-memory elicitation and subsequent reconsolidation. We discuss the limitations inherent in the reverse-translational approach taken and its opportunities for expanding the framework of exposure therapy.

Causally Probing the Role of the Hippocampus in Fear Discrimination: A Precision Functional Mapping-Guided, Transcranial Magnetic Stimulation Study in Participants With Posttraumatic Stress Symptoms.

Background: Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety. A dominant model posits that hippocampal pattern separation failures drive overgeneralization. Hippocampal network-targeted transcranial magnetic stimulation (HNT-TMS) has been shown to strengthen hippocampal-dependent learning/memory processes. However, no study has examined whether HNT-TMS can alter fear learning/memory. Methods: Continuous theta burst stimulation was delivered to individualized left posterior parietal stimulation sites derived via seed-based connectivity, precision functional mapping, and electric field modeling methods. A vertex control site was also stimulated in a within-participant, randomized controlled design. Continuous theta burst stimulation was delivered prior to 2 visual discrimination tasks (1 fear based, 1 neutral). Multilevel models were used to model and test data. Participants were undergraduates with posttraumatic stress symptoms (final n = 25). Results: Main analyses did not indicate that HNT-TMS strengthened discrimination. However, multilevel interaction analyses revealed that HNT-TMS strengthened fear discrimination in participants with lower fear sensitization (indexed by responses to a control stimulus with no similarity to the conditioned fear cue) across multiple indices (anxiety ratings: ß = 0.10, 95% CI, 0.04 to 0.17, p = .001; risk ratings: ß = 0.07, 95% CI, 0.00 to 0.13, p = .037). Conclusions: Overgeneralization is an associative process that reflects deficient discrimination of the fear cue from similar cues. In contrast, sensitization reflects nonassociative responding unrelated to fear cue similarity. Our results suggest that HNT-TMS may selectively sharpen fear discrimination when associative response patterns, which putatively implicate the hippocampus, are more strongly engaged.

Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety that is thought to be driven by deficient hippocampal discrimination. Using hippocampal network­targeted transcranial magnetic stimulation (HNT-TMS) in healthy participants with symptoms of posttraumatic stress, Webler et al. report that HNT-TMS did not strengthen discrimination overall, but it did strengthen fear discrimination in participants with lower fear sensitization. Sensitization reflects nonassociative fear responding unrelated to fear cue similarity and therefore is not expected to engage the hippocampal discrimination function. These results suggest that HNT-TMS may selectively sharpen fear discrimination when the hippocampal discrimination function is more strongly engaged.

Causal network localization of brain stimulation targets for trait anxiety.

Transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) can treat some neuropsychiatric disorders, but there is no consensus approach for identifying new targets. We localized causal circuit-based targets for anxiety that converged across multiple natural experiments. Lesions (n=451) and TMS sites (n=111) that modify anxiety mapped to a common normative brain circuit (r=0.68, p=0.01). In an independent dataset (n=300), individualized TMS site connectivity to this circuit predicted anxiety change (p=0.02). Subthalamic DBS sites overlapping the circuit caused more anxiety (n=74, p=0.006), thus demonstrating a network-level effect, as the circuit was derived without any subthalamic sites. The circuit was specific to trait versus state anxiety in datasets that measured both (p=0.003). Broadly, this illustrates a pathway for discovering novel circuit-based targets across neuropsychiatric disorders.

Causally mapping human threat extinction relevant circuits with depolarizing brain stimulation methods.

Laboratory threat extinction paradigms and exposure-based therapy both involve repeated, safe confrontation with stimuli previously experienced as threatening. This fundamental procedural overlap supports laboratory threat extinction as a compelling analogue of exposure-based therapy. Threat extinction impairments have been detected in clinical anxiety and may contribute to exposure-based therapy non-response and relapse. However, efforts to improve exposure outcomes using techniques that boost extinction - primarily rodent extinction - have largely failed to date, potentially due to fundamental differences between rodent and human neurobiology. In this review, we articulate a comprehensive pre-clinical human research agenda designed to overcome these failures. We describe how connectivity guided depolarizing brain stimulation methods (i.e., TMS and DBS) can be applied concurrently with threat extinction and dual threat reconsolidation-extinction paradigms to causally map human extinction relevant circuits and inform the optimal integration of these methods with exposure-based therapy. We highlight candidate targets including the amygdala, hippocampus, ventromedial prefrontal cortex, dorsal anterior cingulate cortex, and mesolimbic structures, and propose hypotheses about how stimulation delivered at specific learning phases could strengthen threat extinction.

DLPFC stimulation alters working memory related activations and performance: An interleaved TMS-fMRI study.

BACKGROUND: Findings from correlative neuroimaging studies link increased frontoparietal network (FPN) activation and default mode network (DMN) deactivation to enhanced high cognitive demand processing. To causally investigate FPN-DMN contributions to high cognitive demand processing, the current interleaved TMS-fMRI study simultaneously manipulated and indexed neural activity while tracking cognitive performance during high and low cognitive load conditions. METHODS: Twenty participants completed an n-back task consisting of four conditions (0-back, 0-backTMS, 2-back, 2-backTMS) while undergoing interleaved TMS-fMRI. During TMS concurrent with n-back blocks, TMS single pulses were delivered to the left DLPFC at 100% motor-threshold every 2.4s. RESULTS: TMS delivered during high cognitive load strengthened cognitive processing. FPN node activations and DMN node deactivations were increased in the high versus low cognitive load TMS condition. Contrary to our hypothesis, TMS did not increase high load related activation in FPN nodes. However, as hypothesized, increased DMN node deactivations emerged as a function of TMS during high load (right angular gyrus) and from interactions between cognitive load and TMS (right middle temporal gyrus). Load and TMS combined to dampen activation within the DMN at trend level (p = .058). Deactivation in a dorsomedial DMN node was associated with TMS driven improvements in high load cognitive processing. CONCLUSIONS: Exogenous perturbation of the DLPFC via single pulse TMS amplified DMN node deactivations and enhanced high cognitive demand processing. Neurobehavioral findings linking these effects hint at a promising, albeit preliminary, cognitive control substrate requiring replication in higher-powered studies that use control stimulation.

Pre-COVID-19 fear conditioning responses predict COVID-19-related anxiety: evidence from an exploratory study.

BACKGROUND AND OBJECTIVES: Fear conditioning represents the prevailing model by which organisms acquire novel threat contingencies. However, little work has been devoted to linking laboratory measures of fear conditioning to the development of real-world threat responses. To fill this gap, the present study explored whether individual differences in a laboratory-based fear conditioning measure could predict levels of COVID-19-related anxiety and avoidance assessed during the first month of the pandemic. DESIGN AND METHOD: Forty-eight undergraduate students who had previously participated in two fear conditioning experiments prior to COVID-19 completed a survey assessing COVID-19 anxiety and avoidance. The fear conditioning experiment involved learning to discriminate between a shape contingently associated with mild electric shock (CS+) and two other shapes that were not (CS-). RESULTS: Increased subjective anxiety to our laboratory CS+ prior to the pandemic predicted heightened COVID-19 anxiety. Follow-up analyses revealed that participants with high COVID-19 anxiety exhibited increased anxiety to CS+ during the final experimental block relative to participants with low COVID-19 anxiety. CONCLUSIONS: Findings from this exploratory study tentatively implicate fear conditioning in the development of real-world fear responses and underscore the importance of investigating laboratory fear conditioning as a predictor of anxiety responses to real-world threats.

The neurobiology of human fear generalization: meta-analysis and working neural model.

Fear generalization to stimuli resembling a conditioned danger-cue (CS+) is a fundamental dynamic of classical fear-conditioning. Despite the ubiquity of fear generalization in human experience and its known pathogenic contribution to clinical anxiety, neural investigations of human generalization have only recently begun. The present work provides the first meta-analysis of this growing literature to delineate brain substrates of conditioned fear-generalization and formulate a working neural model. Included studies (K = 6, N = 176) reported whole-brain fMRI results and applied generalization-gradient methodology to identify brain activations that gradually strengthen (positive generalization) or weaken (negative generalization) as presented stimuli increase in CS+ resemblance. Positive generalization was instantiated in cingulo-opercular, frontoparietal, striatal-thalamic, and midbrain regions (locus coeruleus, periaqueductal grey, ventral tegmental area), while negative generalization was implemented in default-mode network nodes (ventromedial prefrontal cortex, hippocampus, middle temporal gyrus, angular gyrus) and amygdala. Findings are integrated within an updated neural account of generalization centering on the hippocampus, its modulation by locus coeruleus and basolateral amygdala, and the excitation of threat- or safety-related loci by the hippocampus.

Cognitive Behavioral Therapy to Sustain the Antidepressant Effects of Ketamine in Treatment-Resistant Depression: A Randomized Clinical Trial.

INTRODUCTION: Ketamine has emerged as a rapid-acting antidepressant. While ongoing treatment can prevent relapse, concerns exist regarding long-term exposure. OBJECTIVE: We conducted a randomized trial to examine the feasibility and efficacy of cognitive behavioral therapy (CBT) following intravenous ketamine in treatment-resistant depression (TRD). METHODS: Subjects with TRD were recruited and treated with 6 intravenous infusions of ketamine over 3 weeks. Subjects who experienced a clinical response (≥50% improvement in depression severity) were then randomized to receiving CBT or treatment as usual (TAU) for an additional 14 weeks, using a sequential treatment model. RESULTS: Of the 42 patients who signed consent, 28 patients achieved a response and were randomized to CBT or TAU. When measured using the Montgomery-Asberg Depression Rating Scale (primary outcome measure), the effect size at the end of the study was moderate (Cohen d = 0.65; 95% CI -0.55 to 1.82), though the group-by-time interaction effect was not significant. There was a significant group-by-time interaction as measured by the Quick Inventory of Depressive Symptomatology (F = 4.58; p = 0.033), favoring a greater sustained improvement in the CBT group. This corresponded to a moderate-to-large effect size of the Cohen d = 0.71 (95% CI -0.30 to 1.70) at the end of the study (14 weeks following the last ketamine infusion). In a subset of patients (N = 20) who underwent cognitive testing using the emotional N-back assessments before and after ketamine, ketamine responders showed improvement in the accuracy of emotional N-back (t[8] = 2.33; p < 0.05) whereas nonresponders did not (t[10] <1; p ns). CONCLUSIONS: This proof-of-concept study provides preliminary data indicating that CBT may sustain the antidepressant effects of ketamine in TRD. Further study and optimization of this treatment approach in well-powered clinical trials is recommended.

Decreased interhemispheric connectivity and increased cortical excitability in unmedicated schizophrenia: A prefrontal interleaved TMS fMRI study.

BACKGROUND: Prefrontal abnormalities in schizophrenia have consistently emerged from resting state and cognitive neuroimaging studies. However, these correlative findings require causal verification via combined imaging/stimulation approaches. To date, no interleaved transcranial magnetic stimulation and functional magnetic resonance imaging study (TMS fMRI) has probed putative prefrontal cortex abnormalities in schizophrenia. OBJECTIVE: /Hypothesis: We hypothesized that subjects with schizophrenia would show significant hyperexcitability at the site of stimulation (BA9) and decreased interhemispheric functional connectivity. METHODS: We enrolled 19 unmedicated subjects with schizophrenia and 22 controls. All subjects underwent brain imaging using a 3T MRI scanner with a SENSE coil. They also underwent a single TMS fMRI session involving motor threshold (rMT) determination, structural imaging, and a parametric TMS fMRI protocol with 10 Hz triplet pulses at 0, 80, 100 and 120% rMT. Scanning involved a surface MR coil optimized for bilateral prefrontal cortex image acquisition. RESULTS: Of the original 41 enrolled subjects, 8 subjects with schizophrenia and 11 controls met full criteria for final data analyses. At equal TMS intensity, subjects with schizophrenia showed hyperexcitability in left BA9 (p = 0.0157; max z-score = 4.7) and neighboring BA46 (p = 0.019; max z-score = 4.47). Controls showed more contralateral functional connectivity between left BA9 and right BA9 through increased activation in right BA9 (p = 0.02; max z-score = 3.4). GM density in subjects with schizophrenia positively correlated with normalized prefrontal to motor cortex ratio of the corresponding distance from skull to cortex ratio (S-BA9/S-MC) (r = 0.83, p = 0.004). CONCLUSIONS: Subjects with schizophrenia showed hyperexcitability in left BA9 and impaired interhemispheric functional connectivity compared to controls. Interleaved TMS fMRI is a promising tool to investigate prefrontal dysfunction in schizophrenia.

Maturational phase of hippocampal neurogenesis and cognitive flexibility.

INTRODUCTION: Pattern separation aids cognitive flexibility by reducing interference between closely related memories. Dentate gyrus (DG) neurogenesis may facilitate pattern separation by blocking memory retrieval via inhibition of non-neurogenic downstream CA3 neurons. We hypothesized that immature adult-born DG neurons would be associated with decreased CA3 activation and increased cognitive flexibility. METHOD: Two groups of adult male rats were tested either on the place avoidance task (PAT) (unflipped condition) or a subtly altered-PAT (flipped condition). Four weeks prior, the rats were injected with the mitotic marker BrdU. Immature new neurons were detected by the microtubule protein doublecortin (DCX). Cells that took up BrdU and expressed NeuN were identified as relatively more mature neurons. Synaptic activation was determined by c-Fos expression. Adaptation to the flipped versus unflipped condition reflected a measure of cognitive flexibility. RESULTS: CA3 but not DG c-Fos was lower in the flipped versus unflipped condition [p = 0.002]. CA3 c-Fos correlated inversely with flipped task performance and immature (DCX) neurons with primary and secondary but not tertiary dendrites or more mature (BrdU + NeuN) new neurons. CA3 c-Fos was a significant predictor for the flipped versus unflipped condition specifically for DCX versus BrdU-NeuN neurons. CONCLUSION: Immature new neurons (DCX+) without tertiary dendrites may be preferentially implicated in cognitive flexibility relative to more mature new neurons (BrdU-NeuN). In combination with decreased CA3 activation in the flipped PAT, the functional contribution of these immature DG neurons may involve the inhibition of postsynaptic CA3 neurons containing traces of previously salient conditioned memories.

Acute and Longer-Term Outcomes Using Ketamine as a Clinical Treatment at the Yale Psychiatric Hospital.

OBJECTIVE: Ketamine has emerged as a rapid-acting antidepressant, though controversy remains whether sufficient data exist to justify its use outside of research protocols. In October 2014, the authors' institution began providing ketamine as an off-label therapy on a case-by-case basis for patients unable to participate in research protocols. Here, the participant experience during 29 months of providing ketamine as a clinical treatment for severe and treatment-resistant mood disorders through February 2017 is described. METHODS: Patients were initially treated with a single- or double-infusion protocol (0.5 mg/kg for 40 minutes intravenously) and were later transitioned to a 4-infusion protocol over 2 weeks. RESULTS: Fifty-four patients received ketamine, with 518 total infusions performed. A subset of 44 patients with mood disorders initiated the 4-infusion protocol, of whom 45.5% responded and 27.3% remitted by the fourth infusion. A subsample (n = 14) received ketamine on a long-term basis, ranging from 12 to 45 total treatments, over a course of 14 to 126 weeks. No evidence was found of cognitive decline, increased proclivity to delusions, or emergence of symptoms consistent with cystitis in this subsample. CONCLUSIONS: In general, ketamine infusions were tolerated well. The response and remission rates in this clinical sample were lower than those observed in some research protocols. The small number of patients who were treated on a maintenance schedule limits the conclusions that can be drawn regarding the long-term safety of ketamine; however, no long-term adverse effects were observed in this sample.

Serum and plasma brain-derived neurotrophic factor and response in a randomized controlled trial of riluzole for treatment resistant depression.

BACKGROUND: Serum brain-derived neurotrophic factor (BDNF) is decreased in individuals with major depressive disorder (MDD). Pre-clinical and clinical reports suggest that the glutamate release inhibitor riluzole increases BDNF and may have antidepressant properties. Here we report serum (sBDNF) and plasma (pBDNF) levels from a randomized controlled, adjunctive, sequential parallel comparison design trial of riluzole in MDD. METHODS: Serum and plasma BDNF samples were drawn at baseline and weeks 6 and 8 from 55 subjects randomized to adjunctive treatment with riluzole or placebo for 8 weeks. RESULTS: Riluzole responders had lower baseline serum (19.08 ng/ml [SD 9.22] v. 28.80 ng/ml [9.63], p = 0.08) and plasma (2.72 ng/ml [1.07] v. 4.60 ng/ml [1.69], p = 0.06) BDNF compared to non-responders at a trend level. This pattern was nominally seen in placebo responders for baseline pBDNF to some degree (1.21 ng/ml [SD 1.29] v. 3.58 ng/ml [SD 1.67], p = 0.12) but not in baseline sBDNF. LIMITATIONS: A number of limitations warrant comment, including the small sample size of viable BDNF samples and the small number of riluzole responders. CONCLUSIONS: Preliminary evidence reported here suggests that lower baseline BDNF may be associated with better clinical response to riluzole.

Neurobiology of the dorsolateral prefrontal cortex in GAD: Aberrant neurometabolic correlation to hippocampus and relationship to anxiety sensitivity and IQ.

INTRODUCTION: The neurometabolism underlying the cognitive and affective symptoms associated with generalized anxiety disorder (GAD) remain poorly understood. After we have linked worry to intelligence in patients with GAD, we hypothesized that aberrant neurometabolic correlations between hippocampus and neocortical regions may underlie a shared substrate in GAD patients for both anxiety sensitivity and intelligence. METHODS: GAD patients (n = 16; F = 11) and healthy volunteers (n = 16; F = 10) were assessed using 1H-MRSI. Co-axial planes I [hippocampus (HIPP)] and co-axial plane III [dorsolateral prefrontal cortex (DLPFC), central gyrus (CG)] were examined. Using general linear models, we examined resting metabolite concentrations using HIPP as a hub to CG and DLPFC. Neocortical ROIs were related to Anxiety Sensitivity Index (ASI) and Full Scale IQ (FSIQ) in GAD patients versus controls. RESULTS: Right hippocampal Cho/Cr directly predicted left DLPFC Cho/Cr in GAD (r = 0.75), an effect distinguishable (p = 0.0004) from controls. Left HIPP Cho/Cr positively predicted left CG Cho/Cr in GAD, an effect distinguishable from controls. In patients, both left and right DLPFC Cho/Cr positively predicted ASI but only left DLPFC Cho/Cr inversely predicted IQ. By contrast, IQ in controls correlated directly with left CG Cho/Cr. LIMITATIONS: Small sample size precluded us from investigating how gender and FSIQ subscales related to neurochemical correlations in the ROIs examined. CONCLUSIONS: Aberrant resting state neurochemical correlation between left DLPFC and right HIPP may contribute to GAD symptomatology. Unlike controls, in GAD, IQ and worry may share a common yet inverse neurometabolic substrate in left DLPFC.