Childhood stress, gender, and cognitive control: Midline theta power.

The emergence of psychiatric symptoms is a common consequence of childhood stress exposure. However, there are a dearth of reliable clinical hallmarks or physiological biomarkers to predict post-trauma symptom emergence. The objective of this study was to examine if childhood stressors and stress-related symptoms are associated with altered midline theta power (MTP) during cognitive control demands, and how these associations interact with gender and early adversity. N = 53 children (ages 9-13 years old) from a longitudinal study of children maltreated during early childhood and non-maltreated children participated in this study. EEG recorded neural activity during a Zoo-Themed Go/No-Go task. Stress-related symptoms, recent stressful events, and other adversity experiences were identified. MTP was analyzed with clinical variables in a series of follow-up analyses. The number of stressors in the past six months was negatively correlated with MTP in those with low preschool adversity, but not in those with high preschool adversity. MTP was higher in girls than in boys, and the associations of MTP with stressors and symptoms were moderated by gender. MTP was negatively associated with stressors in the past six months in girls, while in boys, MTP was associated with stress-related symptoms. Childhood stressful events were associated with reduced MTP during cognitive control demands, and this was finding was moderated by gender and early life adversity. These preliminary findings suggest that boys and girls may process stressful experiences in distinct ways, and preschool adversity may potentially blunt the interaction between current stress and neural dynamics. However, ongoing investigation is needed.

Neurocysticercosis: Isolated Lesion in the Left Middle Frontal Gyrus.

OBJECTIVE: Neurocysticercosis (NCC) is one of the most common parasitic infections of the central nervous system. We present a case study of a 21-year-old African man with an isolated NCC lesion to the left middle frontal gyrus, which is also known as the dorsolateral prefrontal cortex (dlPFC). METHOD: A neuropsychological evaluation was requested by the patient's inpatient psychiatry team regarding worsening attention and depressive symptoms approximately 6 months after NCC diagnosis and treatment. RESULTS: Neuropsychological findings revealed deficits in the aspects of executive functioning, attention, working memory, and significant depressive symptoms. CONCLUSION: To our knowledge, this is the first case study of its kind demonstrating deficits in cognitive functioning consistent with the dlPFC lesion location. Sociocultural and linguistic considerations, clinical findings, and limitations are discussed.

Predictors of Long-Term Exercise Engagement in Patients With Obsessive-Compulsive Disorder: The Role of Physical Activity Enjoyment.

Most U.S. adults, even more so those with psychiatric conditions like obsessive-compulsive disorder (OCD), do not engage in the recommended amount of physical activity (PA), despite the wide array of physical and mental health benefits associated with exercise. Therefore, it is essential to identify mechanistic factors that drive long-term exercise engagement so they can be targeted. Using the science of behavior change (SOBC) framework, this study examined potential predictors of long-term exercise engagement as a first step towards identifying modifiable mechanisms, in individuals with OCD, such as PA enjoyment, positive or negative affect, and behavioral activation. Fifty-six low-active patients (mean age = 38.8 ±â€¯13.0, 64% female) with a primary diagnosis of OCD were randomized to either aerobic exercise (AE; n = 28) or health education (HE; n = 28), and completed measures of exercise engagement, PA enjoyment, behavioral activation, and positive and negative affect at baseline, postintervention, and 3-, 6-, and 12-month follow-up. Significant predictors of long-term exercise engagement up to 6-months postintervention were baseline PA (Estimate = 0.29, 95%CI [0.09, 0.49], p = .005) and higher baseline PA enjoyment (Estimate = 1.09, 95%CI [0.30, 1.89], p = .008). Change in PA enjoyment from baseline to postintervention was greater in AE vs. HE, t(44) = -2.06, p = .046, d = -0.61, but endpoint PA enjoyment did not predict follow-up exercise engagement above and beyond baseline PA enjoyment. Other hypothesized potential mechanisms (baseline affect or behavioral activation) did not significantly predict exercise engagement. Results suggest that PA enjoyment may be an important modifiable target mechanism for intervention, even prior to a formal exercise intervention. Next steps aligned with the SOBC framework are discussed, including examining intervention strategies to target PA enjoyment, particularly among individuals with OCD or other psychiatric conditions, who may benefit most from long-term exercise engagement's effects on physical and mental health.

Prevalence and correlates of lifetime suicide attempt in obsessive-compulsive disorder with major depression.

BACKGROUND: Little is known about specific obsessive-compulsive clinical features associated with lifetime history of suicide attempt in individuals with obsessive-compulsive disorder (OCD) and major depression. METHODS: The study sample included 515 adults with OCD and a history of major depression. In exploratory analyses, we compared the distributions of demographic characteristics and clinical features in those with and without a history of attempted suicide and used logistic regression to evaluate the association between specific obsessive-compulsive clinical features and lifetime suicide attempt. RESULTS: Sixty-four (12%) of the participants reported a lifetime history of suicide attempt. Those who had attempted suicide were more likely to report having experienced violent or horrific images (52% vs. 30%; p < 0.001). The odds of lifetime suicide attempt were more than twice as great in participants with versus without violent or horrific images (O.R. = 2.46, 95%, CI = 1.45-4.19; p < 0.001), even after adjustment for other risk correlates of attempted suicide, including alcohol dependence, post-traumatic stress disorder, parental conflict, excessive physical discipline, and number of episodes of depression. The association between violent or horrific images and attempted suicide was especially strong in men, 18-29 year olds, those with post-traumatic stress disorder, and those with particular childhood adversities. CONCLUSIONS: Violent or horrific images are strongly associated with lifetime suicide attempts in OCD-affected individuals with a history of major depression. Prospective clinical and epidemiological studies are needed to elucidate the basis of this relationship.

Response Inhibition in Youth Undergoing Intensive Treatment for Obsessive Compulsive Disorder.

Response Inhibition (RI) is the ability to suppress behaviors that are inappropriate for a given context. Obsessive-compulsive disorder (OCD) has been associated with impaired RI in adults as measured by the Stop Signal Task (SST). Conflicting results have been found in terms of the relationship between OCD severity and SST performance, and no studies to date have examined the relationship between SST and response to OCD treatment. Also relatively unknown is whether RI performance in OCD is associated with developmental or gender differences. This naturalistic study examined the relationship between SST performance, OCD severity, and OCD treatment response in a pediatric sample undergoing intensive treatment involving exposure and response prevention and medication management (n = 36). The SST and Children's Yale-Brown Obsessive Compulsive Scale (CYBOCS) were administered at admission and program discharge. OCD severity was not significantly related to stop signal reaction time (SSRT) in the whole sample and among subgroups divided by age and gender. Baseline SSRT and SSRT change did not predict CYBOCS change across treatment in the whole sample, but exploratory analyses indicated both were significant predictors among female adolescents. Results suggest there may be developmental gender differences in the relationship between RI and clinical improvement in pediatric OCD.

Spatial normalization discrepancies between native and MNI152 brain template scans in gamma ventral capsulotomy patients.

In neurosurgery, spatial normalization emerged as a tool to minimize inter-subject variability and study target point locations based on standard coordinates. The Montreal Neurological Institute's 152 brain template (MNI152) has become the most widely utilized in neuroimaging studies, but has been noted to introduce partial volume effects, distortions, and increase structure size in all directions (x/y/z axes). These discrepancies question the accuracy of the MNI template, as well as its utility for studies that examine and form conclusions from group-level data. Given that surgical precision in obsessive-compulsive disorder is essential to patient outcomes, we retrospectively investigated lesion size and location in patients (n = 21) who underwent capsulotomy for intractable OCD, comparing deviations in the native scans to those in standard space. MNI measurements were significantly larger than native measurements across several structures in both coronal and axial slices, and we found that MNI transformation increases the size of many subcortical structures in a significant and proportional way for both females and males. These findings urge caution when using MNI as a reference space, as well as a stronger consideration of population-specific brain templates when examining connectivity-based networks.

Central nervous system involvement by mantle cell lymphoma.

Involvement of the central nervous system (CNS) is a rare complication of mantle cell lymphoma (MCL) with limited treatment options. We report the outcomes of 36 patients with CNS involvement compared to 72 matched control MCL patients without CNS involvement. Four patients (11%) with CNS MCL were diagnosed with CNS involvement at time of MCL diagnosis. Median OS from MCL diagnosis was 50.3 months (95% CI: 22.8-79.6) for the CNS MCL group compared to 97.1 months (95% CI: 82.8-NR; p= <0.001) for the control group. Median OS from CNS involvement was 4.7 months (95% CI: 2.3-6.7). CNS involvement by MCL has dismal outcomes as evident by a short median OS and PFS after CNS involvement. Advanced stage, blastoid variant, elevated LDH, and elevated Ki67 at MCL diagnosis were features more commonly seen in the CNS MCL cohort.

Limitations of performance validity tests in dementia evaluations: The role of base rates.

Performance validity tests (PVTs) are frequently used to detect invalid performance on cognitive testing. The inclusion of PVTs in cognitive test batteries is commonplace irrespective of the condition of interest. However, base rates of invalid performance vary across clinical populations. Research accounting for base rates of invalid performance in varying clinical populations and PVT classification accuracy rates are not commonly synthesized. To address this gap, the present study examined the clinical utility of select PVTs used with older adults presenting for dementia evaluations. We computed posterior probabilities of invalid performance for the select PVTs using an estimated 5% base rate of invalid performance based on prior published studies. Posterior probabilities of invalid performance based on a PVT failure (i.e., invalid performance identified as invalid) ranged from 7.3% to 60.3% across PVTs; posterior probabilities of a false positive (i.e., valid performance identified as invalid) ranged from 39.7% to 92.7%. Conversely, posterior probabilities of a true negative (i.e., valid performance identified as valid) ranged from 95.7% to 99.3%; posterior probabilities of a false negative (i.e., invalid performance identified as valid) ranged from 0.7% to 4.3%. Results call into question the utility of PVTs in dementia evaluations. Consequently, the use of PVTs in dementia evaluations is likely to erroneously identify valid test data as invalid (i.e., false-positive error) at a frequency that exceeds the estimated 5% base rate of invalid performance. Further research examining correlates of invalid performance among older adults will clarify base rate estimates and potentially enhance the utility of PVTs. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The Patient Lived-Experience of Ventral Capsulotomy for Obsessive-Compulsive Disorder: An Interpretive Phenomenological Analysis of Neuroablative Psychiatric Neurosurgery.

Ventral Capsulotomy (VC) is a surgical intervention for treatment-resistant Obsessive-Compulsive Disorder (OCD). Despite clinical studies, little is known about patient perception and lived experience after neurosurgery for severe OCD. To examine the lived experiences of patients who have undergone VC for severe, treatment-resistant OCD through qualitative analysis. We conducted semi-structured interviews with six participants treated with VC for OCD. Interviews were analyzed using Interpretive Phenomenological Analysis. The following themes emerged: (1) After years of conventional treatments, patients felt neurosurgery was their "last hope" and described themselves as "desperate," (2) While some described the surgery as a "supernatural experience," patients also demonstrated understanding of the scientific procedure, its risks and potential benefits, (3) The surgical experience itself was positive or neutral, which was linked to trust in the clinical team, (4) Post-surgery, participants described months of heightened fear as they awaited lesion formation and functional improvement. (5) Patients consistently contextualized outcome in the context of their own life goals. Patients undergoing VC have positive views of this neurosurgical intervention, but psychiatric neurosurgical teams should anticipate patient discomfort with the time needed to achieve behavioral improvement following surgery and emphasize the importance of post-operative psychiatric care.

Differential assessment of frontally-mediated behaviors between self- and informant-report in patients with obsessive-compulsive disorder following gamma ventral capsulotomy.

Obsessive-Compulsive Disorder (OCD) is a debilitating disorder causing marked distress and functional impairment. While advances in behavioral and pharmacotherapies have been effective for a majority of patients with OCD, 10-30% remain treatment refractory and severely impaired. For a subset of treatment-resistant individuals with the most severe and disabling (intractable) illness, gamma ventral capsulotomy (GVC) appears effective in reducing OCD symptoms and functional impairment. However, the effects of the ventral internal capsule lesion via GVC surgery on executive function in everyday life have been minimally investigated. Examining behavioral outcomes of GVC also provides a rare opportunity to probe the functional importance of the ventral prefrontal-subcortical connections of the internal capsule white matter tract in a relatively homogenous sample of patients with comparable white matter lesions. The present study investigated changes in frontally-mediated behaviors, measured by the Frontal Systems Behavior Scale (FrSBe), following GVC in 45 individuals with severe and otherwise intractable OCD, as rated by patients themselves and family members. Linear mixed effects models revealed a significant improvement in patient self-ratings on the FrSBe after surgery, while family ratings did not significantly change. Interestingly, improvement on the FrSBe for both self and family raters was significantly correlated with improvement in OCD symptomatology post-surgery, as measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). At the group level, we found no evidence of decline in frontally-mediated behaviors assessed by the FrSBe as a result of focal white matter disconnection via GVC. However, we cannot rule out the possibility that placebo effects or compromised patient self-awareness or insight contributed to the significant improvement in self ratings. Our measures may also have limited sensitivity to more selective impairments that could result from a small lesion to the ventral internal capsule. The present study demonstrates the need for detailed investigation of cognitive and behavioral changes as important factors when considering GVC as a viable treatment option for patients with refractory OCD.

Patient-specific connectomic models correlate with, but do not reliably predict, outcomes in deep brain stimulation for obsessive-compulsive disorder.

Deep brain stimulation (DBS) of the ventral internal capsule/ventral striatum (VCVS) is an emerging treatment for obsessive-compulsive disorder (OCD). Recently, multiple studies using normative connectomes have correlated DBS outcomes to stimulation of specific white matter tracts. Those studies did not test whether these correlations are clinically predictive, and did not apply cross-validation approaches that are necessary for biomarker development. Further, they did not account for the possibility of systematic differences between DBS patients and the non-diagnosed controls used in normative connectomes. To address these gaps, we performed patient-specific diffusion imaging in 8 patients who underwent VCVS DBS for OCD. We delineated tracts connecting thalamus and subthalamic nucleus (STN) to prefrontal cortex via VCVS. We then calculated which tracts were likely activated by individual patients' DBS settings. We fit multiple statistical models to predict both OCD and depression outcomes from tract activation. We further attempted to predict hypomania, a VCVS DBS complication. We assessed all models' performance on held-out test sets. With this best-practices approach, no model predicted OCD response, depression response, or hypomania above chance. Coefficient inspection partly supported prior reports, in that capture of tracts projecting to cingulate cortex was associated with both YBOCS and MADRS response. In contrast to prior reports, however, tracts connected to STN were not reliably correlated with response. Thus, patient-specific imaging and a guideline-adherent analysis were unable to identify a tractographic target with sufficient effect size to drive clinical decision-making or predict individual outcomes. These findings suggest caution in interpreting the results of normative connectome studies.

Understanding cingulotomy's therapeutic effect in OCD through computer models.

Cingulotomy is therapeutic in OCD, but what are the possible mechanisms? Computer models that formalize cortical OCD abnormalities and anterior cingulate cortex (ACC) function can help answer this. At the neural dynamics level, cortical dynamics in OCD have been modeled using attractor networks, where activity patterns resistant to change denote the inability to switch to new patterns, which can reflect inflexible thinking patterns or behaviors. From that perspective, cingulotomy might reduce the influence of difficult-to-escape ACC attractor dynamics on other cortical areas. At the functional level, computer formulations based on model-free reinforcement learning (RL) have been used to describe the multitude of phenomena ACC is involved in, such as tracking the timing of expected outcomes and estimating the cost of exerting cognitive control and effort. Different elements of model-free RL models of ACC could be affected by the inflexible cortical dynamics, making it challenging to update their values. An agent can also use a world model, a representation of how the states of the world change, to plan its actions, through model-based RL. OCD has been hypothesized to be driven by reduced certainty of how the brain's world model describes changes. Cingulotomy might improve such uncertainties about the world and one's actions, making it possible to trust the outcomes of these actions more and thus reduce the urge to collect more sensory information in the form of compulsions. Connecting the neural dynamics models with the functional formulations can provide new ways of understanding the role of ACC in OCD, with potential therapeutic insights.

Double blind randomized controlled trial of deep brain stimulation for obsessive-compulsive disorder: Clinical trial design.

Obsessive-compulsive disorder (OCD), a leading cause of disability, affects ~1-2% of the population, and can be distressing and disabling. About 1/3 of individuals demonstrate poor responsiveness to conventional treatments. A small proportion of these individuals may be deep brain stimulation (DBS) candidates. Candidacy is assessed through a multidisciplinary process including assessment of illness severity, chronicity, and functional impact. Optimization failure, despite multiple treatments, is critical during screening. Few patients nationwide are eligible for OCD DBS and thus a multi-center approach was necessary to obtain adequate sample size. The study was conducted over a six-year period and was a NIH-funded, eight-center sham-controlled trial of DBS targeting the ventral capsule/ventral striatum (VC/VS) region. There were 269 individuals who initially contacted the sites, in order to achieve 27 participants enrolled. Study enrollment required extensive review for eligibility, which was overseen by an independent advisory board. Disabling OCD had to be persistent for ≥5 years despite exhaustive medication and behavioral treatment. The final cohort was derived from a detailed consent process that included consent monitoring. Mean illness duration was 27.2 years. OCD symptom subtypes and psychiatric comorbidities varied, but all had severe disability with impaired quality of life and functioning. Participants were randomized to receive sham or active DBS for three months. Following this period, all participants received active DBS. Treatment assignment was masked to participants and raters and assessments were blinded. The final sample was consistent in demographic characteristics and clinical features when compared to other contemporary published prospective studies of OCD DBS. We report the clinical trial design, methods, and general demographics of this OCD DBS sample.

Magnetic Resonance Imaging-Guided Laser Thermal Ventral Capsulotomy for Intractable Obsessive-Compulsive Disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a disabling condition characterized by intrusive thoughts and repetitive behaviors. A subset of individuals have severe, treatment-resistant illness and are nonresponsive to medication or behavioral therapies. Without response to conventional therapeutic options, surgical intervention becomes an appropriate consideration. OBJECTIVE: To report clinical outcomes and the safety profile of bilateral ventral anterior capsulotomy for OCD using magnetic resonance (MR)-guided laser interstitial thermal therapy (LITT) in 10 patients followed for 6 to 24 mo. METHODS: A total of 10 patients underwent LITT for severe OCD; 1 patient withdrew prior to follow-up. LITT is a minimally invasive ablative technique performed with precise targeting and use of thermography under MR guidance. Lesions of the ventral anterior limb of the internal capsule by other techniques have been shown to be efficacious in prior studies. RESULTS: A total of 7 of the 9 patients were considered full responders (77.8%; Yale-Brown Obsessive-Compulsive Scale change ≥35%). Adverse effects included transient apathy/amotivation postsurgery (2 patients). One patient had a small tract hemorrhage where the laser fiber traversed the cerebral cortex as well as persistent insomnia postsurgery. One individual died after a drug overdose 7 mo postsurgery, which was judged unrelated to the surgery. CONCLUSION: LITT ventral capsulotomy was generally well tolerated, with promising evidence of effectiveness in the largest such series to date. Results were comparable to those after gamma knife ventral capsulotomy, as well as ventral anterior limb deep brain stimulation.

Fructose Promotes Cytoprotection in Melanoma Tumors and Resistance to Immunotherapy.

Checkpoint blockade immunotherapy relies on the empowerment of the immune system to fight cancer. Why some patients fail to achieve durable clinical responses is not well understood, but unique individual factors such as diet, obesity, and related metabolic syndrome could play a role. The link between obesity and patient outcomes remains controversial and has been mired by conflicting reports and limited mechanistic insight. We addressed this in a C57BL/6 mouse model of diet-induced obesity using a Western diet high in both fats and sugars. Obese mice bearing B16 melanoma or MC38 carcinoma tumors had impaired immune responses to immunotherapy and a reduced capacity to control tumor progression. Unexpectedly, these compromised therapeutic outcomes were independent of body mass and, instead, were directly attributed to dietary fructose. Melanoma tumors in mice on the high-fructose diet were resistant to immunotherapy and showed increased expression of the cytoprotective enzyme heme oxygenase-1 (HO-1). This increase in HO-1 protein was recapitulated in human A375 melanoma cells exposed to fructose in culture. Induced expression of HO-1 shielded tumor cells from immune-mediated killing and was critical for resistance to checkpoint blockade immunotherapy, which could be overcome in vivo using a small-molecule inhibitor of HO-1. This study reveals dietary fructose as a driver of tumor immune evasion, identifying HO-1 expression as a mechanism of resistance and a promising molecular target for combination cancer immunotherapy.See article by Khojandi et al., p. 214.