Parent perceptions of various treatment approaches for PANS and PANDAS.

Pediatric autoimmune neuropsychiatric disorder (PANDAS) is characterized by sudden, dramatic onset obsessive-compulsive disorder (OCD) following a Group A Streptococcus infection. Pediatric acute neuropsychiatric syndrome (PANS) refers to sudden, dramatic onset OCD and/or restricted eating triggered by infections and other inflammatory reactions. A variety of treatments have been utilized for PANS/PANDAS; however, there is no "gold standard" intervention protocol. Parental expectations of a given treatment have been found to improve a child's overall treatment experience; however, parent attitudes towards PANS/PANDAS treatments are unknown, which was the purpose of this study. An online survey was distributed to 208 parents of children with self-reported PANS/PANDAS. Treatments were grouped together within overarching categories (i.e., psychotherapy, psychiatric/psychotropic, inflammation/infection mitigation, supplements, lifestyle changes, and surgery). Categorically, parents rated inflammation/infection mitigation interventions and lifestyle changes as most appropriate, and psychiatric/psychotropic interventions as least appropriate. At the individual level, treatments including antibiotics, non-steroidal anti-inflammatory drugs, intravenous immunoglobulin, and family counseling received ratings between "appropriate" and "extremely appropriate" Alternatively, treatments including deep brain stimulation, transcranial magnetic stimulation, antidepressant medications, and exposure and response prevention received ratings between "inappropriate" and "extremely inappropriate." Study limitations include a lack of gender and race representation in our sample. Findings indicate a need for dissemination of current, relevant research to the parent population as well as further examination of the parent experience throughout onset, diagnosis, and treatment.

Efficacy of deep brain stimulation for treatment-resistant depression: systematic review and meta-analysis.

BACKGROUND: Treatment-resistant depression (TRD) affects about 30% of individuals with major depressive disorder. Deep brain stimulation (DBS) is an investigational intervention for TRD with varied results. We undertook this meta-analysis to synthesize outcome data across trial designs, anatomical targets, and institutions to better establish efficacy and side effect profiles. METHODS: We conducted a systematic PubMed review following PRISMA guidelines. Seven randomized-controlled trials (n=198) and eight open-label trials (n=77) were included, spanning 2009-2020. Outcome measures included Hamilton Depression Rating Scale or Montgomery-Åsberg Depression Rating Scale scores, as well as response and remission rates over time. Outcomes were tracked at last follow-up and quantified as a time course using model-based network meta-analysis. Linear mixed models were fit to individual patient data to identify covariates. RESULTS: DBS achieved 47% improvement in long-term depression scale scores, with an estimated time to reach 50% improvement around 23 months. There were no significant subgroup effects of stimulation target, time of last follow-up, sex, age of disease onset, or duration of disease, but open-label trials showed significantly greater treatment effects compared to randomized controlled trials. Long-term (12-60 month) response and remission rates were 48% and 35%, respectively. The time course of improvement with active stimulation could not be adequately distinguished from that with sham stimulation, when available. CONCLUSIONS: DBS produces significant chronic improvement in symptoms of TRD. The limited sham-controlled data, however, does not demonstrate significant improvement over placebo. Future advancements in stimulation optimization and careful blinding and placebo schemes are important next steps for this therapy.

Stereo-Electroencephalography-Guided Network Neuromodulation for Psychiatric Disorders: The Neurophysiology Monitoring Unit.

BACKGROUND AND OBJECTIVES: Recent advances in stereotactic and functional neurosurgery have brought forth the stereo-electroencephalography approach which allows deeper interrogation and characterization of the contributions of deep structures to neural and affective functioning. We argue that this approach can and should be brought to bear on the notoriously intractable issue of defining the pathophysiology of refractory psychiatric disorders and developing patient-specific optimized stimulation therapies. METHODS: We have developed a suite of methods for maximally leveraging the stereo-electroencephalography approach for an innovative application to understand affective disorders, with high translatability across the broader range of refractory neuropsychiatric conditions. RESULTS: This article provides a roadmap for determining desired electrode coverage, tracking high-resolution research recordings across a large number of electrodes, synchronizing intracranial signals with ongoing research tasks and other data streams, applying intracranial stimulation during recording, and design choices for patient comfort and safety. CONCLUSION: These methods can be implemented across other neuropsychiatric conditions needing intensive electrophysiological characterization to define biomarkers and more effectively guide therapeutic decision-making in cases of severe and treatment-refractory disease.

Intracranial Directed Connectivity Links Subregions of the Prefrontal Cortex to Major Depression.

Understanding the neural basis of major depressive disorder (MDD) is vital to guiding neuromodulatory treatments. The available evidence supports the hypothesis that MDD is fundamentally a disease of cortical disinhibition, where breakdowns of inhibitory neural systems lead to diminished emotion regulation and intrusive ruminations. Recent research also points towards network changes in the brain, especially within the prefrontal cortex (PFC), as primary sources of MDD etiology. However, due to limitations in spatiotemporal resolution and clinical opportunities for intracranial recordings, this hypothesis has not been directly tested. We recorded intracranial EEG from the dorsolateral (dlPFC), orbitofrontal (OFC), and anterior cingulate cortices (ACC) in neurosurgical patients with MDD. We measured daily fluctuations in self-reported depression severity alongside directed connectivity between these PFC subregions. We focused primarily on delta oscillations (1-3 Hz), which have been linked to GABAergic inhibitory control and intracortical communication. Depression symptoms worsened when connectivity within the left vs. right PFC became imbalanced. In the left hemisphere, all directed connectivity towards the ACC, from the dlPFC and OFC, was positively correlated with depression severity. In the right hemisphere, directed connectivity between the OFC and dlPFC increased with depression severity as well. This is the first evidence that delta oscillations flowing between prefrontal subregions transiently increase intensity when people are experiencing more negative mood. These findings support the overarching hypothesis that MDD worsens with prefrontal disinhibition.

Beta activity in human anterior cingulate cortex mediates reward biases.

The rewards that we get from our choices and actions can have a major influence on our future behavior. Understanding how reward biasing of behavior is implemented in the brain is important for many reasons, including the fact that diminution in reward biasing is a hallmark of clinical depression. We hypothesized that reward biasing is mediated by the anterior cingulate cortex (ACC), a cortical hub region associated with the integration of reward and executive control and with the etiology of depression. To test this hypothesis, we recorded neural activity during a biased judgment task in patients undergoing intracranial monitoring for either epilepsy or major depressive disorder. We found that beta (12-30 Hz) oscillations in the ACC predicted both associated reward and the size of the choice bias, and also tracked reward receipt, thereby predicting bias on future trials. We found reduced magnitude of bias in depressed patients, in whom the beta-specific effects were correspondingly reduced. Our findings suggest that ACC beta oscillations may orchestrate the learning of reward information to guide adaptive choice, and, more broadly, suggest a potential biomarker for anhedonia and point to future development of interventions to enhance reward impact for therapeutic benefit.

Disruption of neural periodicity predicts clinical response after deep brain stimulation for obsessive-compulsive disorder.

Recent advances in surgical neuromodulation have enabled chronic and continuous intracranial monitoring during everyday life. We used this opportunity to identify neural predictors of clinical state in 12 individuals with treatment-resistant obsessive-compulsive disorder (OCD) receiving deep brain stimulation (DBS) therapy ( NCT05915741 ). We developed our neurobehavioral models based on continuous neural recordings in the region of the ventral striatum in an initial cohort of five patients and tested and validated them in a held-out cohort of seven additional patients. Before DBS activation, in the most symptomatic state, theta/alpha (9 Hz) power evidenced a prominent circadian pattern and a high degree of predictability. In patients with persistent symptoms (non-responders), predictability of the neural data remained consistently high. On the other hand, in patients who improved symptomatically (responders), predictability of the neural data was significantly diminished. This neural feature accurately classified clinical status even in patients with limited duration recordings, indicating generalizability that could facilitate therapeutic decision-making.

Insula uses overlapping codes for emotion in self and others.

In daily life, we must recognize others' emotions so we can respond appropriately. This ability may rely, at least in part, on neural responses similar to those associated with our own emotions. We hypothesized that the insula, a cortical region near the junction of the temporal, parietal, and frontal lobes, may play a key role in this process. We recorded local field potential (LFP) activity in human neurosurgical patients performing two tasks, one focused on identifying their own emotional response and one on identifying facial emotional responses in others. We found matching patterns of gamma- and high-gamma band activity for the two tasks in the insula. Three other regions (MTL, ACC, and OFC) clearly encoded both self- and other-emotions, but used orthogonal activity patterns to do so. These results support the hypothesis that the insula plays a particularly important role in mediating between experienced vs. observed emotions.

Pediatric Treatment-Resistant Obsessive Compulsive Disorder: Treatment Options and Challenges.

Pediatric obsessive-compulsive disorder (OCD) is a chronic, potentially debilitating psychiatric condition. Although effective treatments exist, at least 10% of youth do not achieve remission despite receiving first-line treatments. This article reviews the extant, albeit limited, evidence supporting treatment approaches for youth with treatment-resistant OCD. A literature search for articles addressing pediatric treatment-resistant OCD was conducted through April 11, 2024. These results were augmented by searching for treatment-resistant OCD in adults; treatment strategies discovered for the adult population were then searched in the context of children and adolescents. In general, intensive treatment programs and antipsychotic augmentation of an antidepressant had the most substantial and consistent evidence base for treatment-resistant youth with OCD, although studies were limited and of relatively poor methodological quality (i.e., open trials, naturalistic studies). Several pharmacological approaches (clomipramine, antipsychotics [e.g., aripiprazole, risperidone], riluzole, ketamine, D-cycloserine, memantine, topiramate, N-acetylcysteine, ondansetron), largely based on supporting data among adults, have received varying levels of investigation and support. There is nascent support for how to treat pediatric treatment-resistant OCD. Future treatment studies need to consider how to manage the significant minority of youth who fail to benefit from first-line treatment approaches.

A Low-Intensity Transcranial Focused Ultrasound Parameter Exploration Study of the Ventral Capsule/Ventral Striatum.

OBJECTIVES: Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) is effective for treatment-resistant obsessive-compulsive disorder (OCD); however, DBS is associated with neurosurgical risks. Transcranial focused ultrasound (tFUS) is a newer form of noninvasive (ie, nonsurgical) stimulation that can modulate deeper regions, such as the VC/VS. tFUS parameters have just begun to be studied and have often not been compared in the same participants. We explored the effects of three VC/VS tFUS protocols and an entorhinal cortex (ErC) tFUS session on the VC/VS and cortico-striato-thalamo-cortical circuit (CSTC) in healthy individuals for later application to patients with OCD. MATERIALS AND METHODS: Twelve individuals participated in a total of 48 sessions of tFUS in this exploratory multisite, within-subject parameter study. We collected resting-state, reward task, and arterial spin-labeled (ASL) magnetic resonance imaging scans before and after ErC tFUS and three VC/VS tFUS sessions with different pulse repetition frequencies (PRFs), pulse widths (PWs), and duty cycles (DCs). RESULTS: VC/VS protocol A (PRF = 10 Hz, PW = 5 ms, 5% DC) was associated with increased putamen activation during a reward task (p = 0.003), and increased VC/VS resting-state functional connectivity (rsFC) with the anterior cingulate cortex (p = 0.022) and orbitofrontal cortex (p = 0.004). VC/VS protocol C (PRF = 125 Hz, PW = 4 ms, 50% DC) was associated with decreased VC/VS rsFC with the putamen (p = 0.017), and increased VC/VS rsFC with the globus pallidus (p = 0.008). VC/VS protocol B (PRF = 125 Hz, PW = 0.4 ms, 5% DC) was not associated with changes in task-related CSTC activation or rsFC. None of the protocols affected CSTC ASL perfusion. CONCLUSIONS: This study began to explore the multidimensional parameter space of an emerging form of noninvasive brain stimulation, tFUS. Our preliminary findings in a small sample suggest that VC/VS tFUS should continue to be investigated for future noninvasive treatment of OCD.

Parent-Led Cognitive Behavioral Teletherapy for Anxiety in Autistic Youth: A Randomized Trial Comparing Two Levels of Therapist Support.

Parent-led cognitive behavioral therapy (CBT) is an efficient, promising form of therapy that may be well suited for autistic youth with anxiety disorders, though to date it has been minimally tested. In this study, 87 autistic youth (7 to 13 years old) with anxiety disorders and their parents were randomized to two forms of parent-led CBT in which parents led their child through a guided CBT workbook across 12 weeks: one with low therapist contact (four 30-minute telehealth calls), and one with standard therapist contact (ten 60-minute telehealth calls). Anxiety, functional impairment, and autism features significantly declined across therapy, without differences between groups. High satisfaction was reported in both groups, though significantly higher satisfaction ratings were reported in standard-contact CBT. Responder rates were 69% of completers at posttreatment (70% in standard contact, 68% in low contact) and 86% at 3-month follow-up (86% in standard contact, 87% in low contact). Low-contact CBT was estimated to incur an average cost of $755.70 per family compared with $1,978.34 in standard-contact CBT. Parent-led CBT with minimal or standard therapist contact both appear to be effective CBT delivery formats for autistic youth with anxiety disorders, with significant cost savings for low-contact CBT.

Family Accommodation in Children and Adolescents With Misophonia.

Family accommodation (e.g., reassurance, modifying routines, assisting avoidance) has not been explored among youth with misophonia but may have important clinical and intervention implications. We examined family accommodation in 102 children and adolescents with interview-confirmed misophonia and compared its frequency and content to family accommodation in 95 children and adolescents with anxiety disorders. Findings showed that family accommodation was ubiquitous in pediatric misophonia and may be even more frequent than in youth with anxiety disorders. Assisting the child, participating in misophonia-related behaviors, and modifying family routines were endorsed by more than 70% of parents of children with misophonia. Further, compared to parents of children with anxiety disorders, parents of children with misophonia more frequently reported child distress and anger when they did not accommodate. Family accommodation was moderately to strongly associated with misophonia severity even when accounting for co-occurring internalizing and externalizing symptoms and sociodemographic factors. This first study of family accommodation in pediatric misophonia suggests accommodation may be an important clinical feature. A notable study limitation is that the measure of misophonia did not delineate between adaptive versus maladaptive accommodations. Excessive and maladaptive accommodation may be one potential candidate to target in interventions when considered within a broader treatment plan. Importantly, adaptive accommodations should also be considered in day-to-day management if they improve functioning and quality of life.

Co-occurring PTSD in intensive OCD treatment: Impact on treatment trajectory vs. response.

BACKGROUND: Obsessive-compulsive disorder (OCD) and co-occurring posttraumatic stress disorder (PTSD) is associated with more severe and chronic OCD. However, findings regarding treatment effectiveness of cognitive behavioral treatment (CBT) with exposure and response prevention (ERP) with this comorbidity are mixed. Research aimed at understanding the precise barriers to OCD treatment effectiveness for individuals with co-occurring PTSD may help elucidate unique treatment needs. METHODS: The current study used linear regression and latent growth curve analysis comparing treatment response and trajectory from patients with OCD (n = 3083, 94.2 %) and OCD + PTSD (n = 191, 5.2 %) who received CBT with ERP in two major intensive OCD treatment programs. RESULTS: Although patients with OCD + PTSD evidenced similar trajectories of overall severity change, patients at one site required nearly 11 additional treatment days to achieve comparable reduction in OCD severity. Further, at the dimensional level, those with OCD + PTSD had poorer treatment response for unacceptable thoughts and symmetry symptoms. The moderate effect for unacceptable thoughts, indicating the widest gap in treatment response, suggests these symptoms may be particularly relevant to PTSD. LIMITATIONS: Findings are limited by a naturalistic treatment sample with variation in treatment provision. CONCLUSIONS: Findings emphasize caution in using a one-size-fits-all approach for patients with co-occurring OCD + PTSD within intensive OCD treatment programs, as broadly defined outcomes (e.g., reduction in overall severity) may not translate to reduction in the nuanced symptom dimensions likely to intersect with trauma. Unacceptable thoughts and symmetry symptoms, when co-occurring with PTSD, may require a trauma-focused treatment approach within intensive OCD treatment.

Perceived worsening of obsessive-compulsive disorder symptoms after childbirth in women and men: An understudied phenomenon.

The aim of this study was to examine worsening of OCD symptoms after childbirth in individuals seeking assessment or treatment of OCD. The postpartum period may make parents biologically and psychologically vulnerable to OCD symptoms. Participants included 222 parents with OCD who completed surveys through a self-help website. Most women and almost half of men with self-reported OCD reported an increase in OCD symptoms following childbirth. Retrospective report of perceived worsening of OCD symptoms after childbirth was associated with more aggressive obsessions for both men and women, in comparison to individuals whose OCD symptoms did not worsen around childbirth. Women whose OCD symptoms worsened after childbirth reported more impairment in social functioning than individuals whose symptoms did not worsen. These results highlight the need to develop a better understanding of aggressive obsessions in parents, and improve education about prevalence, content, assessment, and intervention for aggression-focused intrusive thoughts.

Efficacy and acceptability of cognitive-behavioral therapy and serotonin reuptake inhibitors for pediatric obsessive-compulsive disorder: a network meta-analysis.

BACKGROUND: Cognitive-behavioral therapy (CBT) and serotonin reuptake inhibitors (SRIs) are recommended treatments for pediatric obsessive-compulsive disorder (OCD), but their relative efficacy and acceptability have not been comprehensively examined. Further, it remains unclear whether the efficacy of in-person CBT is conserved when delivered in other formats, such as over telephone/webcam or as Internet-delivered CBT (ICBT). METHODS: PubMed, PsycINFO, trial registries, and previous systematic reviews were searched for randomized controlled trials (RCTs) comparing CBT (in-person, webcam/telephone-delivered, or ICBT) or SRIs with control conditions or each other. Network meta-analyses were conducted to examine efficacy (post-treatment Children's Yale-Brown Obsessive Compulsive Scale) and acceptability (treatment discontinuation). Confidence in effect estimates was evaluated with CINeMA (Confidence in Network Meta-Analysis). RESULTS: Thirty eligible RCTs and 35 contrasts comprising 2,057 youth with OCD were identified. In-person CBT was significantly more efficacious than ICBT, waitlist, relaxation training, and pill placebo (MD range: 3.95-11.10; CINeMA estimate of confidence: moderate) but did not differ significantly from CBT delivered via webcam/telephone (MD: 0.85 [-2.51, 4.21]; moderate), SRIs (MD: 3.07 [-0.07, 6.20]; low), or the combination of in-person CBT and SRIs (MD: -1.20 [-5.29, 2.91]; low). SRIs were significantly more efficacious than pill placebo (MD: 4.59 [2.70, 6.48]; low) and waitlist (MD: 8.03 [4.24, 11.82]; moderate). No significant differences for acceptability emerged, but confidence in estimates was low. CONCLUSIONS: In-person CBT and SRIs produce clear benefits compared to waitlist and pill placebo and should be integral parts of the clinical management of pediatric OCD, with in-person CBT overall having a stronger evidence base. The combination of in-person CBT and SRIs may be most efficacious, but few studies hinder firm conclusions. The efficacy of CBT appears conserved when delivered via webcam/telephone, while more trials evaluating ICBT are needed.

The clinical presentation of major depressive disorder in youth with co-occurring obsessive-compulsive disorder.

BACKGROUND: Major depressive disorder (MDD) is common in youth and among the most frequent comorbid disorders in pediatric obsessive-compulsive disorder (OCD), but it is unclear whether the presence of OCD affects the symptom presentation of MDD in youth. METHODS: A sample of youth with OCD and MDD (n = 124) and a sample of youth with MDD but no OCD (n = 673) completed the Patient Health Questionnaire for Adolescents (PHQ-A). The overall and symptom-level presentation of MDD were examined using group comparisons and network analysis. RESULTS: Youth with MDD and OCD, compared to those with MDD and no OCD, had more severe MDD (Cohen's d = 0.39) and more reported moderate to severe depression (75 % vs 61 %). When accounting for demographic variables and the overall severity of MDD, those with comorbid OCD reported lower levels of anhedonia and more severe difficulties with psychomotor retardation/agitation. No significant differences in the interconnections among symptoms emerged. LIMITATIONS: Data were cross-sectional and self-reported, gold standard diagnostic tools were not used to assess OCD, and the sample size for the group with MDD and OCD was relatively small yielding low statistical power for network analysis. CONCLUSIONS: Youth with MDD and OCD have more severe MDD than those with MDD and no OCD and they experience more psychomotor issues and less anhedonia, which may relate to the behavioral activation characteristic of OCD.

Alterations in attentional processing in youth with misophonia: A phenotypical cross-comparison with anxiety patients.

BACKGROUND: Misophonia is a complex condition characterized by extreme emotional distress in response to specific sounds or specific visual stimuli. Despite a growing body of clinical and neuroscientific literature, the etiology of this condition remains unclear. Hyperarousal, that is, a state of heightened alertness and disinhibition, as a core feature of misophonia is supported by behavioral and neuroimaging literature and might represent a viable clinical target for the development of both behavioral and pharmacological interventions. The aim of this study was to investigate how hyperarousal might be linked to neurocognitive processes associated with vigilance and stimulus discrimination in youth with misophonia. METHODS: We compared 72 children and adolescents with misophonia (13.74 ± 2.44 years) (64 % female) and 89 children and adolescents with anxiety (12.35 ± 2.57 years) (58.4 % female) on behavioral and signal detection performance of the immediate memory task (IMT). Anxiety patients were used as a clinical control group to distinguish attentional processes specific for misophonia. RESULTS: Both groups demonstrated similar behavioral performance, including response rate and reaction time. However, misophonia was associated with elevated stimulus discrimination (d prime), which in turn was positively correlated with the severity of misophonia trigger reports. CONCLUSIONS: Our findings are in line with previous cognitive and neuroimaging studies, and support an arousal-based model of misophonia, where individuals with misophonia experience a state of heightened vigilance, being more aware of stimuli in the environment. Our findings provide a neurocognitive basis for future study of neurochemical imaging that might further progress towards clinical targets.

Obsessive-Compulsive Disorder in Children and Adolescents.

Obsessive-compulsive disorder (OCD) in children and adolescents is a neurobehavioral condition that can lead to functional impairment in multiple domains and decreased quality of life. We review the clinical presentation, diagnostic considerations, and common comorbidities of pediatric OCD. An overview of the biological and psychological models of OCD is provided along with a discussion of developmental considerations in youth. We also describe evidence-based treatments for OCD in childhood and adolescence, including cognitive behavioral therapy (CBT) with exposure and response prevention (ERP) and pharmacotherapy. Finally, research evaluating the delivery of CBT in different formats and modalities is discussed, and we conclude with suggestions for future research directions.

Deep Brain Stimulation for Obsessive-Compulsive Disorder: Optimal Stimulation Sites.

BACKGROUND: Deep brain stimulation (DBS) is a promising treatment option for treatment-refractory obsessive-compulsive disorder (OCD). Several stimulation targets have been used, mostly in and around the anterior limb of the internal capsule and ventral striatum. However, the precise target within this region remains a matter of debate. METHODS: Here, we retrospectively studied a multicenter cohort of 82 patients with OCD who underwent DBS of the ventral capsule/ventral striatum and mapped optimal stimulation sites in this region. RESULTS: DBS sweet-spot mapping performed on a discovery set of 58 patients revealed 2 optimal stimulation sites associated with improvements on the Yale-Brown Obsessive Compulsive Scale, one in the anterior limb of the internal capsule that overlapped with a previously identified OCD-DBS response tract and one in the region of the inferior thalamic peduncle and bed nucleus of the stria terminalis. Critically, the nucleus accumbens proper and anterior commissure were associated with beneficial but suboptimal clinical improvements. Moreover, overlap with the resulting sweet- and sour-spots significantly estimated variance in outcomes in an independent cohort of 22 patients from 2 additional DBS centers. Finally, beyond obsessive-compulsive symptoms, stimulation of the anterior site was associated with optimal outcomes for both depression and anxiety, while the posterior site was only associated with improvements in depression. CONCLUSIONS: Our results suggest how to refine targeting of DBS in OCD and may be helpful in guiding DBS programming in existing patients.