Neurobiological Causes Research Articles

Culturally Responsive CBT for Psychological and Physical Symptoms in Pakistani Youth: Role of Religious and Cultural Attunement

Cognitive Behavioral Therapy (CBT) is used widely throughout the world in diverse populations for successful treatment of a wide range of psychiatric and comorbid conditions. Over the years clinicians have been making efforts to culturally adapt CBT to various groups. This paper discusses the assessment and treatment of a young female from Pakistan with depression and anxiety with comorbid headache. After ruling out all organic causes, the treatment continued over 20 sessions with the initial phase consisting of introduction to CBT, risk assessment, and identification of treatment goals. Following this, the patient was helped in identifying automatic thoughts, feelings, and behaviors. Finally, tools such as thought substitutions, reappraisals, and positive diversions were used effectively to decrease automatic negative thoughts. A focus on the patient’s religio-cultural identity was maintained throughout. Understanding of contextual factors like religio-cultural values and family dynamics helped to bring about favorable therapy outcomes. A case conceptualization that cohesively addressed factors relating to ethnicity, class, and gender yielded a positive result in our case. Involvement of the family and psychoeducation regarding neurobiological causes also proved to be helpful. Such an approach can facilitate a culturally responsive application of CBT in Pakistani youth experiencing comorbid medical and psychiatric disorders.

Impairments in expression of devaluation in a Pavlovian goal-tracking task, but not a free operant devaluation task, after fentanyl exposure in female rats

In laboratory animals, there are numerous demonstrations that past exposure to drugs of abuse can lead to devaluation impairments weeks after the final drug exposure, with the majority of these demonstrations examining effects of exposure to psychostimulants. There has been minimal investigation into whether prior exposure to opiates can lead to devaluation impairments. Here, we first trained female rats that two separate cuelights predicted two different foods and measured Pavlovian goal-tracking responses (Experiment 1) or trained female rats to press two levers to earn two different foods and measured this operant response (Experiment 2). In both experiments, we subsequently gave the rats injections of fentanyl twice daily for 6 days, and then tested rats for conditioned responses after satiation on one of the foods 48-h after the final injection. We found that rats were impaired in the expression of devaluation in the Pavlovian task after fentanyl exposure, but were unimpaired in the expression of devaluation in the operant task. The pattern of results is most consistent with an impairment in lateral orbitofrontal cortex function, but additional research is needed to determine the neurobiological cause of this pattern of results.

Identification of the Hepatic Metabolites of Flumazenil and their Kinetic Application in Neuroimaging.

Studies of the neurobiological causes of anxiety disorders have suggested that the γ-aminobutyric acid (GABA) system increases synaptic concentrations and enhances the affinity of GABAA (type A) receptors for benzodiazepine ligands. Flumazenil antagonizes the benzodiazepine-binding site of the GABA/benzodiazepine receptor (BZR) complex in the central nervous system (CNS). The investigation of flumazenil metabolites using liquid chromatography (LC)-tandem mass spectrometry will provide a complete understanding of the in vivo metabolism of flumazenil and accelerate radiopharmaceutical inspection and registration. The main goal of this study was to investigate the use of reversed-phase high performance liquid chromatography (PR-HPLC), coupled with electrospray ionization triple-quadrupole tandem mass spectrometry (ESI-QqQ MS), to identify flumazenil and its metabolites in the hepatic matrix. Carrier-free nucleophilic fluorination with an automatic synthesizer for [18F]flumazenil, combined with nano-positron emission tomography (NanoPET)/computed tomography (CT) imaging, was used to predict the biodistribution in normal rats. The study showed that 50% of the flumazenil was biotransformed by the rat liver homogenate in 60 min, whereas one metabolite (M1) was a methyl transesterification product of flumazenil. In the rat liver microsomal system, two metabolites were identified (M2 and M3), as their carboxylic acid and hydroxylated ethyl ester forms between 10 and 120 min, respectively. A total of 10-30 min post-injection of [18F]flumazenil showed an immediate decreased in the distribution ratio observed in the plasma. Nevertheless, a higher ratio of the complete [18F]flumazenil compound could be used for subsequent animal studies. [18F] According to in vivo nanoPET/CT imaging and ex vivo biodistribution assays, flumazenil also showed significant effects on GABAA receptor availability in the amygdala, prefrontal cortex, cortex, and hippocampus in the rat brain, indicating the formation of metabolites. We reported the completion of the biotransformation of flumazenil by the hepatic system, as well as [18F]flumazenil's potential as an ideal ligand and PET agent for the determination of the GABAA/BZR complex for multiplex neurological syndromes at the clinical stage.

Precision-based approaches to delirium in critical illness: A narrative review.

Delirium occurs in critical illness and is associated with poor clinical outcomes, having a longstanding impact on survivors. Understanding the complexity of delirium in critical illness and its deleterious outcome has expanded since early reports. Delirium is a culmination of predisposing and precipitating risk factors that result in a transition to delirium. Known risks range from advanced age, frailty, medication exposure or withdrawal, sedation depth, and sepsis. Because of its multifactorial nature, different clinical phenotypes, and potential neurobiological causes, a precise approach to reducing delirium in critical illness requires a broad understanding of its complexity. Refinement in the categorization of delirium subtypes or phenotypes (i.e., psychomotor classifications) requires attention. Recent advances in the association of clinical phenotypes with clinical outcomes expand our understanding and highlight potentially modifiable targets. Several delirium biomarkers in critical care have been examined, with disrupted functional connectivity being precise in detecting delirium. Recent advances reinforce delirium as an acute, and partially modifiable, brain dysfunction, and place emphasis on the importance of mechanistic pathways including cholinergic activity and glucose metabolism. Pharmacologic agents have been assessed in randomized controlled prevention and treatment trials, with a disappointing lack of efficacy. Antipsychotics remain widely used after "negative" trials, yet may have a role in specific subtypes. However, antipsychotics do not appear to improve clinical outcomes. Alpha-2 agonists perhaps hold greater potential for current use and future investigation. The role of thiamine appears promising, yet requires evidence. Looking forward, clinical pharmacists should prioritize the mitigation of predisposing and precipitating risk factors as able. Future research is needed within individual delirium psychomotor subtypes and clinical phenotypes to identify modifiable targets that hold the potential to improve not only delirium duration and severity, but long-term outcomes including cognitive impairment.

Quantifying numerical and spatial reliability of hippocampal and amygdala subdivisions in FreeSurfer

On-going, large-scale neuroimaging initiatives can aid in uncovering neurobiological causes and correlates of poor mental health, disease pathology, and many other important conditions. As projects grow in scale with hundreds, even thousands, of individual participants and scans collected, quantification of brain structures by automated algorithms is becoming the only truly tractable approach. Here, we assessed the spatial and numerical reliability for newly deployed automated segmentation of hippocampal subfields and amygdala nuclei in FreeSurfer 7. In a sample of participants with repeated structural imaging scans (N = 928), we found numerical reliability (as assessed by intraclass correlations, ICCs) was reasonable. Approximately 95% of hippocampal subfields had “excellent” numerical reliability (ICCs ≥ 0.90), while only 67% of amygdala subnuclei met this same threshold. In terms of spatial reliability, 58% of hippocampal subfields and 44% of amygdala subnuclei had Dice coefficients ≥ 0.70. Notably, multiple regions had poor numerical and/or spatial reliability. We also examined correlations between spatial reliability and person-level factors (e.g., participant age; T1 image quality). Both sex and image scan quality were related to variations in spatial reliability metrics. Examined collectively, our work suggests caution should be exercised for a few hippocampal subfields and amygdala nuclei with more variable reliability.Graphical

Brain-predicted age difference mediates the association between PROMIS sleep impairment, and self-reported pain measure in persons with knee pain

Knee pain, the most common cause of musculoskeletal pain (MSK), constitutes a severe public health burden. Its neurobiological causes, however, remain poorly understood. Among many possible causes, it has been proposed that sleep problems could lead to an increase in chronic pain symptomatology, which may be driven by central nervous system changes. In fact, we previously found that brain cortical thickness mediated the relationship between sleep qualities and pain severity in older adults with MSK. We also demonstrated a significant difference in a machine-learning-derived brain-aging biomarker between participants with low-and high-impact knee pain. Considering this, we examined whether brain aging was associated with self-reported sleep and pain measures, and whether brain aging mediated the relationship between sleep problems and knee pain. Exploratory Spearman and Pearson partial correlations, controlling for age, sex, race and study site, showed a significant association of brain aging with sleep related impairment and self-reported pain measures. Moreover, mediation analysis showed that brain aging significantly mediated the effect of sleep related impairment on clinical pain and physical symptoms. Our findings extend our prior work demonstrating advanced brain aging among individuals with chronic pain and the mediating role of brain-aging on the association between sleep and pain severity. Future longitudinal studies are needed to further understand whether the brain can be a therapeutic target to reverse the possible effect of sleep problems on chronic pain.

Protein Misfolding and Aggregation in the Brain: Common Pathogenetic Pathways in Neurodegenerative and Mental Disorders.

Mental disorders represent common brain diseases characterized by substantial impairments of social and cognitive functions. The neurobiological causes and mechanisms of psychopathologies still have not been definitively determined. Various forms of brain proteinopathies, which include a disruption of protein conformations and the formation of protein aggregates in brain tissues, may be a possible cause behind the development of psychiatric disorders. Proteinopathies are known to be the main cause of neurodegeneration, but much less attention is given to the role of protein impairments in psychiatric disorders' pathogenesis, such as depression and schizophrenia. For this reason, the aim of this review was to discuss the potential contribution of protein illnesses in the development of psychopathologies. The first part of the review describes the possible mechanisms of disruption to protein folding and aggregation in the cell: endoplasmic reticulum stress, dysfunction of chaperone proteins, altered mitochondrial function, and impaired autophagy processes. The second part of the review addresses the known proteins whose aggregation in brain tissue has been observed in psychiatric disorders (amyloid, tau protein, α-synuclein, DISC-1, disbindin-1, CRMP1, SNAP25, TRIOBP, NPAS3, GluA1, FABP, and ankyrin-G).

Horizons in Human Aging Neuroscience: From Normal Neural Aging to Mental (Fr)Agility.

While aging is an important risk factor for neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease, age-related cognitive decline can also manifest without apparent neurodegenerative changes. In this review, we discuss molecular, cellular, and network changes that occur during normal aging in the absence of neurodegenerative disease. Emerging findings reveal that these changes include metabolic alterations, oxidative stress, DNA damage, inflammation, calcium dyshomeostasis, and several other hallmarks of age-related neural changes that do not act on their own, but are often interconnected and together may underlie age-related alterations in brain plasticity and cognitive function. Importantly, age-related cognitive decline may not be reduced to a single neurobiological cause, but should instead be considered in terms of a densely connected system that underlies age-related cognitive alterations. We speculate that a decline in one hallmark of neural aging may trigger a decline in other, otherwise thus far stable subsystems, thereby triggering a cascade that may at some point also incur a decline of cognitive functions and mental well-being. Beyond studying the effects of these factors in isolation, considerable insight may be gained by studying the larger picture that entails a representative collection of such factors and their interactions, ranging from molecules to neural networks. Finally, we discuss some potential interventions that may help to prevent these alterations, thereby reducing cognitive decline and mental fragility, and enhancing mental well-being, and healthy aging.

How Can Animal Models Inform the Understanding of Cognitive Inflexibility in Patients with Anorexia Nervosa?

Deficits in cognitive flexibility are consistently seen in patients with anorexia nervosa (AN). This type of cognitive impairment is thought to be associated with the persistence of AN because it leads to deeply ingrained patterns of thought and behaviour that are highly resistant to change. Neurobiological drivers of cognitive inflexibility have some commonalities with the abnormal brain functional outcomes described in patients with AN, including disrupted prefrontal cortical function, and dysregulated dopamine and serotonin neurotransmitter systems. The activity-based anorexia (ABA) model recapitulates the key features of AN in human patients, including rapid weight loss caused by self-starvation and hyperactivity, supporting its application in investigating the cognitive and neurobiological causes of pathological weight loss. The aim of this review is to describe the relationship between AN, neural function and cognitive flexibility in human patients, and to highlight how new techniques in behavioural neuroscience can improve the utility of animal models of AN to inform the development of novel therapeutics.

Comparing the pathology of equine stereotypical behaviours to obsessive-compulsive and related disorder in humans: An exploratory Delphi study

Limited evidence supports the hypothesised link between Obsessive-Compulsive and Related Disorders (OCRD) and Equine Stereotypical Behaviours (ESB), despite the existence of many non-human animal OCRD models. ESBs are viewed as aversive behaviours or ‘stable vices’ by the general horse owning population, in stark contrast to the psychological disorders OCRDs are known to be. ESBs have been linked to intensive domestication and sub-optimal living conditions and current ESB management strategies are known to be more harmful than relieving. An anonymous three-round Delphi study was conducted with the expertise of five panellists heavily involved in the fields of human, horse and other animal behaviour, welfare and medicine to gain perspective of the extent of similarities and differences between OCRD and ESB. The main elements considered are neurology and neurological dysfunction, causal factors, aetiology, behavioural presentations, effects on welfare and the potential benefits and harms of recognising ESB as a manifestation of OCRD. Round One consisted of a series of open-ended questions to gather common themes on which to base the Round Two Likert-style scale questions and further open-ended questions, the answers to which formed statements used in Round Three. The panellists were asked to specify reasons for agreement or disagreement directed towards reaching consensus. Qualitative analysis was used throughout including open coding in Rounds One and Two. A tentative consensus was reached in that all panellists agree that OCRD and ESB are comparable conditions which share some causal factors, e.g. neurotransmitter pathway and signalling dysfunctions, stress in early life and genetic predispositions. However, there was some dispute over the cognitive underpinnings leading to hesitations surrounding the nature, or even existence of, obsessive thoughts and therefore the neurobiological causes of compulsive behaviours in horses. It was noted that the vastly different lifestyles of humans and husbandry of horses play an important role in the nature and presentations of OCRD and ESB, and most agreed that diagnosing ESB as a non-human presentation of OCRD would be beneficial to increasing owner and carer awareness of the importance of high welfare standards. However, this was not deemed to be essential, whereas improving knowledge available to owners and carers was.

Attachment-Based Treatment for Anxiety Disorders Use of spontaneity as a mode of relating to resolve anxiety

Although we have established effective treatments for anxiety disorders,the problem is on the rise worldwide, and the effect sizesfor treatments suggest that advancements are needed. Part of the reason for the limitations in our treatments may be because they are designed to address the disorder’s symptoms rather than its underlying cause. This paper is geared toward presenting a likely neurobiological cause and a proposed treatment. There is significant evidence that the basis for anxiety is a combination of stress, especially interpersonal stress, and an inability to find solutions to resolve it. Anxiety is the result of this lack of coping ability. The part of the brain involved in designing these coping strategies, especially when the stressor is complex and emotion-based, is the dorsolateral prefrontal cortex. That is because it is the brain’s “sketch pad,” in that it allows us to think of solutions on a “symbolic” rather than a concrete basis.Anxiety arises when the person is unable to use this brain region effectively in formulating solutions, and instead designs ineffective solutions. The reason for that deficit may stem from early childhood, during a phase of attachment in which parents do not engage spontaneously in child-induced play. The mother is unable to be spontaneous in sharing the child’s play,which is needed for the child to generate his or her own solutions to problems. This leads to an inability of the child’s dorsolateral prefrontal cortex structure to properly develop. This will manifest as a lack of “insight,” or ability to generate spontaneous solutions to problems instead focusing on routinized solutions to emotion-based problems later in life that often do not work. Evidence is provided in a case report of a patient with an anxiety disorder who could not solve his interpersonal problems because he lacked the necessary insight. This deficit was so profound that he could not use insight-based psychotherapy and found use of medication too sedating. By modelling a more spontaneous give and take between the therapist and the patient’s wife, who served as a “co-therapist,”the patient was able to learn to develop his own insight. His wife would tell the therapist the problems the patient was unable to tell him and would help the patient to learn to respond to the interpretations offered by the therapist. The patient learned how to imitate his wife and describe his problems, and then to imitate the therapist and generate his own insight. As this occurred, his anxiety was resolved. The basis of the attachment that developed with his therapists was based on the use of spontaneity, from which the patient learned his own insights resolving his anxiety.

Attachment-Based Treatment for Anxiety Disorders Use of spontaneity as a mode of relating to resolve anxiety

Although we have established effective treatments for anxiety disorders,the problem is on the rise worldwide, and the effect sizesfor treatments suggest that advancements are needed. Part of the reason for the limitations in our treatments may be because they are designed to address the disorder’s symptoms rather than its underlying cause. This paper is geared toward presenting a likely neurobiological cause and a proposed treatment. There is significant evidence that the basis for anxiety is a combination of stress, especially interpersonal stress, and an inability to find solutions to resolve it. Anxiety is the result of this lack of coping ability. The part of the brain involved in designing these coping strategies, especially when the stressor is complex and emotion-based, is the dorsolateral prefrontal cortex. That is because it is the brain’s “sketch pad,” in that it allows us to think of solutions on a “symbolic” rather than a concrete basis.Anxiety arises when the person is unable to use this brain region effectively in formulating solutions, and instead designs ineffective solutions. The reason for that deficit may stem from early childhood, during a phase of attachment in which parents do not engage spontaneously in child-induced play. The mother is unable to be spontaneous in sharing the child’s play,which is needed for the child to generate his or her own solutions to problems. This leads to an inability of the child’s dorsolateral prefrontal cortex structure to properly develop. This will manifest as a lack of “insight,” or ability to generate spontaneous solutions to problems instead focusing on routinized solutions to emotion-based problems later in life that often do not work. Evidence is provided in a case report of a patient with an anxiety disorder who could not solve his interpersonal problems because he lacked the necessary insight. This deficit was so profound that he could not use insight-based psychotherapy and found use of medication too sedating. By modelling a more spontaneous give and take between the therapist and the patient’s wife, who served as a “co-therapist,”the patient was able to learn to develop his own insight. His wife would tell the therapist the problems the patient was unable to tell him and would help the patient to learn to respond to the interpretations offered by the therapist. The patient learned how to imitate his wife and describe his problems, and then to imitate the therapist and generate his own insight. As this occurred, his anxiety was resolved. The basis of the attachment that developed with his therapists was based on the use of spontaneity, from which the patient learned his own insights resolving his anxiety.

Developing Multimodal Dynamic Functional Connectivity as a Neuroimaging Biomarker.

Background: In spite of increasing evidence highlighting the role of dynamic functional connectivity (FC) in characterizing mental disorders, there is a lack of (a) reliable statistical methods to compute dynamic connectivity and (b) rigorous dynamic FC-based approaches for predicting mental health outcomes in heterogeneous disorders such as post-traumatic stress disorder (PTSD). Methods: In one of the first such efforts, we develop a reliable and accurate approach for estimating dynamic FC guided by brain structural connectivity (SC) computed using diffusion tensor imaging data and investigate the potential of the proposed multimodal dynamic FC to predict continuous mental health outcomes. We develop concrete measures of temporal network variability that are predictive of PTSD resilience, and identify regions whose temporal connectivity fluctuations are significantly related to resilience. Results: Our results illustrate that the multimodal approach is more sensitive to connectivity change points, it can clearly detect localized brain regions with the dynamic network features such as small-worldedness, clustering coefficients, and efficiency associated with resilience, and that it has superior predictive performance compared with existing static and dynamic network models when modeling PTSD resilience. Discussion: While the majority of resting-state network modeling in psychiatry has focused on static FC, our novel multimodal dynamic network analyses that are sensitive to network fluctuations allowed us to provide a model of neural correlates of resilience with high accuracy compared with existing static connectivity approaches or those that do not use brain SC information, and provided us with an expanded understanding of the neurobiological causes for PTSD. Impact statement The methods developed in this article provide reliable and accurate dynamic functional connectivity (FC) approaches by fusing multimodal imaging data that are highly predictive of continuous clinical phenotypes in heterogeneous mental disorders. Currently, there is very little theoretical work to explain how network dynamics might contribute to individual differences in behavior or psychiatric symptoms. Our analysis conclusively discovers localized brain resting-state networks, regions, and connections where variations in dynamic FC (that is estimated after incorporating brain structural connectivity information) are associated with post-traumatic stress disorder resilience, which could potentially provide valuable tools for the development of neural circuit modeling in psychiatry in the future.

Clinical and Translational Implications of an Emerging Developmental Substructure for Autism.

A vast share of the population-attributable risk for autism relates to inherited polygenic risk. A growing number of studies in the past five years have indicated that inherited susceptibility may operate through a finite number of early developmental liabilities that, in various permutations and combinations, jointly predict familial recurrence of the convergent syndrome of social communication disability that defines the condition. Here, we synthesize this body of research to derive evidence for a novel developmental substructure for autism, which has profound implications for ongoing discovery efforts to elucidate its neurobiological causes, and to inform future clinical and biomarker studies, early interventions, and personalized approaches to therapy.

Disease Modification in Epilepsy: Behavioural Accompaniments.

According to the definition of epileptogenesis, "disease modification" refers to every clinically relevant therapeutic outcome which does not necessarily prevent epilepsy onset but significantly improves the disease course by reducing seizure burden and/or decreases concomitant comorbidities. In this light, understanding comorbidities development, their characteristics, and the neurobiological causes represents a major issue both in clinical and preclinical research. This chapter is summarizing and critically evaluating the preclinical improvements over time in the study of epilepsy comorbidities reconsidering some of them according to the newer results. Furthermore, we highlight limitations and possibilities both in the methods used and in the mechanisms considered. The latter have been analysed also as potential therapeutic targets for therapy development. Finally, differences and similarities between induced epilepsy models and genetic models have been underlined in the chapter.

Dysfunctional auditory gamma oscillations in developmental dyslexia: A potential target for a tACS-based intervention.

Interventions in developmental dyslexia typically consist of orthography-based reading and writing trainings. However, their efficacy is limited and, consequently, the symptoms persist into adulthood. Critical for this lack of efficacy is the still ongoing debate about the core deficit in dyslexia and its underlying neurobiological causes. There is ample evidence on phonological as well as auditory temporal processing deficits in dyslexia and, on the other hand, cortical gamma oscillations in the auditory cortex as functionally relevant for the extraction of linguistically meaningful information units from the acoustic signal. The present work aims to shed more light on the link between auditory gamma oscillations, phonological awareness, and literacy skills in dyslexia. By mean of EEG, individual gamma frequencies were assessed in a group of children and adolescents diagnosed with dyslexia as well as in an age-matched control group with typical literacy skills. Furthermore, phonological awareness was assessed in both groups, while in dyslexic participants also reading and writing performance was measured. We found significantly lower gamma peak frequencies as well as lower phonological awareness scores in dyslexic participants compared to age-matched controls. Additionally, results showed a positive correlation between the individual gamma frequency and phonological awareness. Our data suggest a hierarchical structure of neural gamma oscillations, phonological awareness, and literacy skills. Thereby, the results emphasize altered gamma oscillation not only as a core deficit in dyslexia but also as a potential target for future causal interventions. We discuss these findings considering non-invasive brain stimulation techniques and suggest transcranial alternating current stimulation as a promising approach to normalize dysfunctional oscillations in dyslexia.

Memory as Imagination: Mind Science in Bellow's Short Fiction

Abstract This article analyzes the narrative memories in Saul Bellow's short fiction using a cognitive approach. Memory failures, memory distortions, emotional memories, and some other problems with memories in the stories are confronted through a lens that memory researchers call “mental time travel” or memory-imagination cognitive system. This article argues that Bellow's narrative styles and techniques of mind presentation in the second half of the twentieth century are consistent with twenty-first century science of the brain and mind, especially in terms of default mode cognitive activities and the imaginativeness of memory. For a clear presentation of the flawed narrative memories depicted in Bellow's short fiction, this article draws upon Daniel L. Schacter's metaphor of “sins of memory” when analyzing the texts from four stories. The application of Schacter's research in the textual analysis differentiates the psychological and neurobiological causes of errors in both memories and narrative memories, with a hope to contribute to the dialogue between literature and science in terms of the nature of narrative and memory.

Effects of genomic copy number variants penetrant for schizophrenia on cortical thickness and surface area in healthy individuals: analysis of the UK Biobank.

Schizophrenia is a highly heritable disorder with undetermined neurobiological causes. Understanding the impact on brain anatomy of carrying genetic risk for the disorder will contribute to uncovering its neurobiological underpinnings. To examine the effect of rare copy number variants (CNVs) associated with schizophrenia on brain cortical anatomy in a sample of unaffected participants from the UK Biobank. We used regression analyses to compare cortical thickness and surface area (total and across gyri) between 120 unaffected carriers of rare CNVs associated with schizophrenia and 16 670 participants without any pathogenic CNV. A measure of cortical thickness and surface area covariance across gyri was also compared between groups. Carrier status was associated with reduced surface area (β = -0.020 mm2, P < 0.001) and less robustly with increased cortical thickness (β = 0.015 mm, P = 0.035), and with increased covariance in thickness (carriers z = 0.31 v. non-carriers z = 0.22, P < 0.0005). Associations were mainly present in frontal and parietal areas and driven by a limited number of rare risk alleles included in our analyses (mainly 15q11.2 deletion for surface area and 16p13.11 duplication for thickness covariance). Results for surface area conformed with previous clinical findings, supporting surface area reductions as an indicator of genetic liability for schizophrenia. Results for cortical thickness, though, argued against its validity as a potential risk marker. Increased structural thickness covariance across gyri also appears related to risk for schizophrenia. The heterogeneity found across the effects of rare risk alleles suggests potential different neurobiological gateways into schizophrenia's phenotype.

COVID-19 Catatonia—Would We Even Know?

COVID-19 Catatonia—Would We Even Know?

Sociocultural determinants and patterns of healthcare utilization for epilepsy care in Uganda

ObjectiveEpilepsy is a global public health concern, with the majority of cases occurring in lower- and middle-income countries where the treatment gap remains formidable. In this study, we simultaneously explore how beliefs about epilepsy causation, perceived barriers to care, seizure disorder characteristics, and demographics influence the initial choice of healthcare for epilepsy and its impact on attaining biomedical care (BMC). MethodsThis study utilized the baseline sample (n = 626) from a prospective cohort study of people with epilepsy (PWE) attending three public hospitals in Uganda (Mulago National Referral Hospital, Butabika National Referral Mental Hospital, and Mbarara Regional Referral Hospital) for epilepsy care. Patient and household demographics, clinical seizure disorder characteristics, and sociocultural questionnaires were administered. Logistic regression and principal component analyses (PCA) were conducted to examine associations with the choice of primary seizure treatment. ResultsThe sample was 49% female, and 24% lived in rural settings. A biomedical health facility was the first point of care for 355 (56.7%) participants, while 229 (36.6%) first sought care from a traditional healer and 42 (6.7%) from a pastoral healer. Preliminary inspection of candidate predictors using relaxed criteria for significance (p < 0.20) identified several factors potentially associated with a greater odds of seeking BMC first. Demographic predictors included older caredriver (decision-maker for the participant) age (odds ratio [OR]: 1.01, 95% confidence interval [CI]: [0.99, 1.02], p-value: 0.09), greater caredriver education level (OR = 1.21, 95% CI: [1.07, 1.37], p-value = 0.003), and lower ratio of sick to healthy family members (OR = 0.77 [0.56, 1.05], P = 0.097). For clinical predictors, none of the proposed predictors associated significantly with seeking BMC first. Self-report causation predictors associated with a greater odds of seeking BMC first included higher belief in biological causes of epilepsy (OR = 1.31 [0.92, 1.88], P = 0.133) and lower belief in socio-spiritual causes of epilepsy (OR = 0.68 [0.56, 0.84], P < 0.001). In the multivariate model, only higher caredriver education (OR = 1.19 [1.04, 1.36], P = 0.009) and lower belief in socio-spiritual causes of epilepsy (OR = 0.69 [0.56, 0.86], P < 0.01) remained as predictors of seeking BMC first. Additionally, PCA revealed a pattern which included high income with low beliefs in nonbiological causes of epilepsy as being associated with seeking BMC first (OR = 1.32 [1.12, 1.55], p = 0.001). Despite reaching some form of care faster, individuals seeking care from traditional or pastoral healers experienced a significant delay to eventual BMC (P < 0.001), with an average delay of more than two years (traditional healer: 2.53 years [1.98, 3.24]; pastoral care: 2.18 [1.21, 3.91]). ConclusionsCoupled with low economic and educational status, belief in spiritual causation of epilepsy is a dominant determinant of opting for traditional or pastoral healing over BMC, regardless of concurrent belief in biological etiologies. There is a prolonged delay to eventual BMC for PWE who begin their treatment seeking with nonallopathic providers, and although nonallopathic healers provide PWE with benefits not provided by BMC, this notable delay likely prevents earlier administration of evidence-based care with known efficacy. Based on these findings, initiatives to increase public awareness of neurobiological causes of epilepsy and effectiveness of biomedical drug treatments may be effective in preventing delays to care, as would programs designed to facilitate cooperation and referral among traditional, faith-based, and biomedical providers.This article is part of the Special Issue “The Intersection of Culture, Resources, and Disease: Epilepsy Care in Uganda”