The genetic architecture of youth anxiety: a study protocol.

BACKGROUND: Anxiety disorders are the most common psychiatric problems among Canadian youth and typically have an onset in childhood or adolescence. They are characterized by high rates of relapse and chronicity, often resulting in substantial impairment across the lifespan. Genetic factors play an important role in the vulnerability toward anxiety disorders. However, genetic contribution to anxiety in youth is not well understood and can change across developmental stages. Large-scale genetic studies of youth are needed with detailed assessments of symptoms of anxiety disorders and their major comorbidities to inform early intervention or preventative strategies and suggest novel targets for therapeutics and personalization of care. METHODS: The Genetic Architecture of Youth Anxiety (GAYA) study is a Pan-Canadian effort of clinical and genetic experts with specific recruitment sites in Calgary, Halifax, Hamilton, Toronto, and Vancouver. Youth aged 10-19 (n = 13,000) will be recruited from both clinical and community settings and will provide saliva samples, complete online questionnaires on demographics, symptoms of mental health concerns, and behavioural inhibition, and complete neurocognitive tasks. A subset of youth will be offered access to a self-managed Internet-based cognitive behavioral therapy resource. Analyses will focus on the identification of novel genetic risk loci for anxiety disorders in youth and assess how much of the genetic risk for anxiety disorders is unique or shared across the life span. DISCUSSION: Results will substantially inform early intervention or preventative strategies and suggest novel targets for therapeutics and personalization of care. Given that the GAYA study will be the biggest genomic study of anxiety disorders in youth in Canada, this project will further foster collaborations nationally and across the world.

Estradiol Replacement as a Potential Enhancer of Working Memory and Neuroplasticity in Hypogonadal Trans Women.

INTRODUCTION: The cognitive effects of cross-sex hormone therapy (CSHT) are not well understood. In cisgender individuals, sex hormone therapy can impact neurotransmitter levels and structural anatomy. Similarly, in gender-diverse persons, CSHT has been associated with neural adaptations, such as growth in brain structures resembling those observed in cisgender individuals of the same sex. Hormone-related changes in learning and memory, as seen in menopause, are associated with physiological hypogonadism or a decline in hormones, such as estradiol. The present study examined the effect of estradiol administration in humans on glutamate concentration in brain regions involved in semantic and working memory (i.e., the dorsolateral prefrontal cortex [DLPFC], the posterior hippocampus, and the pregenual anterior cingulate cortex) and its relationship with memory. METHODS: Eighteen trans women (male biological sex assigned at birth) ceased CSHT for 30 days for a washout phase (t1) upon study enrollment to reach a hypogonadal state. Working and semantic memory, cognition, hormonal assays, and brain imaging were assessed. Participants resumed CSHT for 60 days for a replacement phase (t2), after which the same evaluations from t1 were repeated. RESULTS: Estradiol increased among trans women after 60 days of resumed CSHT with significant improvements in semantic memory compared to the hypogonadal phase. Working memory recall was significantly and positively correlated to glutamate in the DLPFC during the reinstatement phase, although the relationship was not moderated by levels of estradiol. DISCUSSION: These results may have clinical implications for the therapeutic effects of estradiol replacement, serving as a protective factor against cognitive decline and impairment for trans women post-gonadectomy.

A systematic review of the neural correlates of sexual minority stress: towards an intersectional minority mosaic framework with implications for a future research agenda.

BACKGROUND: Systemic oppression, particularly towards sexual minorities, continues to be deeply rooted in the bedrock of many societies globally. Experiences with minority stressors (e.g. discrimination, hate-crimes, internalized homonegativity, rejection sensitivity, and microaggressions or everyday indignities) have been consistently linked to adverse mental health outcomes. Elucidating the neural adaptations associated with minority stress exposure will be critical for furthering our understanding of how sexual minorities become disproportionately affected by mental health burdens.Following PRISMA-guidelines, we systematically reviewed published neuroimaging studies that compared neural dynamics among sexual minority and heterosexual populations, aggregating information pertaining to any measurement of minority stress and relevant clinical phenomena. RESULTS: Only 1 of 13 studies eligible for inclusion examined minority stress directly, where all other studies focused on investigating the neurobiological basis of sexual orientation. In our narrative synthesis, we highlight important themes that suggest minority stress exposure may be associated with decreased activation and functional connectivity within the default-mode network (related to the sense-of-self and social cognition), and summarize preliminary evidence related to aberrant neural dynamics within the salience network (involved in threat detection and fear processing) and the central executive network (involved in executive functioning and emotion regulation). Importantly, this parallels neural adaptations commonly observed among individuals with posttraumatic stress disorder (PTSD) in the aftermath of trauma and supports the inclusion of insidious forms of trauma related to minority stress within models of PTSD. CONCLUSIONS: Taken together, minority stress may have several shared neuropsychological pathways with PTSD and stress-related disorders. Here, we outline a detailed research agenda that provides an overview of literature linking sexual minority stress to PTSD and insidious trauma, moral affect (including shame and guilt), and mental health risk/resiliency, in addition to racial, ethnic, and gender related minority stress. Finally, we propose a novel minority mosaic framework designed to inform future directions of minority stress neuroimaging research from an intersectional lens.

Antecedentes: La opresión sistémica, en particular hacia las minorías sexuales, sigue estando profundamente arraigada en los cimientos de muchas sociedades a nivel mundial. Las experiencias con los factores de estrés de las minorías (por ejemplo, la discriminación, los delitos de odio, la homonegatividad interiorizada, la sensibilidad al rechazo y las microagresiones o humillaciones cotidianas) se han relacionado sistemáticamente con resultados adversos para la salud mental. La elucidación de las adaptaciones neuronales asociadas con la exposición al estrés de las minorías será fundamental para avanzar en nuestra comprensión de cómo las minorías sexuales se ven afectadas de manera desproporcionada por las cargas de salud mental.Métodos: Siguiendo las directrices PRISMA, revisamos sistemáticamente los estudios de neuroimagen publicados que comparaban la dinámica neural entre las poblaciones de minorías sexuales y heterosexuales, agregando la información relativa a cualquier medición del estrés de minorías y los fenómenos clínicos relevantes.Resultados: Sólo 1 de los 13 estudios elegibles para su inclusión examinó directamente el estrés de las minorías, mientras que todos los demás estudios se centraron en investigar las bases neurobiológicas de la orientación sexual. En nuestra síntesis narrativa, destacamos temas importantes que sugieren que la exposición al estrés de las minorías puede estar asociada con la disminución de la activación y la conectividad funcional dentro de la red del modo por defecto (relacionada con el sentido del yo y la cognición social), y resumimos la evidencia preliminar relacionada con la dinámica neuronal aberrante dentro de la red de saliencia (involucrada en la detección de amenazas y el procesamiento del miedo) y la red ejecutiva central (involucrada en el funcionamiento ejecutivo y la regulación de las emociones). Es importante destacar que esto es paralelo a las adaptaciones neuronales comúnmente observadas entre los individuos con trastorno de estrés postraumático (TEPT) después del trauma y apoya la inclusión de formas insidiosas de trauma relacionadas con el estrés de las minorías dentro de los modelos de TEPT.Conclusiones: En conjunto, el estrés de las minorías puede tener varias vías neuropsicológicas compartidas con el TEPT y los trastornos relacionados con el estrés. Aquí, esbozamos una agenda de investigación detallada que proporciona una visión general de la literatura que vincula el estrés de las minorías sexuales con el TEPT y el trauma insidioso, el afecto moral (incluyendo la vergüenza y la culpa), y el riesgo/resiliencia de la salud mental, además del estrés de las minorías relacionadas con la raza, la etnia y el género. Por último, proponemos un marco de mosaico de minorías novedoso diseñado para informar sobre las futuras direcciones de la investigación de neuroimagen del estrés de las minorías desde una perspectiva interseccional.

Increased gray matter following mindfulness-based stress reduction in breast cancer survivors with chronic neuropathic pain: preliminary evidence using voxel-based morphometry.

PURPOSE: To investigate the impact of Mindfulness-Based Stress Reduction (MBSR) on gray matter volume (GMV) in female breast cancer survivors who suffer from chronic neuropathic pain (CNP). METHODS: Voxel-based morphometry (VBM) was used to explore differences in GMV in 13 MBSR trainees and 10 waitlisted controls, with MRI scans and self-report measures completed pre- and post-8 weeks of training. RESULTS: Compared to controls, the MBSR group had greater GMV in the angular gyrus and middle frontal gyrus post-training. The MBSR group's right parahippocampal gyrus GMV increased from pre- to post-training, whereas the control group's left parahippocampal gyrus, precuneus, middle temporal gyrus, and right cuneus GMV decreased over the same time period. Pain interference was significantly reduced and mindfulness was significantly increased following MBSR for the intervention group only. CONCLUSIONS: MBSR was associated with increased GMV in regions where GMV is known to (1) increase with mindfulness and reorientation of attention and (2) decrease with the experience of chronic neuropathic pain. By contrast, the control group's decreases in GMV may be due to the negative effects of CNP which potentially may be reduced with MBSR, though further research is needed. IMPLICATIONS FOR CANCER SURVIVORS: Given the poor efficiency of pharmacotherapies in a high percentage of women with neuropathic pain following breast cancer treatment, adjunct methods are required. MBSR may affect the brain to help alter attention and perception of pain, thus playing a potentially important role in the path to wellness for breast cancer survivors.

Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial.

(Reprinted with permission from The American Journal of Psychiatry 2019; 176:401-409).

Breast cancer survivors living with chronic neuropathic pain show improved brain health following mindfulness-based stress reduction: a preliminary diffusion tensor imaging study.

PURPOSE: The present study explores the benefits of an 8-week mindfulness-based stress reduction (MBSR) program to white matter integrity among breast cancer survivors experiencing chronic neuropathic pain (CNP). METHODS: Twenty-three women were randomly assigned to either a MBSR treatment group (n = 13) or a waitlist control group (n = 10). Participants were imaged with MRI prior to and post-MBSR training using diffusion tensor imaging. RESULTS: Compared with controls, the MBSR group showed a significant increase in fractional anisotropy (FA), particularly in the left subcortical regions including the uncinate fasciculus, amygdala, and hippocampus, as well as in the external capsule and in the left sagittal stratum. No decreases to FA were found in any brain regions following MBSR training. The FA values also negatively correlated with the pain severity and pain interference scores from the BRIEF pain questionnaire. CONCLUSIONS: The present findings demonstrate that MBSR training may enhance the integrity of cerebral white matter that coincides with a reduction in pain perception. Further research with a larger sample size is required. IMPLICATIONS FOR CANCER SURVIVORS: This study highlights the potential for MBSR, as a non-pharmacological intervention, to provide both brain health improvement and pain perception relief for female breast cancer survivors experiencing CNP.

Single and repeated ketamine infusions for reduction of suicidal ideation in treatment-resistant depression.

Repeated administration of subanesthetic intravenous ketamine may prolong the rapid decrease in suicidal ideation (SI) elicited by single infusions. The purpose of this secondary analysis was to evaluate reduction in SI with a single ketamine infusion compared with an active control, and prolonged suppression of SI with repeated and maintenance infusions. Thirty-seven participants with treatment-resistant depression (TRD) and baseline SI first received a single ketamine infusion during a randomized, double-blind crossover with midazolam. Following relapse of depressive symptoms, participants received six open-label ketamine infusions administered thrice-weekly over 2 weeks. Antidepressant responders (≥50% decrease in Montgomery-Åsberg Depression Rating Scale [MADRS] scores) received four further open-label infusions administered once-weekly. Changes in SI were assessed with the suicide items on the MADRS (item 10, MADRS-SI) and the Quick Inventory of Depressive Symptomatology-Self Report (item 12, QIDS-SI). Linear mixed models revealed that compared with midazolam, a single ketamine infusion elicited larger reduction in SI (P = 0.01), with maximal effects measured at 7 days postinfusion (P < 0.001, Cohen's d = 0.83). Participants had cumulative reductions in MADRS-SI scores with repeated infusions (P < 0.001), and no further change with maintenance infusions (P = 0.94). QIDS-SI results were consistent with MADRS-SI. Overall, 69% of participants had a complete alleviation of SI following repeated infusions. In TRD, single and repeated ketamine infusions resulted in decreases in SI which were maintained with once-weekly maintenance infusions. This study adds to the growing body of research suggesting ketamine as a possible novel treatment strategy for SI in mood disorders.

Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial.

OBJECTIVE: Subanesthetic ketamine doses have been shown to have rapid yet transient antidepressant effects in patients with treatment-resistant depression, which may be prolonged by repeated administration. The purpose of this study was to evaluate the antidepressant effects of a single ketamine infusion, a series of repeated ketamine infusions, and prolongation of response with maintenance infusions. METHODS: Forty-one participants with treatment-resistant depression completed a single-site randomized double-blind crossover comparison of single infusions of ketamine and midazolam (an active placebo control). After relapse of depressive symptoms, participants received a course of six open-label ketamine infusions administered thrice weekly over 2 weeks. Responders, classified as those participants who had a ≥50% decrease in their scores on the Montgomery-Åsberg Depression Rating Scale (MADRS), received four additional infusions administered once weekly (maintenance phase). RESULTS: Compared with midazolam, a single ketamine infusion elicited a significantly greater reduction in depressive symptoms at the primary efficacy endpoint (24 hours postinfusion). Linear mixed models revealed cumulative antidepressant effects with repeated infusions and doubling of the antidepressant response rate. Fifty-nine percent of participants met response criteria after repeated infusions, with a median of three infusions required before achieving response. Participants had no further change in MADRS scores during weekly maintenance infusions. CONCLUSIONS: Repeated ketamine infusions have cumulative and sustained antidepressant effects. Reductions in depressive symptoms were maintained among responders through once-weekly infusions. These findings provide novel data on efficacious administration strategies for ketamine in patients with treatment-resistant depression. Future studies should further expand on optimizing administration to better translate the use of ketamine into clinical settings.

Comparative evaluation of group-based mindfulness-based stress reduction and cognitive behavioural therapy for the treatment and management of chronic pain: A systematic review and network meta-analysis.

QUESTION: This review compares mindfulness-based stress reduction (MBSR) to cognitive-behavioural therapy (CBT) in its ability to improve physical functioning and reduce pain intensity and distress in patients with chronic pain (CP), when evaluated against control conditions. STUDY SELECTION AND ANALYSIS: Ovid MEDLINE, EmbaseClassic+Embase, PsycINFO and the Cochrane Library were searched to identify randomised controlled trials. The primary outcome measure was physical functioning. Secondary outcomes were pain intensity and depression symptoms. We used random and fixed effects (RE and FE) network meta-analyses (NMA) to compare MBSR, CBT and control interventions on the standardised mean difference scale. FINDINGS: Twenty-one studies were included: 13 CBT vs control (n=1095), 7 MBSR vs control (n=545) and 1 MBSR vs CBT vs control (n=341). Of the 21 articles, 12 were determined to be of fair or good quality. Findings from RE NMA for change in physical functioning, pain intensity and depression revealed clinically important advantages relative to control for MBSR and CBT, but no evidence of an important difference between MBSR and CBT was found. CONCLUSIONS: This review suggests that MBSR offers another potentially helpful intervention for CP management. Additional research using consistent measures is required to guide decisions about providing CBT or MBSR.

Neural impact of low-level alcohol use on response inhibition: An fMRI investigation in young adults.

It is widely known that alcohol consumption adversely affects human health, particularly in the immature developing brains of adolescents and young adults, which may also have a long-lasting impact on executive functioning. The present study investigated the neural activity of 28 young adults from the Ottawa Prenatal Prospective Study (OPPS) using functional magnetic resonance imaging (fMRI). The purpose of this study was to discover the impact of regular low-level alcohol consumption on response inhibition as the participants performed a Go/No-Go task. Results indicated that, despite a lack of performance differences, young adults who use alcohol on a regular basis differ significantly from those who do not use alcohol regularly (if at all) with respect to their neural activity as the circuitry engaged in response inhibition is being challenged. Specifically, areas that showed significantly more activation in users compared to controls included the left hippocampus, parahippocampal gyrus, superior frontal gyrus, precentral gyrus, right superior parietal lobule, and the cerebellum. These results suggest that even in low amounts, regular consumption of alcohol may have a significant impact on neurophysiological functioning during response inhibition in the developing brain of youth.

Prenatal marijuana exposure impacts executive functioning into young adulthood: An fMRI study.

Understanding the potentially harmful long term consequences of prenatal marijuana exposure is important given the increase in number of pregnant women smoking marijuana to relieve morning sickness. Altered executive functioning is one area of research that has suggested negative consequences of prenatal marijuana exposure into adolescence. Investigating if these findings continue into young adulthood and exploring the neural basis of these effects was the purpose of this research. Thirty one young adults (ages 18-22years) from the longitudinal Ottawa Prenatal Prospective Study (OPPS) underwent functional magnetic resonance imaging (fMRI) during four tasks; 1) Visuospatial 2-Back, 2) Go/NoGo, 3) Letter 2-Back and 4) Counting Stroop task. Sixteen participants were prenatally exposed to marijuana while 15 had no prenatal marijuana exposure. Task performance was similar for both groups but blood flow was significantly different between the groups. This paper presents the results for all 4 tasks, highlighting the consistently increased left posterior brain activity in the prenatally exposed group compared with the control group. These alterations in neurophysiological functioning of young adults prenatally exposed to marijuana emphasizes the importance of education for women in child bearing years, as well as for policy makers and physicians interested in the welfare of both the pregnant women and their offspring's future success.

The relationship between mindfulness, pain intensity, pain catastrophizing, depression, and quality of life among cancer survivors living with chronic neuropathic pain.

PURPOSE: This study aims to examine if mindfulness is associated with pain catastrophizing, depression, disability, and health-related quality of life (HRQOL) in cancer survivors with chronic neuropathic pain (CNP). METHOD: We conducted a cross-sectional survey with cancer survivors experiencing CNP. Participants (n = 76) were men (24 %) and women (76 %) with an average age of 56.5 years (SD = 9.4). Participants were at least 1 year post-treatment, with no evidence of cancer, and with symptoms of neuropathic pain for more than three months. Participants completed the Five Facets Mindfulness Questionnaire (FFMQ), along with measures of pain intensity, pain catastrophizing, pain interference, depression, and HRQOL. RESULTS: Mindfulness was negatively correlated with pain intensity, pain catastrophizing, pain interference, and depression, and it was positively correlated with mental health-related HRQOL. Regression analyses demonstrated that mindfulness was a negative predictor of pain intensity and depression and a positive predictor of mental HRQOL after controlling for pain catastrophizing, age, and gender. The two mindfulness facets that were most consistently associated with better outcomes were non-judging and acting with awareness. Mindfulness significantly moderated the relationships between pain intensity and pain catastrophizing and between pain intensity and pain interference. CONCLUSION: It appears that mindfulness mitigates the impact of pain experiences in cancer survivors experiencing CNP post-treatment. IMPLICATIONS FOR CANCER SURVIVORS: This study suggests that mindfulness is associated with better adjustment to CNP. This provides the foundation to explore whether mindfulness-based interventions improve quality of life among cancer survivors living with CNP.

Effects of low-level alcohol use on cognitive interference: an fMRI study in young adults.

Alcohol consumption is widely known to adversely affect human health. Its neuropathology is largely evident in the cerebellum and frontal lobes, particularly in the immature brains of adolescents and young adults. It may also have a long-lasting impact on executive functioning. The Ottawa Prenatal Prospective Study (OPPS) has followed participants over 20 years, from birth to young adulthood, and has collected data on potentially confounding lifestyle variables, such as prenatal drug exposure and current drug use. The present study investigated the neural activity of 29 young adults from the OPPS using fMRI. The main objective was to discover the impact of regular low-level alcohol consumption on the cognitive interference of these participants, as they performed a Counting Stroop task. Results indicated that, despite a lack of performance differences, young adults who use alcohol on a regular basis differ significantly from non-users with respect to their neural activity as they perform this task. Areas that were significantly more activated in users compared to non-users included the cerebellum, thalamus, fusiform gyrus, prefrontal cortex, and precuneus. The observed activity suggests a significant impact of early alcohol use on neurocognitive functioning despite relatively low levels of alcohol consumption.

Comparative evaluation of group-based mindfulness-based stress reduction and cognitive behavioral therapy for the treatment and management of chronic pain disorders: protocol for a systematic review and meta-analysis with indirect comparisons.

BACKGROUND: Chronic pain disorders impact the physical, psychological, social, and financial well-being of between 10%-30% of Canadians. The primary aims of psychological interventions targeting chronic pain disorders are to reduce patients' pain-related disability and to improve their quality of life. Cognitive behavioral therapy (CBT) is the prevailing treatment for chronic pain, however mindfulness-based stress reduction (MBSR) has displayed promise as an alternative treatment option. The objective of this systematic review and meta-analysis is to compare MBSR to CBT in their relative ability to reduce pain-related disability and intensity, to alleviate emotional distress, and to improve global functioning in chronic pain patients. METHODS/DESIGN: We will conduct a systematic review with meta-analyses to compare MBSR to CBT in the treatment of chronic pain disorders in adults. We will report our review according to the recommendations provided by the PRISMA statement. Randomized studies will be included and the literature search will comprise Ovid MEDLINE®, Ovid MEDLINE® In-Process & Other Non-Indexed Citations, Embase Classic+Embase, PsycINFO, the Cochrane Library on Wiley, including CENTRAL, Cochrane Database of Systematic Reviews, DARE, and HTA. Study selection and data extraction will be conducted by independent investigators and in duplicate. Outcomes of interest will include pain interference, pain intensity, emotional functioning, and patient global impression of change. The Cochrane risk of bias tool will be used to assess risk of bias of included studies. As we anticipate that scales used to measure participant responses will be related but varied from study to study, standardized mean differences will be used to compare effect sizes between treatment modalities. Given the possibility of little or no head-to-head evidence comparing MBSR with CBT, we will use indirect treatment comparison methodology to assess the relative effectiveness of these interventions. DISCUSSION: The findings from this study will assist patients and treatment providers to make informed decisions regarding evidence-based treatment selection for chronic pain disorders. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014009356.

Translating the impact of exercise on cognition: methodological issues in animal research.

Physical exercise and fitness have been proposed as potential factors that promote healthy cognitive aging. Some of the support for this hypothesis has come from animal research. Animal studies are also used to propose the physiological mechanisms underlying the cognitive performance improvement associated with exercise. In the present review and meta-analysis, we discuss several methodological problems that limit the contribution of animal studies to the understanding of the putative effects of exercise on cognitive aging. We suggest that the most likely measure to equate exercise intensity in rodent and humans may be oxygen consumption (VO2) because observed values are surprisingly similar in young and older rodents and humans. For practical reasons, several animal studies use young rodents kept in social isolation. We show that social isolation is associated with an enhanced impact of exercise on cognitive performance but not on some physiological measures thought to mediate the effect of exercise. Surprisingly, two months or more of exercise intervention appeared to be ineffective to promote cognitive performance compared to shorter durations. We argue that impact of exercise in socially isolated animals is explained by an alleviation of environmental impoverishment as much as an effect of physical exercise. It is possible that the introduction of exercise in rodents is partly mediated by environmental changes. It may explain why larger effects are observed for the shorter durations of exercise while much smaller effects are found after longer periods of exercise.

An examination of early neural and cognitive alterations in hippocampal-spatial function of ghrelin receptor-deficient rats.

Ghrelin, a hormone implicated in the regulation of feeding and energy balance, has also been associated with neural function underlying learning and memory. These effects are thought to be mediated by ghrelin targeting receptors at extra hypothalamic sites such as the hippocampus. Exogenous ghrelin administration increases dendritic spine density in the hippocampal CA1 region and neurogenesis in the dentate gyrus (DG), while improving memory in rats. In the present study, we sought to determine whether rats lacking the ghrelin receptor would show early neural or cognitive decline measured via hippocampal integrity (spine density and neurogenesis) and spatial learning and memory. As such, we used young and middle-aged adult rats with mutations to the gene encoding for the ghrelin receptor (GHS-R KO) and wildtype (WT) littermates to determine differences in performance on hippocampal-dependent tasks (the water maze and radial arm maze). In addition, we examined the hippocampal dentate gyrus of these rats for differences in dendritic spine density and cell proliferation (doublecortin). Overall, results demonstrated that spine density and doublecortin staining in the dentate gyrus of the young GHS-R KO group was similar to that seen in middle-aged groups (both KO and WT) and lower than the young WT group. Middle-aged GHS-R KO and WT groups showed deficits on the radial arm maze food-motivated task but not the water maze task. These data suggest that impaired ghrelin signaling leads to an early onset decrement in hippocampal structural integrity that may manifest in non- spatial-related behavioral deficits.