Etiological Factors and Symptom Triggers in Functional Motor Symptoms and Functional Seizures: A Pilot Investigation.

OBJECTIVE: This study examined etiological factors and symptom triggers of functional motor symptoms (FMS) or functional seizures (FS) and assessed potential relationships with relevant clinical features (i.e., functional symptoms, quality of life, and general functioning). METHODS: Seventeen participants with FMS or FS and 17 healthy control participants underwent an in-depth clinical interview and completed questionnaires assessing adverse life events, psychological and physical symptoms, alexithymia, autistic traits, illness perceptions, health-related quality of life (HRQoL), and work and social functioning. RESULTS: Participants with FMS or FS perceived various causes of the disorder, including physical symptoms (65%), emotional problems (53%), adverse life events (47%), and work-related factors (29%). Triggers of FMS and FS included physical activity or exertion (59%), stress and emotions (59%), sensory experiences (47%), and fatigue (41%). Compared with healthy control participants, participants with FMS or FS reported more adverse events during adolescence and higher levels of alexithymia, somatoform dissociation, psychological dissociation (disengagement, depersonalization, and derealization), anxiety, depression, and physical symptoms. Participants with FMS or FS had worse HRQoL than healthy control participants and impaired work and social functioning. There were inverse associations between HRQoL scores and somatoform dissociation, anxiety, and adverse life events. CONCLUSIONS: Participants with FMS or FS reported diverse biopsychosocial etiological factors and symptom triggers. Ongoing psychological symptoms and lifetime adverse experiences were associated with worse HRQoL. Future studies will examine these factors in larger samples of individuals with FMS or FS to better understand their shared and distinct etiological underpinnings.

Mother-infant interaction and infant development in women at risk of postpartum psychosis with and without a postpartum relapse.

BACKGROUND: This study aimed to investigate mother-infant interaction and infant development in women at-risk of postpartum psychosis (PP), with and without a postpartum relapse. METHODS: 103 women (and their offspring) were included, 43 at-risk-of-PP because of a diagnosis of bipolar disorder, schizoaffective disorder or previous PP, and 60 with no current/previous mental illness or family history of PP. Of the at-risk women, 18 developed a psychiatric relapse within 4 weeks after delivery (AR-unwell), while 25 remained symptom-free (AR-well). Mother-infant interaction was assessed using the CARE-Index at 8 weeks' and 12 months' postpartum and infant development using the Bayley-III at 12 months' postpartum. RESULTS: Women at-risk-of-PP as a group, regardless of whether they developed a psychiatric relapse within 4 weeks after delivery, had less synchronous mother-infant interactions and had infants with less optimal cognitive, language, motor and socio-emotional development than healthy controls. In particular, boys of at-risk women had the lowest scores in cognitive, language and motor development and in mother-infant interaction, while girls of the at-risk women had the lowest scores in socio-emotional development. The synchrony in the dyad predicted infant cognitive and language development. There was no evidence for a difference in mother-infant interaction nor in infant development between the AR-unwell and AR-well groups. CONCLUSIONS: These results suggest that, while there is a lack of evidence that an early postpartum relapse in women at-risk-of-PP could represent a risk for the infant per se, maternal risk for PP may be associated with less optimal mother-infant interaction and infant development.

Preliminary evidence that ketamine alters anterior cingulate resting-state functional connectivity in depressed individuals.

Activity changes within the anterior cingulate cortex (ACC) are implicated in the antidepressant effects of ketamine, but the ACC is cytoarchitectonically and functionally heterogeneous and ketamine's effects may be subregion specific. In the context of a double-blind randomized placebo-controlled crossover trial investigating the clinical and resting-state fMRI effects of intravenous ketamine vs. placebo in patients with treatment resistant depression (TRD) vs. healthy volunteers (HV), we used seed-based resting-state functional connectivity (rsFC) analyses to determine differential changes in subgenual ACC (sgACC), perigenual ACC (pgACC) and dorsal ACC (dACC) rsFC two days post-infusion. Across cingulate subregions, ketamine differentially modulated rsFC to the right insula and anterior ventromedial prefrontal cortex, compared to placebo, in TRD vs. HV; changes to pgACC-insula connectivity correlated with improvements in depression scores. Post-hoc analysis of each cingulate subregion separately revealed differential modulation of sgACC-hippocampal, sgACC-vmPFC, pgACC-posterior cingulate, and dACC-supramarginal gyrus connectivity. By comparing rsFC changes following ketamine vs. placebo in the TRD group alone, we found that sgACC rsFC was most substantially modulated by ketamine vs. placebo. Changes to sgACC-pgACC, sgACC-ventral striatal, and sgACC-dACC connectivity correlated with improvements in anhedonia symptoms. This preliminary evidence suggests that accurate segmentation of the ACC is needed to understand the precise effects of ketamine's antidepressant and anti-anhedonic action.

Unravelling the influence of affective stimulation on functional neurological symptoms: a pilot experiment examining potential mechanisms.

BACKGROUND: Differences in affective processing have previously been shown in functional neurological disorder (FND); however, the mechanistic relevance is uncertain. We tested the hypotheses that highly arousing affective stimulation would result in elevated subjective functional neurological symptoms (FNS), and this would be associated with elevated autonomic reactivity. The possible influence of cognitive detachment was also explored. METHOD: Individuals diagnosed with FND (motor symptoms/seizures; n=14) and healthy controls (n=14) viewed Positive, Negative and Neutral images in blocks, while passively observing the stimuli ('Watch') or detaching themselves ('Distance'). The FND group rated their primary FNS, and all participants rated subjective physical (arousal, pain, fatigue) and psychological states (positive/negative affect, dissociation), immediately after each block. Skin conductance (SC) and heart rate (HR) were monitored continuously. RESULTS: FNS ratings were higher after Negative compared with Positive and Neutral blocks in the FND group (p=0.002, ηp 2=0.386); however, this effect was diminished in the Distance condition relative to the Watch condition (p=0.018, ηp 2=0.267). SC and/or HR correlated with FNS ratings in the Negative-Watch and Neutral-Distance conditions (r values=0.527-0.672, p values=0.006-0.035). The groups did not differ in subjective affect or perceived arousal (p values=0.541-0.919, ηp 2=<0.001-0.015). CONCLUSIONS: Emotionally significant events may exert an influence on FNS which is related to autonomic activation rather than altered subjective affect or perceived arousal. This influence may be modulated by cognitive detachment. Further work is needed to determine the relevance and neural bases of these processes in specific FND phenotypes.

Rapid white matter changes in children with conduct problems during a parenting intervention.

Studies report that the microstructural integrity of the uncinate fasciculus (UF; connecting the anterior temporal lobe to the orbitofrontal cortex) is abnormal in adults with psychopathy and children with conduct problems (CP), especially those with high callous-unemotional (CU) traits. However, it is unknown if these abnormalities are 'fixed' or 'reversible'. Therefore, we tested the hypothesis that a reduction in CP symptoms, following a parenting intervention, would be associated with altered microstructural integrity in the UF. Using diffusion tensor imaging tractography we studied microstructural differences (mean diffusivity (MD) and radial diffusivity (RD)) in the UF of 43 typically developing (TD) and 67 boys with CP before and after a 14-week parenting intervention. We also assessed whether clinical response in CP symptoms or CU traits explained changes in microstructure following the intervention. Prior to intervention, measures of MD and RD in the UF were increased in CP compared to TD boys. Following intervention, we found that the CP group had a significant reduction in RD and MD. Further, these microstructural changes were driven by the group of children whose CU traits improved (but not CP symptoms as hypothesized). No significant microstructural changes were observed in the TD group. Our findings suggest, for the first time, that microstructural abnormalities in the brains of children with CP may be reversible following parenting intervention.

Opioid Mechanisms and the Treatment of Depression.

Opioid receptors are widely expressed in the brain, and the opioid system has a key role in modulating mood, reward processing and stress responsivity. There is mounting evidence that the endogenous opioid system may be dysregulated in depression and that drug treatments targeting mu, delta and kappa opioid receptors may show antidepressant potential. The mechanisms underlying the therapeutic effects of opioid system engagement are complex and likely multi-factorial. This chapter explores various pathways through which the modulation of the opioid system may influence depression. These include impacts on monoaminergic systems, the regulation of stress and the hypothalamic-pituitary-adrenal axis, the immune system and inflammation, brain-derived neurotrophic factors, neurogenesis and neuroplasticity, social pain and social reward, as well as expectancy and placebo effects. A greater understanding of the diverse mechanisms through which opioid system modulation may improve depressive symptoms could ultimately aid in the development of safe and effective alternative treatments for individuals with difficult-to-treat depression.

Acute effects of mifepristone on emotional processing related brain activity: A functional MRI study.

The Hypothalamic-pituitary-adrenal (HPA) axis plays an important role in the pathophysiology of mood disorders, and preliminary data suggests that glucocorticoid receptor (GR) antagonism may be an important therapeutic mechanism. The effects of modulating HPA axis function on emotional processing related brain activity, which may be abnormal in depressed mood, is poorly understood. This study used a pharmacological functional magnetic resonance imaging (fMRI) design to determine the effects of the GR and progesterone receptor antagonist mifepristone on emotional faces processing task related brain activations in 19 right-handed healthy male participants. Each participant received 600 mg mifepristone or placebo on two separate imaging days and then performed an emotional processing fMRI task four hours later. The effect of mifepristone on task related brain activations was determined using Region-of-Interest (ROI) analyses and an exploratory whole brain voxel-wise analyses. No significant changes were observed in the defined ROIs (amygdala, anterior cingulate cortex, insula) or in the exploratory whole brain analyses that was associated with mifepristone administration in either the angry vs happy faces or angry and happy faces vs implicit baseline contrasts. Task reaction times and accuracy were similar in both mifepristone and placebo conditions (all p > 0.05). Our study failed to show significant evidence of modulation of emotional processing related brain activity associated with acute mifepristone administration. Future research should use fMRI to investigate the longer-term administration effects of mifepristone on mood in healthy participants and people with mood disorders to provide a deeper understanding of the potential effects on depressive symptoms.

Objective and subjective neurocognitive functioning in functional motor symptoms and functional seizures: preliminary findings.

INTRODUCTION: This study aimed to provide a preliminary assessment of objective and subjective neurocognitive functioning in individuals with functional motor symptoms (FMS) and/or functional seizures (FS). We tested the hypotheses that the FMS/FS group would display poorer objective attentional and executive functioning, altered social cognition, and reduced metacognitive accuracy. METHOD: Individuals with FMS/FS (n = 16) and healthy controls (HCs, n = 17) completed an abbreviated CANTAB battery, and measures of intellectual functioning, subjective cognitive complaints, performance validity, and comorbid symptoms. Subjective performance ratings were obtained to assess local metacognitive accuracy. RESULTS: The groups were comparable in age (p = 0.45), sex (p = 0.62), IQ (p = 0.57), and performance validity (p-values = 0.10-0.91). We observed no impairment on any CANTAB test in this FMS/FS sample compared to HCs, although the FMS/FS group displayed shorter reaction times on the Emotional Bias task (anger) (p = 0.01, np2 = 0.20). The groups did not differ in subjective performance ratings (p-values 0.15). Whilst CANTAB attentional set-shifting performance (total trials/errors) correlated with subjective performance ratings in HCs (p-values<0.005, rs = -0.85), these correlations were non-significant in the FMS/FS sample (p-values = 0.10-0.13, rs-values = -0.46-0.50). The FMS/FS group reported more daily cognitive complaints than HCs (p = 0.006, g = 0.92), which were associated with subjective performance ratings on CANTAB sustained attention (p = 0.001, rs = -0.74) and working memory tests (p < 0.001, rs = -0.75), and with depression (p = 0.003, rs = 0.70), and somatoform (p = 0.003, rs = 0.70) and psychological dissociation (p-values<0.005, rs-values = 0.67-0.85). CONCLUSIONS: These results suggest a discordance between objective and subjective neurocognitive functioning in this FMS/FS sample, reflecting intact test performance alongside poorer subjective cognitive functioning. Further investigation of neurocognitive functioning in FND subgroups is necessary.

Interoception in functional motor symptoms and functional seizures: Preliminary evidence of intact accuracy alongside reduced insight and altered sensibility.

Altered interoception may be a pathophysiological mechanism in functional neurological disorder (FND). However, findings have been inconsistent across interoceptive dimensions in FND including functional motor symptoms (FMS) and seizures (FS). Here, individuals with FMS/FS (n = 17) and healthy controls (HC, n = 17) completed measures of interoceptive accuracy and insight (adapted heartbeat tracking task [HTT] with confidence ratings), a time estimation control task (TET) and the Multidimensional Assessment of Interoceptive Awareness-2 (MAIA-2) to assess interoceptive sensibility. The groups did not differ in interoceptive accuracy (p = 1.00, g = 0.00) or confidence (p = .99, g = 0.004), although the FMS/FS group displayed lower scores on the "Not-Distracting" (p < .001, g = 1.42) and "Trusting" (p = .005, g = 1.17) MAIA-2 subscales, relative to HCs. The groups did not differ in TET performance (p = .82, g = 0.08). There was a positive relationship between HTT accuracy and confidence (insight) in HCs (r = .61, p = .016) but not in FMS/FS (r = 0.11, p = .69). HTT confidence was positively correlated with MAIA-2 "Self-Regulation" (r = 0.77, p = .002) and negatively correlated with FND symptom severity (r = -0.84, p < .001) and impact (r = -0.86, p < .001) in FMS/FS. Impaired interoceptive accuracy may not be a core feature in FMS/FS, but reduced insight and altered sensibility may be relevant. Reduced certainty in self-evaluations of bodily experiences may contribute to the pathogenesis of FND symptoms.

Ketamine-induced changes in resting state connectivity, 2 h after the drug administration in patients with remitted depression.

BACKGROUND: Resting state connectivity studies link ketamine's antidepressant effects with normalisation of the brain connectivity changes that are observed in depression. These changes, however, usually co-occur with improvement in depressive symptoms, making it difficult to attribute these changes to ketamine's effects per se. AIMS: Our aim is to examine the effects of ketamine in brain connectivity, 2 h after its administration in a cohort of volunteers with remitted depression. Any significant changes observed in this study could provide insight of ketamine's antidepressant mechanism as they are not accompanied by symptom changes. METHODS: In total, 35 participants with remitted depression (21 females, mean age = 28.5 years) participated in a double-blind, placebo-controlled study of ketamine (0.5 mg/kg) or saline. Resting state scans were acquired approximately 2 h after the ketamine infusion. Brain connectivity was examined using a seed-based approach (ventral striatum, amygdala, hippocampus, posterior cingulate cortex and subgenual anterior cingulate cortex (sgACC)) and a brain network analysis (independent component analysis). RESULTS: Decreased connectivity between the sgACC and the amygdala was observed approximately 2 h after the ketamine infusion, compared to placebo (pFWE < 0.05). The executive network presented with altered connectivity with different cortical and subcortical regions. Within the network, the left hippocampus and right amygdala had decreased connectivity (pFWE < 0.05). CONCLUSIONS: Our findings support a model whereby ketamine would change the connectivity of brain areas and networks that are important for cognitive processing and emotional regulation. These changes could also be an indirect indicator of the plasticity changes induced by the drug.

Single-dose effects of methylphenidate and atomoxetine on functional connectivity during an n-back task in boys with ADHD.

RATIONALE: Working memory deficits and associated neurofunctional abnormalities are frequently reported in attention-deficit/hyperactivity disorder (ADHD). Methylphenidate and atomoxetine improve working memory performance and increase activation of regions under-functioning in ADHD. Additionally, methylphenidate has been observed to modulate functional networks involved in working memory. No research, however, has examined the effects of atomoxetine or compared the two drugs. OBJECTIVES: This study aimed to test methylphenidate and atomoxetine effects on functional connectivity during working memory in boys with ADHD. METHODS: We tested comparative effects of methylphenidate and atomoxetine on functional connectivity during the n-back task in 19 medication-naïve boys with ADHD (10-15 years old) relative to placebo and assessed potential normalisation effects of brain dysfunctions under placebo relative to 20 age-matched neurotypical boys. Patients were scanned in a randomised, double-blind, cross-over design under single doses of methylphenidate, atomoxetine, and placebo. Controls were scanned once, unmedicated. RESULTS: Patients under placebo showed abnormally increased connectivity between right superior parietal gyrus (rSPG) and left central operculum/insula. This hyperconnectivity was not observed when patients were under methylphenidate or atomoxetine. Furthermore, under methylphenidate, patients showed increased connectivity relative to controls between right middle frontal gyrus (rMFG) and cingulo-temporo-parietal and striato-thalamic regions, and between rSPG and cingulo-parietal areas. Interrogating these networks within patients revealed increased connectivity between both rMFG and rSPG and right supramarginal gyrus under methylphenidate relative to placebo. Nonetheless, no differences across drug conditions were observed within patients at whole brain level. No drug effects on performance were observed. CONCLUSIONS: This study shows shared modulating effects of methylphenidate and atomoxetine on parieto-insular connectivity but exclusive effects of methylphenidate on connectivity increases in fronto-temporo-parietal and fronto-striato-thalamic networks in ADHD.

Molecular-enriched functional connectivity in the human brain using multiband multi-echo simultaneous ASL/BOLD fMRI.

Receptor-enriched analysis of functional connectivity by targets (REACT) is a strategy to enrich functional MRI (fMRI) data with molecular information on the neurotransmitter distribution density in the human brain, providing a biological basis to the functional connectivity (FC) analysis. Although this approach has been used in BOLD fMRI studies only so far, extending its use to ASL imaging would provide many advantages, including the more direct link of ASL with neuronal activity compared to BOLD and its suitability for pharmacological MRI studies assessing drug effects on baseline brain function. Here, we applied REACT to simultaneous ASL/BOLD resting-state fMRI data of 29 healthy subjects and estimated the ASL and BOLD FC maps related to six molecular systems. We then compared the ASL and BOLD FC maps in terms of spatial similarity, and evaluated and compared the test-retest reproducibility of each modality. We found robust spatial patterns of molecular-enriched FC for both modalities, moderate similarity between BOLD and ASL FC maps and comparable reproducibility for all but one molecular-enriched functional networks. Our findings showed that ASL is as informative as BOLD in detecting functional circuits associated with specific molecular pathways, and that the two modalities may provide complementary information related to these circuits.

Abnormal Glutamatergic and Serotonergic Connectivity in Visual Snow Syndrome and Migraine with Aura.

OBJECTIVE: Neuropharmacological changes in visual snow syndrome (VSS) are poorly understood. We aimed to use receptor target maps combined with resting functional magnetic resonance imaging (fMRI) data to identify which neurotransmitters might modulate brain circuits involved in VSS. METHODS: We used Receptor-Enriched Analysis of Functional Connectivity by Targets (REACT) to estimate and compare the molecular-enriched functional networks related to 5 neurotransmitter systems of patients with VSS (n = 24), healthy controls (HCs; n = 24), and migraine patients ([MIG], n = 25, 15 of whom had migraine with aura [MwA]). For REACT we used receptor density templates for the transporters of noradrenaline, dopamine, and serotonin, GABA-A and NMDA receptors, as well as 5HT1B and 5HT2A receptors, and estimated the subject-specific voxel-wise maps of functional connectivity (FC). We then performed voxel-wise comparisons of these maps among HCs, MIG, and VSS. RESULTS: Patients with VSS had reduced FC in glutamatergic networks localized in the anterior cingulate cortex (ACC) compared to HCs and patients with migraine, and reduced FC in serotoninergic networks localized in the insula, temporal pole, and orbitofrontal cortex compared to controls, similar to patients with migraine with aura. Patients with VSS also showed reduced FC in 5HT2A -enriched networks, largely localized in occipito-temporo-parietal association cortices. As revealed by subgroup analyses, these changes were independent of, and analogous to, those found in patients with migraine with aura. INTERPRETATION: Our results show that glutamate and serotonin are involved in brain connectivity alterations in areas of the visual, salience, and limbic systems in VSS. Importantly, altered serotonergic connectivity is independent of migraine in VSS, and simultaneously comparable to that of migraine with aura, highlighting a shared biology between the disorders. ANN NEUROL 2023;94:873-884.

Temporal profile of intranasal oxytocin in the human autonomic nervous system at rest: An electrocardiography and pupillometry study.

BACKGROUND: Human social behavior is modulated by oxytocin (OT). Intranasal administration of OT (IN-OT) is a noninvasive route shown to elicit changes in the autonomic nervous system (ANS) activity; however, IN-OT's effect on the temporal profile of ANS activity at rest is yet to be described. AIMS: We aimed to describe the temporal profile of IN-OT at six 10-min time windows from 15- to 100-min post-administration in 20 male participants at rest while continuously recording their pupillary in an eyes-open condition and cardiac activity in eyes-open and eyes-closed conditions. METHODS: We used a double-blind, placebo-controlled, within-subjects design study where we extracted two proxies of parasympathetic nervous system (PNS) activity: high-frequency heart rate variability (HF-HRV) and pupillary unrest index (PUI); and a proxy of sympathetic nervous system activity: sample entropy of the pupillary unrest. RESULTS: In the eyes-open condition, we found an effect of IN-OT on the proxies of PNS activity: decreased PUI in the three-time windows post-administration spanning 65-100 min, and as an exploratory finding, an increased HF-HRV in the 80-85 min time window. CONCLUSIONS: We suggest there is a role of OT in PNS regulation that may be consistent with OT's currently theorized role in the facilitation of alertness and approach behavior.

Reduced cortical cerebral blood flow in antipsychotic-free first-episode psychosis and relationship to treatment response.

BACKGROUND: Altered cerebral blood flow (CBF) has been found in people at risk for psychosis, with first-episode psychosis (FEP) and with chronic schizophrenia (SCZ). Studies using arterial spin labelling (ASL) have shown reduction of cortical CBF and increased subcortical CBF in SCZ. Previous studies have investigated CBF using ASL in FEP, reporting increased CBF in striatum and reduced CBF in frontal cortex. However, as these people were taking antipsychotics, it is unclear whether these changes are related to the disorder or antipsychotic treatment and how they relate to treatment response. METHODS: We examined CBF in FEP free from antipsychotic medication (N = 21), compared to healthy controls (N = 22). Both absolute and relative-to-global CBF were assessed. We also investigated the association between baseline CBF and treatment response in a partially nested follow-up study (N = 14). RESULTS: There was significantly lower absolute CBF in frontal cortex (Cohen's d = 0.84, p = 0.009) and no differences in striatum or hippocampus. Whole brain voxel-wise analysis revealed widespread cortical reductions in absolute CBF in large cortical clusters that encompassed occipital, parietal and frontal cortices (Threshold-Free Cluster Enhancement (TFCE)-corrected <0.05). No differences were found in relative-to-global CBF in the selected region of interests and in voxel-wise analysis. Relative-to-global frontal CBF was correlated with percentage change in total Positive and Negative Syndrome Scale after antipsychotic treatment (r = 0.67, p = 0.008). CONCLUSIONS: These results show lower cortical absolute perfusion in FEP prior to starting antipsychotic treatment and suggest relative-to-global frontal CBF as assessed with magnetic resonance imaging could potentially serve as a biomarker for antipsychotic response.

Task-Based Functional Connectivity in Attention-Deficit/Hyperactivity Disorder: A Systematic Review.

Altered neurocognitive functioning is a key feature of attention-deficit/hyperactivity disorder (ADHD), and increasing numbers of studies assess task-based functional connectivity in the disorder. We systematically reviewed and critically appraised functional magnetic resonance imaging (fMRI) task-based functional connectivity studies in ADHD. A systematic search conducted up to September 2020 found 34 studies, including 51 comparisons. Comparisons were divided into investigations of ADHD neuropathology (37 comparing ADHD and typical development, 2 comparing individuals with ADHD and their nonsymptomatic siblings, 2 comparing remitted and persistent ADHD, and 1 exploring ADHD symptom severity) and the effects of interventions (8 investigations of stimulant effects and 1 study of fMRI neurofeedback). Large heterogeneity in study methodologies prevented a meta-analysis; thus, the data were summarized as a narrative synthesis. Across cognitive domains, functional connectivity in the cingulo-opercular, sensorimotor, visual, subcortical, and executive control networks in ADHD consistently differed from neurotypical populations. Furthermore, literature comparing individuals with ADHD and their nonsymptomatic siblings as well as adults with ADHD and their remitted peers showed ADHD-related abnormalities in similar sensorimotor and subcortical (primarily striatal) networks. Interventions modulated those dysfunctional networks, with the most consistent action on functional connections with the striatum, anterior cingulate cortex, occipital regions, and midline default mode network structures. Although methodological issues limited many of the reviewed studies, the use of task-based functional connectivity approaches has the potential to broaden the understanding of the neural underpinnings of ADHD and the mechanisms of action of ADHD treatments.

A Prospective Study of the Impact of Severe Childhood Deprivation on Brain White Matter in Adult Adoptees: Widespread Localized Reductions in Volume But Unaffected Microstructural Organization.

Early childhood neglect can impact brain development across the lifespan. Using voxel-based approaches we recently reported that severe and time-limited institutional deprivation in early childhood was linked to substantial reductions in total brain volume in adulthood, >20 years later. Here, we extend this analysis to explore deprivation-related regional white matter volume and microstructural organization using diffusion-based techniques. A combination of tensor-based morphometry (TBM) analysis and tractography was conducted on diffusion-weighted imaging (DWI) data from 59 young adults who spent between 3 and 41 months in the severely depriving Romanian institutions of the 1980s before being adopted into United Kingdom families, and 20 nondeprived age-matched United Kingdom controls. Independent of total volume, institutional deprivation was associated with smaller volumes in localized regions across a range of white matter tracts including (1) long-ranging association fibers such as bilateral inferior longitudinal fasciculus (ILF), bilateral inferior fronto-occipital fasciculus (IFOF), left superior longitudinal fasciculi (SLFs), and left arcuate fasciculus; (2) tracts of the limbic circuitry including fornix and cingulum; and (3) projection fibers with the corticospinal tract particularly affected. Tractographic analysis found no evidence of altered microstructural organization of any tract in terms of hindrance modulated orientational anisotropy (HMOA), fractional anisotropy (FA), or mean diffusivity (MD). We provide further evidence for the effects of early neglect on brain development and their persistence in adulthood despite many years of environmental enrichment associated with successful adoption. Localized white matter effects appear limited to volumetric changes with microstructural organization unaffected.

Alpha3/alpha2 power ratios relate to performance on a virtual reality shopping task in ageing adults.

Background: Aspects of cognitive function decline with age. This phenomenon is referred to as age-related cognitive decline (ARCD). Improving the understanding of these changes that occur as part of the ageing process can serve to enhance the detection of the more incapacitating neurodegenerative disorders such as Alzheimer's disease (AD). In this study, we employ novel methods to assess ARCD by exploring the utility of the alpha3/alpha2 electroencephalogram (EEG) power ratio - a marker of AD, and a novel virtual reality (VR) functional cognition task - VStore, in discriminating between young and ageing healthy adults. Materials and methods: Twenty young individuals aged 20-30, and 20 older adults aged 60-70 took part in the study. Participants underwent resting-state EEG and completed VStore and the Cogstate Computerised Cognitive Battery. The difference in alpha3/alpha2 power ratios between the age groups was tested using t-test. In addition, the discriminatory accuracy of VStore and Cogstate were compared using logistic regression and overlying receiver operating characteristic (ROC) curves. Youden's J statistic was used to establish the optimal threshold for sensitivity and specificity and model performance was evaluated with the DeLong's test. Finally, alpha3/alpha2 power ratios were correlated with VStote and Cogstate performance. Results: The difference in alpha3/alpha2 power ratios between age cohorts was not statistically significant. On the other hand, VStore discriminated between age groups with high sensitivity (94%) and specificity (95%) The Cogstate Pre-clinical Alzheimer's Battery achieved a sensitivity of 89% and specificity of 60%, and Cogstate Composite Score achieved a sensitivity of 83% and specificity of 85%. The differences between the discriminatory accuracy of VStore and Cogstate models were statistically significant. Finally, high alpha3/alpha2 power ratios correlated strongly with VStore (r = 0.73), the Cogstate Pre-clinical Alzheimer's Battery (r = -0.67), and Cogstate Composite Score (r = -0.76). Conclusion: While we did not find evidence that the alpha3/alpha2 power ratio is elevated in healthy ageing individuals compared to young individuals, we demonstrated that VStore can classify age cohorts with high accuracy, supporting its utility in the assessment of ARCD. In addition, we found preliminary evidence that elevated alpha3/alpha2 power ratio may be linked to lower cognitive performance.

The opioid system in depression.

Opioid receptors are widely distributed throughout the brain and play an essential role in modulating aspects of human mood, reward, and well-being. Accumulating evidence indicates the endogenous opioid system is dysregulated in depression and that pharmacological modulators of mu, delta, and kappa opioid receptors hold potential for the treatment of depression. Here we review animal and clinical data, highlighting evidence to support: dysregulation of the opioid system in depression, evidence for opioidergic modulation of behavioural processes and brain regions associated with depression, and evidence for opioidergic modulation in antidepressant responses. We evaluate clinical trials that have examined the safety and efficacy of opioidergic agents in depression and consider how the opioid system may be involved in the effects of other treatments, including ketamine, that are currently understood to exert antidepressant effects through non-opioidergic actions. Finally, we explore key neurochemical and molecular mechanisms underlying the potential therapeutic effects of opioid system engagement, that together provides a rationale for further investigation into this relevant target in the treatment of depression.