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.

Poor response to methylphenidate is associated with a smaller dorsal attentive network in adult Attention-Deficit/Hyperactivity Disorder (ADHD).

Stimulants, such as methylphenidate (MPH), are effective in treating attention-deficit/hyperactivity disorder (ADHD), but there is individual variability in response, especially in adults. To improve outcomes, we need to understand the factors associated with adult treatment response. This longitudinal study investigated whether pre-treatment anatomy of the fronto-striatal and fronto-parietal attentional networks was associated with MPH treatment response. 60 adults with ADHD underwent diffusion brain imaging before starting MPH treatment, and response was measured at two months. We tested the association between brain anatomy and treatment response by using regression-based approaches; and compared the identified anatomical characteristics with those of 20 matched neurotypical controls in secondary analyses. Finally, we explored whether combining anatomical with clinical and neuropsychological data through machine learning provided a more comprehensive profile of factors associated with treatment response. At a group level, a smaller left dorsal superior longitudinal fasciculus (SLF I), a tract responsible for the voluntary control of attention, was associated with a significantly lower probability of being responders to two-month MPH-treatment. The association between the volume of the left SLF I and treatment response was driven by improvement on both inattentive and hyperactive/impulsive symptoms. Only non-responders significantly differed from controls in this tract metric. Finally, our machine learning approach identified clinico-neuropsychological factors associated with treatment response, such as higher cognitive performance and symptom severity at baseline. These novel findings add to our understanding of the pathophysiological mechanisms underlying response to MPH, pointing to the dorsal attentive network as playing a key role.

Sexual dimorphism in the social behaviour of Cntnap2-null mice correlates with disrupted synaptic connectivity and increased microglial activity in the anterior cingulate cortex.

A biological understanding of the apparent sex bias in autism is lacking. Here we have identified Cntnap2 KO mice as a model system to help better understand this dimorphism. Using this model, we observed social deficits in juvenile male KO mice only. These male-specific social deficits correlated with reduced spine densities of Layer 2/3 and Layer 5 pyramidal neurons in the Anterior Cingulate Cortex, a forebrain region prominently associated with the control of social behaviour. Furthermore, in male KO mice, microglia showed an increased activated morphology and phagocytosis of synaptic structures compared to WT mice, whereas no differences were seen in female KO and WT mice. Our data suggest that sexually dimorphic microglial activity may be involved in the aetiology of ASD, disrupting the development of neural circuits that control social behaviour by overpruning synapses at a developmentally critical period.

White matter alterations in Attention-Deficit/Hyperactivity Disorder (ADHD): a systematic review of 129 diffusion imaging studies with meta-analysis.

Aberrant anatomical brain connections in attention-deficit/hyperactivity disorder (ADHD) are reported inconsistently across diffusion weighted imaging (DWI) studies. Based on a pre-registered protocol (Prospero: CRD42021259192), we searched PubMed, Ovid, and Web of Knowledge until 26/03/2022 to conduct a systematic review of DWI studies. We performed a quality assessment based on imaging acquisition, preprocessing, and analysis. Using signed differential mapping, we meta-analyzed a subset of the retrieved studies amenable to quantitative evidence synthesis, i.e., tract-based spatial statistics (TBSS) studies, in individuals of any age and, separately, in children, adults, and high-quality datasets. Finally, we conducted meta-regressions to test the effect of age, sex, and medication-naïvety. We included 129 studies (6739 ADHD participants and 6476 controls), of which 25 TBSS studies provided peak coordinates for case-control differences in fractional anisotropy (FA)(32 datasets) and 18 in mean diffusivity (MD)(23 datasets). The systematic review highlighted white matter alterations (especially reduced FA) in projection, commissural and association pathways of individuals with ADHD, which were associated with symptom severity and cognitive deficits. The meta-analysis showed a consistent reduced FA in the splenium and body of the corpus callosum, extending to the cingulum. Lower FA was related to older age, and case-control differences did not survive in the pediatric meta-analysis. About 68% of studies were of low quality, mainly due to acquisitions with non-isotropic voxels or lack of motion correction; and the sensitivity analysis in high-quality datasets yielded no significant results. Findings suggest prominent alterations in posterior interhemispheric connections subserving cognitive and motor functions affected in ADHD, although these might be influenced by non-optimal acquisition parameters/preprocessing. Absence of findings in children may be related to the late development of callosal fibers, which may enhance case-control differences in adulthood. Clinicodemographic and methodological differences were major barriers to consistency and comparability among studies, and should be addressed in future investigations.

Selective Amygdala Hypoactivity to Fear in Boys With Persistent Conduct Problems After Parent Training.

BACKGROUND: Parenting interventions reduce antisocial behavior (ASB) in some children with conduct problems (CPs), but not others. Understanding the neural basis for this disparity is important because persistent ASB is associated with lifelong morbidity and places a huge burden on our health and criminal justice systems. One of the most highly replicated neural correlates of ASB is amygdala hypoactivity to another person's fear. We aimed to assess whether amygdala hypoactivity to fear in children with CPs is remediated following reduction in ASB after successful treatment and/or if it is a marker for persistent ASB. METHODS: We conducted a prospective, case-control study of boys with CPs and typically developing (TD) boys. Both groups (ages 5-10 years) completed 2 magnetic resonance imaging sessions (18 ± 5.8 weeks apart) with ASB assessed at each visit. Participants included boys with CPs following referral to a parenting intervention group and TD boys recruited from the same schools and geographical regions. Final functional magnetic resonance imaging data were available for 36 TD boys and 57 boys with CPs. Boys with CPs were divided into those whose ASB improved (n = 27) or persisted (n = 30) following the intervention. Functional magnetic resonance imaging data assessing fear reactivity were then analyzed using a longitudinal group (TD/improving CPs/persistent CPs) × time point (pre/post) design. RESULTS: Amygdala hypoactivity to fear was observed only in boys with CPs who had persistent ASB and was absent in those whose ASB improved following intervention. CONCLUSIONS: Our findings suggest that amygdala hypoactivity to fear is a marker for ASB that is resistant to change following a parenting intervention and a putative target for future treatments.

Mapping myelin in white matter with T1-weighted/T2-weighted maps: discrepancy with histology and other myelin MRI measures.

The ratio of T1-weighted/T2-weighted magnetic resonance images (T1w/T2w MRI) has been successfully applied at the cortical level since 2011 and is now one of the most used myelin mapping methods. However, no reports have explored the histological validity of T1w/T2w myelin mapping in white matter. Here we compare T1w/T2w with ex vivo postmortem histology and in vivo MRI methods, namely quantitative susceptibility mapping (QSM) and multi-echo T2 myelin water fraction (MWF) mapping techniques. We report a discrepancy between T1w/T2w myelin maps of the human corpus callosum and the histology and analyse the putative causes behind such discrepancy. T1w/T2w does not positively correlate with Luxol Fast Blue (LFB)-Optical Density but shows a weak to moderate, yet significant, negative correlation. On the contrary, MWF is strongly and positively correlated with LFB, whereas T1w/T2w and MWF maps are weakly negatively correlated. The discrepancy between T1w/T2w MRI maps, MWF and histological myelin maps suggests caution in using T1w/T2w as a white matter mapping method at the callosal level. While T1w/T2w imaging may correlate with myelin content at the cortical level, it is not a specific method to map myelin density in white matter.

Tissue optimization strategies for high-quality ex vivo diffusion imaging.

Ex vivo diffusion imaging can be used to study healthy and pathological tissue microstructure in the rodent brain with high resolution, providing a link between in vivo MRI and ex vivo microscopy techniques. Major challenges for the successful acquisition of ex vivo diffusion imaging data however are changes in the relaxivity and diffusivity of brain tissue following perfusion fixation. In this study we address this question by examining the combined effects of tissue preparation factors that influence signal-to-noise ratio (SNR) and consequently image quality, including fixative concentration, contrast agent concentration and tissue rehydration time. We present an optimization strategy combining these factors to manipulate the T 1 and T 2 of fixed tissue and maximize SNR efficiency. We apply this strategy in the rat brain, for a diffusion-weighted spin echo protocol with TE = 27 ms on a 9.4 T scanner with a 39 mm volume coil and 660 mT/m 114 mm gradient insert. We used a reduced fixative concentration of 2% paraformaldehyde (PFA), rehydration time more than 20 days, 15 mM Gd-DTPA in perfusate and TR 250 ms. This resulted in a doubling of SNR and an increase in SNR per unit time of 135% in cortical grey matter and 88% in white matter compared with 4% PFA and no contrast agent. This improved SNR efficiency enabled the acquisition of excellent-quality high-resolution (78 µ m isotropic voxel size) diffusion data with b = 4000 s/mm 2 , 30 diffusion directions and a field of view of 40 × 13 × 18 mm3 in less than 4 days. It was also possible to achieve comparable data quality for a standard resolution (150 µ m) diffusion dataset in 2 1 4 h. In conclusion, the tissue optimization strategy presented here may be used to improve SNR, increase spatial resolution and/or allow faster acquisitions in preclinical ex vivo diffusion MRI experiments.

The connectional anatomy of the temporal lobe.

The idea of a temporal lobe separated from the rest of the hemisphere by reason of its unique structural and functional properties is a clinically useful artifact. While the temporal lobe can be safely defined as the portion of the cerebrum lodged in the middle cranial fossa, the pattern of its connections is a more revealing description of its functional subdivisions and specific contribution to higher cognitive functions. This chapter provides an historical overview of the anatomy of the temporal lobe and an updated framework of temporal lobe connections based on tractography studies of human and nonhuman primates and patients with brain disorders. Compared to monkeys, the human temporal lobe shows a relatively increased connectivity with perisylvian frontal and parietal regions and a set of unique intrinsic connections, which may have supported the evolution of working memory, semantic representation, and language in our species. Conversely, the decreased volume of the anterior (limbic) interhemispheric temporal connections in humans is related to a reduced reliance on olfaction and a partial transference of functions from the anterior commissure to the posterior corpus callosum. Overall the novel data from tractography suggest a revision of current dual stream models for visual and auditory processing.

Birth of the blues: emotional sound processing in infants exposed to prenatal maternal depression.

BACKGROUND: Offspring exposed to prenatal maternal depression (PMD) are vulnerable to depression across their lifespan. The underlying cause(s) for this elevated intergenerational risk is most likely complex. However, depression is underpinned by a dysfunctional frontal-limbic network, associated with core information processing biases (e.g. attending more to sad stimuli). Aberrations in this network might mediate transmission of this vulnerability in infants exposed to PMD. In this study, we aimed to explore the association between foetal exposure to PMD and frontal-limbic network function in infancy, hypothesising that, in response to emotional sounds, infants exposed to PMD would exhibit atypical activity in these regions, relative to those not exposed to PMD. METHOD: We employed a novel functional magnetic resonance imaging sequence to compare brain function, whilst listening to emotional sounds, in 78 full-term infants (3-6 months of age) born to mothers with and without a diagnosis of PMD. RESULTS: After exclusion of 19 datasets due to infants waking up, or moving excessively, we report between-group brain activity differences, between 29 infants exposed to PMD and 29 infants not exposed to PMD, occurring in temporal, striatal, amygdala/parahippocampal and frontal regions (p < 0.005). The offspring exposed to PMD exhibited a relative increase in activation to sad sounds and reduced (or unchanged) activation to happy sounds in frontal-limbic clusters. CONCLUSIONS: Findings of a differential response to positive and negative valanced sounds by 3-6 months of age may have significant implications for our understanding of neural mechanisms that underpin the increased risk for later-life depression in this population.

University students with attention deficit hyperactivity disorder (ADHD): a consensus statement from the UK Adult ADHD Network (UKAAN).

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is associated with poor educational outcomes that can have long-term negative effects on the mental health, wellbeing, and socio-economic outcomes of university students. Mental health provision for university students with ADHD is often inadequate due to long waiting times for access to diagnosis and treatment in specialist National Health Service (NHS) clinics. ADHD is a hidden and marginalised disability, and within higher education in the UK, the categorisation of ADHD as a specific learning difference (or difficulty) may be contributing to this. AIMS: This consensus aims to provide an informed understanding of the impact of ADHD on the educational (or academic) outcomes of university students and highlight an urgent need for timely access to treatment and management. METHODS: The UK Adult ADHD Network (UKAAN) convened a meeting of practitioners and experts from England, Wales, and Scotland, to discuss issues that university students with ADHD can experience or present with during their programme of studies and how best to address them. A report on the collective analysis, evaluation, and opinions of the expert panel and published literature about the impact of ADHD on the educational outcomes of university students is presented. RESULTS: A consensus was reached that offers expert advice, practical guidance, and recommendations to support the medical, education, and disability practitioners working with university students with ADHD. CONCLUSIONS: Practical advice, guidance, and recommendations based on expert consensus can inform the identification of ADHD in university students, personalised interventions, and educational support, as well as contribute to existing research in this topic area. There is a need to move away from prevailing notions within higher education about ADHD being a specific learning difference (or difficulty) and attend to the urgent need for university students with ADHD to have timely access to treatment and support. A multimodal approach can be adapted to support university students with ADHD. This approach would view timely access to treatment, including reasonable adjustments and educational support, as having a positive impact on the academic performance and achievement of university students with ADHD.

The medial occipital longitudinal tract supports early stage encoding of visuospatial information.

Visuospatial learning depends on the parahippocampal place area (PPA), a functionally heterogenous area which current visuospatial processing models place downstream from parietal cortex and only from area V4 of early visual cortex (EVC). However, evidence for anatomical connections between the PPA and other EVC areas is inconsistent, and these connections are not discussed in current models. Through a data-driven analysis based on diffusion MRI tractography, we present evidence that the PPA sits at the confluence of two white matter systems. The first conveys information from the retrosplenial complex to the anterior PPA and runs within the cingulum bundle. The second system connects all peripheral EVC areas to the posterior PPA and corresponds to the medial occipital longitudinal tract (MOLT), a white matter pathway that is distinct from the cingulum and that we describe here in detail. Based on further functional connectivity analysis and meta-analytic data, we propose that the MOLT supports early stage encoding of visuospatial information by allowing direct reciprocal exchange between the PPA and EVC. Our findings may improve symptom interpretation in stroke and tumour patients with damage to the medial occipito-temporal region and call for revisiting current visuospatial processing models.

Repercussions of COVID-19-related national lockdown on Emergency Surgery Department: a longitudinal cohort monocentric study.

BACKGROUND: COVID-19 lockdown restrictions in conjunction with the pervasive hospital fear endured by the vast majority of the population played a fundamental role in discouraging access to emergency departments (EDs). We aimed at investigating whether and how the COVID-19 outbreak limited the access to ED and affected urgent surgical activities during and immediately after the 2-month pandemic-related national lockdown. METHODS: Data regarding patients who accessed to the surgical ED were retrospectively collected. Analyzed time-periods included: "pre-COVID-19 era," "COVID-19 era" considered as the period of full national lockdown and "post-COVID-19 era" after easing of lockdown measures. Consecutive emergency surgical procedures and ED admissions before, during and after COVID-19-lockdown were retrieved and analyzed. RESULTS: There was a significant decrease in overall ED admissions and in all-specialty surgical consultations (P<0.01) throughout the outbreak. Once national lockdown was eased, we recorded a subsequent rebound 5-fold rise of emergency surgical procedures compared to COVID-19 group (P=0.011). Time-to-surgery was significantly greater in "COVID-19 era" and "post-COVID-19 era" compared to "pre-COVID-19" group (22.56±4.78, 75.99±15.89 and 16.73±1.76 hours, respectively) (P<0.01). A raised incidence of postoperative complications emerged in the "COVID-19 era" group (37.5%) compared to pre- and post-COVID groups (9.1% and 12.5%, respectively; P<0.001). Mortality rate in the "COVID-19 era" was 31.3% and 7.5% in "post-COVID-19" group (<0.0001). CONCLUSIONS: This study demonstrates the major reduction of emergency surgical procedures and overall, ED admissions caused by COVID-19 pandemic. The raised rate of postoperative complications and mortality might be likely due to the superior severity of surgical conditions observed in the "COVID-19 era" subjects together with a probable deferred pursuit of medical attention.

Differences in Frontal Network Anatomy Across Primate Species.

The frontal lobe is central to distinctive aspects of human cognition and behavior. Some comparative studies link this to a larger frontal cortex and even larger frontal white matter in humans compared with other primates, yet others dispute these findings. The discrepancies between studies could be explained by limitations of the methods used to quantify volume differences across species, especially when applied to white matter connections. In this study, we used a novel tractography approach to demonstrate that frontal lobe networks, extending within and beyond the frontal lobes, occupy 66% of total brain white matter in humans and 48% in three monkey species: vervets (Chlorocebus aethiops), rhesus macaque (Macaca mulatta) and cynomolgus macaque (Macaca fascicularis), all male. The simian-human differences in proportional frontal tract volume were significant for projection, commissural, and both intralobar and interlobar association tracts. Among the long association tracts, the greatest difference was found for tracts involved in motor planning, auditory memory, top-down control of sensory information, and visuospatial attention, with no significant differences in frontal limbic tracts important for emotional processing and social behaviour. In addition, we found that a nonfrontal tract, the anterior commissure, had a smaller volume fraction in humans, suggesting that the disproportionally large volume of human frontal lobe connections is accompanied by a reduction in the proportion of some nonfrontal connections. These findings support a hypothesis of an overall rearrangement of brain connections during human evolution.SIGNIFICANCE STATEMENT Tractography is a unique tool to map white matter connections in the brains of different species, including humans. This study shows that humans have a greater proportion of frontal lobe connections compared with monkeys, when normalized by total brain white matter volume. In particular, tracts associated with language and higher cognitive functions are disproportionally larger in humans compared with monkeys, whereas other tracts associated with emotional processing are either the same or disproportionally smaller. This supports the hypothesis that the emergence of higher cognitive functions in humans is associated with increased extended frontal connectivity, allowing human brains more efficient cross talk between frontal and other high-order associative areas of the temporal, parietal, and occipital lobes.

Anatomical evidence of an indirect pathway for word repetition.

OBJECTIVE: To combine MRI-based cortical morphometry and diffusion white matter tractography to describe the anatomical correlates of repetition deficits in patients with primary progressive aphasia (PPA). METHODS: The traditional anatomical model of language identifies a network for word repetition that includes Wernicke and Broca regions directly connected via the arcuate fasciculus. Recent tractography findings of an indirect pathway between Wernicke and Broca regions suggest a critical role of the inferior parietal lobe for repetition. To test whether repetition deficits are associated with damage to the direct or indirect pathway between both regions, tractography analysis was performed in 30 patients with PPA (64.27 ± 8.51 years) and 22 healthy controls. Cortical volume measurements were also extracted from 8 perisylvian language areas connected by the direct and indirect pathways. RESULTS: Compared to healthy controls, patients with PPA presented with reduced performance in repetition tasks and increased damage to most of the perisylvian cortical regions and their connections through the indirect pathway. Repetition deficits were prominent in patients with cortical atrophy of the temporo-parietal region with volumetric reductions of the indirect pathway. CONCLUSIONS: The results suggest that in PPA, deficits in repetition are due to damage to the temporo-parietal cortex and its connections to Wernicke and Broca regions. We therefore propose a revised language model that also includes an indirect pathway for repetition, which has important clinical implications for the functional mapping and treatment of neurologic patients.

The anatomy of the human frontal lobe.

Throughout evolution the frontal lobes have progressively acquired a central role in most aspects of cognition and behavior. In humans, frontal lobe functions are conditional on the development of an intricate set of short- and long-range connections that guarantee direct access to sensory information and control over regions dedicated to planning and motor execution. Here the frontal cortical anatomy and the major connections that constitute the local and extended frontal connectivity are reviewed in the context of diffusion tractography studies, contemporary models of frontal lobe functions, and clinical syndromes. A particular focus of this chapter is the use of comparative anatomy and neurodevelopmental data to address the question of how frontal networks evolved and what this signified for unique human abilities.

Frontal pathways in cognitive control: direct evidence from intraoperative stimulation and diffusion tractography.

A key aspect of cognitive control is the management of conflicting incoming information to achieve a goal, termed 'interference control'. Although the role of the right frontal lobe in interference control is evident, the white matter tracts subserving this cognitive process remain unclear. To investigate this, we studied the effect of transient network disruption (by means of direct electrical stimulation) and permanent disconnection (resulting from neurosurgical resection) on interference control processes, using the Stroop test in the intraoperative and extraoperative neurosurgical setting. We evaluated the sites at which errors could be produced by direct electrical stimulation during an intraoperative Stroop test in 34 patients with frontal right hemisphere glioma. Lesion-symptom mapping was used to evaluate the relationship between the resection cavities and postoperative performance on the Stroop test of this group compared with an additional 29 control patients who did not perform the intraoperative test (63 patients in total aged 17-77 years; 28 female). We then examined tract disruption and disconnection in a subset of eight patients who underwent both the intraoperative Stroop test and high angular resolution diffusion imaging (HARDI) tractography. The results showed that, intraoperatively, the majority of sites associated with errors during Stroop test performance and concurrent subcortical stimulation clustered in a region of white matter medial to the right inferior frontal gyrus, lateral and superior to the striatum. Patients who underwent the intraoperative test maintained cognitive control ability at the 1-month follow-up (P = 0.003). Lesion-symptom analysis showed resection of the right inferior frontal gyrus was associated with slower postoperative Stroop test ability (corrected for multiple comparisons, 5000 permutations). The stimulation sites associated with intraoperative errors most commonly corresponded with the inferior fronto-striatal tracts and anterior thalamic radiation (over 75% of patients), although the latter was commonly resected without postoperative deficits on the Stroop test (in 60% of patients). Our results show converging evidence to support a critical role for the inferior frontal gyrus in interference control processes. The intraoperative data combined with tractography suggests that cortico-subcortical tracts, over cortico-cortical connections, may be vital in maintaining efficiency of cognitive control processes. This suggests the importance of their preservation during resection of right frontal tumours.

Physiological parameters for Prognosis in Abdominal Sepsis (PIPAS) Study: a WSES observational study.

Background: Timing and adequacy of peritoneal source control are the most important pillars in the management of patients with acute peritonitis. Therefore, early prognostic evaluation of acute peritonitis is paramount to assess the severity and establish a prompt and appropriate treatment. The objectives of this study were to identify clinical and laboratory predictors for in-hospital mortality in patients with acute peritonitis and to develop a warning score system, based on easily recognizable and assessable variables, globally accepted. Methods: This worldwide multicentre observational study included 153 surgical departments across 56 countries over a 4-month study period between February 1, 2018, and May 31, 2018. Results: A total of 3137 patients were included, with 1815 (57.9%) men and 1322 (42.1%) women, with a median age of 47 years (interquartile range [IQR] 28-66). The overall in-hospital mortality rate was 8.9%, with a median length of stay of 6 days (IQR 4-10). Using multivariable logistic regression, independent variables associated with in-hospital mortality were identified: age > 80 years, malignancy, severe cardiovascular disease, severe chronic kidney disease, respiratory rate ≥ 22 breaths/min, systolic blood pressure < 100 mmHg, AVPU responsiveness scale (voice and unresponsive), blood oxygen saturation level (SpO2) < 90% in air, platelet count < 50,000 cells/mm3, and lactate > 4 mmol/l. These variables were used to create the PIPAS Severity Score, a bedside early warning score for patients with acute peritonitis. The overall mortality was 2.9% for patients who had scores of 0-1, 22.7% for those who had scores of 2-3, 46.8% for those who had scores of 4-5, and 86.7% for those who have scores of 7-8. Conclusions: The simple PIPAS Severity Score can be used on a global level and can help clinicians to identify patients at high risk for treatment failure and mortality.