Toward AI-driven neuroepigenetic imaging biomarker for alcohol use disorder: A proof-of-concept study.

Alcohol use disorder (AUD) is a disorder of clinical and public health significance requiring novel and improved therapeutic solutions. Both environmental and genetic factors play a significant role in its pathophysiology. However, the underlying epigenetic molecular mechanisms that link the gene-environment interaction in AUD remain largely unknown. In this proof-of-concept study, we showed, for the first time, the neuroepigenetic biomarker capability of non-invasive imaging of class I histone deacetylase (HDAC) epigenetic enzymes in the in vivo brain for classifying AUD patients from healthy controls using a machine learning approach in the context of precision diagnosis. Eleven AUD patients and 16 age- and sex-matched healthy controls completed a simultaneous positron emission tomography-magnetic resonance (PET/MR) scan with the HDAC-binding radiotracer [11C]Martinostat. Our results showed lower HDAC expression in the anterior cingulate region in AUD. Furthermore, by applying a genetic algorithm feature selection, we identified five particular brain regions whose combined [11C]Martinostat relative standard uptake value (SUVR) features could reliably classify AUD vs. controls. We validate their promising classification reliability using a support vector machine classifier. These findings inform the potential of in vivo HDAC imaging biomarkers coupled with machine learning tools in the objective diagnosis and molecular translation of AUD that could complement the current diagnostic and statistical manual of mental disorders (DSM)-based intervention to propel precision medicine forward.

Impact of repeated blast exposure on active-duty United States Special Operations Forces.

United States (US) Special Operations Forces (SOF) are frequently exposed to explosive blasts in training and combat, but the effects of repeated blast exposure (RBE) on SOF brain health are incompletely understood. Furthermore, there is no diagnostic test to detect brain injury from RBE. As a result, SOF personnel may experience cognitive, physical, and psychological symptoms for which the cause is never identified, and they may return to training or combat during a period of brain vulnerability. In 30 active-duty US SOF, we assessed the relationship between cumulative blast exposure and cognitive performance, psychological health, physical symptoms, blood proteomics, and neuroimaging measures (Connectome structural and diffusion MRI, 7 Tesla functional MRI, [11C]PBR28 translocator protein [TSPO] positron emission tomography [PET]-MRI, and [18F]MK6240 tau PET-MRI), adjusting for age, combat exposure, and blunt head trauma. Higher blast exposure was associated with increased cortical thickness in the left rostral anterior cingulate cortex (rACC), a finding that remained significant after multiple comparison correction. In uncorrected analyses, higher blast exposure was associated with worse health-related quality of life, decreased functional connectivity in the executive control network, decreased TSPO signal in the right rACC, and increased cortical thickness in the right rACC, right insula, and right medial orbitofrontal cortex-nodes of the executive control, salience, and default mode networks. These observations suggest that the rACC may be susceptible to blast overpressure and that a multimodal, network-based diagnostic approach has the potential to detect brain injury associated with RBE in active-duty SOF.

In vivo translocator protein in females with autism spectrum disorder: a pilot study.

Sex-based differences in the prevalence of autism spectrum disorder (ASD) are well-documented, with a male-to-female ratio of approximately 4:1. The clinical presentation of the core symptoms of ASD can also vary between sexes. Previously, positron emission tomography (PET) studies have identified alterations in the in vivo levels of translocator protein (TSPO)-a mitochondrial protein-in primarily or only male adults with ASD, with our group reporting lower TSPO relative to whole brain mean in males with ASD. However, whether in vivo TSPO levels are altered in females with ASD, specifically, is unknown. This is the first pilot study to measure in vivo TSPO in the brain in adult females with ASD using [11C]PBR28 PET-magnetic resonance imaging (MRI). Twelve adult females with ASD and 10 age- and TSPO genotype-matched controls (CON) completed one or two [11C]PBR28 PET-MRI scans. Females with ASD exhibited elevated [11C]PBR28 standardized uptake value ratio (SUVR) in the midcingulate cortex and splenium of the corpus callosum compared to CON. No brain area showed lower [11C]PBR28 SUVR in females with ASD compared to CON. Test-retest over several months showed stable [11C]PBR28 SUVR across time in both groups. Elevated regional [11C]PBR28 SUVR in females with ASD stand in stark contrast to our previous findings of lower regional [11C]PBR28 SUVR in males with ASD. Preliminary evidence of regionally elevated mitochondrial protein TSPO relative to whole brain mean in ASD females may reflect neuroimmuno-metabolic alterations specific to females with ASD.

Optimizing Brain Health of United States Special Operations Forces.

United States Special Operations Forces (SOF) personnel are frequently exposed to explosive blasts in training and combat. However, the effects of repeated blast exposure on the human brain are incompletely understood. Moreover, there is currently no diagnostic test to detect repeated blast brain injury (rBBI). In this "Human Performance Optimization" article, we discuss how the development and implementation of a reliable diagnostic test for rBBI has the potential to promote SOF brain health, combat readiness, and quality of life.

Striatal dopamine in anhedonia: A simultaneous [11C]raclopride positron emission tomography and functional magnetic resonance imaging investigation.

BACKGROUND: Anhedonia is hypothesized to be associated with blunted mesocorticolimbic dopamine (DA) functioning in samples with major depressive disorder. The purpose of this study was to examine linkages between striatal DA, reward circuitry functioning, anhedonia, and, in an exploratory fashion, self-reported stress, in a transdiagnostic anhedonic sample. METHODS: Participants with (n = 25) and without (n = 12) clinically impairing anhedonia completed a reward-processing task during simultaneous positron emission tomography and magnetic resonance (PET-MR) imaging with [11C]raclopride, a DA D2/D3 receptor antagonist that selectively binds to striatal DA receptors. RESULTS: Relative to controls, the anhedonia group exhibited decreased task-related DA release in the left putamen, caudate, and nucleus accumbens and right putamen and pallidum. There were no group differences in task-related brain activation (fMRI) during reward processing after correcting for multiple comparisons. General functional connectivity (GFC) findings revealed blunted fMRI connectivity between PET-derived striatal seeds and target regions in the anhedonia group. Associations were identified between anhedonia severity and the magnitude of task-related DA release to rewards in the left putamen, but not mesocorticolimbic GFC. CONCLUSIONS: Results provide evidence for reduced striatal DA functioning during reward processing and blunted mesocorticolimbic network functional connectivity in a transdiagnostic sample with clinically significant anhedonia.

Long-Term Effects of Repeated Blast Exposure in United States Special Operations Forces Personnel: A Pilot Study Protocol.

Emerging evidence suggests that repeated blast exposure (RBE) is associated with brain injury in military personnel. United States (U.S.) Special Operations Forces (SOF) personnel experience high rates of blast exposure during training and combat, but the effects of low-level RBE on brain structure and function in SOF have not been comprehensively characterized. Further, the pathophysiological link between RBE-related brain injuries and cognitive, behavioral, and physical symptoms has not been fully elucidated. We present a protocol for an observational pilot study, Long-Term Effects of Repeated Blast Exposure in U.S. SOF Personnel (ReBlast). In this exploratory study, 30 active-duty SOF personnel with RBE will participate in a comprehensive evaluation of: 1) brain network structure and function using Connectome magnetic resonance imaging (MRI) and 7 Tesla MRI; 2) neuroinflammation and tau deposition using positron emission tomography; 3) blood proteomics and metabolomics; 4) behavioral and physical symptoms using self-report measures; and 5) cognition using a battery of conventional and digitized assessments designed to detect subtle deficits in otherwise high-performing individuals. We will identify clinical, neuroimaging, and blood-based phenotypes that are associated with level of RBE, as measured by the Generalized Blast Exposure Value. Candidate biomarkers of RBE-related brain injury will inform the design of a subsequent study that will test a diagnostic assessment battery for detecting RBE-related brain injury. Ultimately, we anticipate that the ReBlast study will facilitate the development of interventions to optimize the brain health, quality of life, and battle readiness of U.S. SOF personnel.

The pandemic brain: Neuroinflammation in non-infected individuals during the COVID-19 pandemic.

While COVID-19 research has seen an explosion in the literature, the impact of pandemic-related societal and lifestyle disruptions on brain health among the uninfected remains underexplored. However, a global increase in the prevalence of fatigue, brain fog, depression and other "sickness behavior"-like symptoms implicates a possible dysregulation in neuroimmune mechanisms even among those never infected by the virus. We compared fifty-seven 'Pre-Pandemic' and fifteen 'Pandemic' datasets from individuals originally enrolled as control subjects for various completed, or ongoing, research studies available in our records, with a confirmed negative test for SARS-CoV-2 antibodies. We used a combination of multimodal molecular brain imaging (simultaneous positron emission tomography / magnetic resonance spectroscopy), behavioral measurements, imaging transcriptomics and serum testing to uncover links between pandemic-related stressors and neuroinflammation. Healthy individuals examined after the enforcement of 2020 lockdown/stay-at-home measures demonstrated elevated brain levels of two independent neuroinflammatory markers (the 18 kDa translocator protein, TSPO, and myoinositol) compared to pre-lockdown subjects. The serum levels of two inflammatory markers (interleukin-16 and monocyte chemoattractant protein-1) were also elevated, although these effects did not reach statistical significance after correcting for multiple comparisons. Subjects endorsing higher symptom burden showed higher TSPO signal in the hippocampus (mood alteration, mental fatigue), intraparietal sulcus and precuneus (physical fatigue), compared to those reporting little/no symptoms. Post-lockdown TSPO signal changes were spatially aligned with the constitutive expression of several genes involved in immune/neuroimmune functions. This work implicates neuroimmune activation as a possible mechanism underlying the non-virally-mediated symptoms experienced by many during the COVID-19 pandemic. Future studies will be needed to corroborate and further interpret these preliminary findings.

Epigenetics of Autism Spectrum Disorder: Histone Deacetylases.

The etiology of autism spectrum disorder (ASD) remains unknown, but gene-environment interactions, mediated through epigenetic mechanisms, are thought to be a key contributing factor. Prenatal environmental factors have been shown to be associated with both increased risk of ASD and altered histone deacetylases (HDACs) or acetylation levels. The relationship between epigenetic changes and gene expression in ASD suggests that alterations in histone acetylation, which lead to changes in gene transcription, may play a key role in ASD. Alterations in the acetylome have been demonstrated for several genes in ASD, including genes involved in synaptic function, neuronal excitability, and immune responses, which are mechanisms previously implicated in ASD. We review preclinical and clinical studies that investigated HDACs and autism-associated behaviors and discuss risk genes for ASD that code for proteins associated with HDACs. HDACs are also implicated in neurodevelopmental disorders with a known genetic etiology, such as 15q11-q13 duplication and Phelan-McDermid syndrome, which share clinical features and diagnostic comorbidities (e.g., epilepsy, anxiety, and intellectual disability) with ASD. Furthermore, we highlight factors that affect the behavioral phenotype of acetylome changes, including sensitive developmental periods and brain region specificity in the context of epigenetic programming.

Ibudilast (MN-166) in amyotrophic lateral sclerosis- an open label, safety and pharmacodynamic trial.

Ibudilast (MN-166) is an inhibitor of macrophage migration inhibitory factor (MIF) and phosphodiesterases 3,4,10 and 11 (Gibson et al., 2006; Cho et al., 2010). Ibudilast attenuates CNS microglial activation and secretion of pro-inflammatory cytokines (Fujimoto et al., 1999; Cho et al., 2010). In vitro evidence suggests that ibudilast is neuroprotective by suppressing neuronal cell death induced by microglial activation. People with ALS have increased microglial activation measured by [11C]PBR28-PET in the motor cortices. The primary objective is to determine the impact of ibudilast on reducing glial activation and neuroaxonal loss in ALS, measured by PBR28-PET and serum Neurofilament light (NfL). The secondary objectives included determining safety and tolerability of ibudilast high dosage (up to 100 mg/day) over 36 weeks. In this open label trial, 35 eligible ALS participants underwent ibudilast treatment up to 100 mg/day for 36 weeks. Of these, 30 participants were enrolled in the main study cohort and were included in biomarker, safety and tolerability analyses. Five additional participants were enrolled in the expanded access arm, who did not meet imaging eligibility criteria and were included in the safety and tolerability analyses. The primary endpoints were median change from baseline in (a) PBR28-PET uptake in primary motor cortices, measured by standard uptake value ratio (SUVR) over 12-24 weeks and (b) serum NfL over 36-40 weeks. The secondary safety and tolerability endpoints were collected through Week 40. The baseline median (range) of PBR28-PET SUVR was 1.033 (0.847, 1.170) and NfL was 60.3 (33.1, 219.3) pg/ml. Participants who completed both pre and post-treatment scans had PBR28-PET SUVR median(range) change from baseline of 0.002 (-0.184, 0.156) , P = 0.5 (n = 22). The median(range) NfL change from baseline was 0.4 pg/ml (-1.8, 17.5), P = 0.2 (n = 10 participants). 30(86%) participants experienced at least one, possibly study drug related adverse event. 13(37%) participants could not tolerate 100 mg/day and underwent dose reduction to 60-80 mg/day and 11(31%) participants discontinued study drug early due to drug related adverse events. The study concludes that following treatment with ibudilast up to 100 mg/day in ALS participants, there were no significant reductions in (a) motor cortical glial activation measured by PBR28-PET SUVR over 12-24 weeks or (b) CNS neuroaxonal loss, measured by serum NfL over 36-40 weeks. Dose reductions and discontinuations due to treatment emergent adverse events were common at this dosage in ALS participants. Future pharmacokinetic and dose-finding studies of ibudilast would help better understand tolerability and target engagement in ALS.

Comparison of Two Clinical Upper Motor Neuron Burden Rating Scales in ALS Using Quantitative Brain Imaging.

Several clinical upper motor neuron burden scales (UMNSs) variably measure brain dysfunction in amyotrophic lateral sclerosis (ALS). Here, we compare relationship of two widely used clinical UMNSs in ALS (Penn and MGH UMNSs) with (a) neuroimaging markers of brain dysfunction and (b) neurological impairment status using the gold-standard functional measure, the revised ALS Functional Rating Scale (ALSFRS-R). MGH UMNS measures hyperreflexia alone, and Penn UMNS measures hyperreflexia, spasticity, and pseudobulbar affect. Twenty-eight ALS participants underwent both Penn and MGH UMNSs, at a matching time-point as a simultaneous [11C]PBR28 positron emission tomography (PBR28-PET)/Magnetic Resonance scan and ALSFRS-R. The two UMNSs were compared for localization and strength of association with neuroimaging markers of: (a) neuroinflammation, PBR28-PET and MR Spectroscopy metabolites (myo-inositol and choline) and (b) corticospinal axonal loss, fractional anisotropy (FA), and MR Spectroscopy metabolite (N-acetylaspartate). Among clinical UMN manifestations, segmental hyperreflexia, spasticity, and pseudobulbar affect occurred in 100, 43, and 18% ALS participants, respectively. Pseudobulbar affect did not map to any specific brain regional dysfunction, while hyperreflexia and spasticity subdomains significantly correlated and colocalized neurobiological changes to corticospinal pathways on whole brain voxel-wise analyses. Both UMNS total scores showed significant and similar strength of association with (a) neuroimaging changes (PBR28-PET, FA, MR Spectroscopy metabolites) in primary motor cortices and (b) severity of functional decline (ALSFRS-R). Hyperreflexia is the most frequent clinical UMN manifestation and correlates best with UMN molecular imaging changes in ALS. Among Penn UMNS's subdomains, hyperreflexia carries the weight of association with neuroimaging markers of biological changes in ALS. A clinical UMN scale comprising hyperreflexia items alone is clinically relevant and sufficient to predict the highest yield of molecular neuroimaging abnormalities in ALS.

A simultaneous [11C]raclopride positron emission tomography and functional magnetic resonance imaging investigation of striatal dopamine binding in autism.

The social motivation hypothesis of autism posits that autism spectrum disorder (ASD) is characterized by impaired motivation to seek out social experience early in life that interferes with the development of social functioning. This framework suggests that impaired mesolimbic dopamine function underlies compromised responses to social rewards in ASD. Although this hypothesis is supported by functional magnetic resonance imaging (fMRI) studies, no molecular imaging study has evaluated striatal dopamine functioning in response to rewards in ASD. Here, we examined striatal functioning during monetary incentive processing in ASD and controls using simultaneous positron emission tomography (PET) and fMRI. Using a bolus + infusion protocol with the D2/D3 dopamine receptor antagonist [11C]raclopride, voxel-wise binding potential (BPND) was compared between groups (controls = 12, ASD = 10) in the striatum. Striatal clusters showing significant between-group BPND differences were used as seeds in whole-brain fMRI general functional connectivity analyses. Relative to controls, the ASD group demonstrated decreased phasic dopamine release to incentives in the bilateral putamen and left caudate, as well as increased functional connectivity between a PET-derived right putamen seed and the precuneus and insula. Within the ASD group, decreased phasic dopamine release in the putamen was related to poorer theory-of-mind skills. Our findings that ASD is characterized by impaired striatal phasic dopamine release to incentives provide support for the social motivation hypothesis of autism. PET-fMRI may be a suitable tool to evaluate novel ASD therapeutics targeting the striatal dopamine system.

In vivo human brain expression of histone deacetylases in bipolar disorder.

The etiology of bipolar disorder (BD) is unknown and the neurobiological underpinnings are not fully understood. Both genetic and environmental factors contribute to the risk of BD, which may be linked through epigenetic mechanisms, including those regulated by histone deacetylase (HDAC) enzymes. This study measures in vivo HDAC expression in individuals with BD for the first time using the HDAC-specific radiotracer [11C]Martinostat. Eleven participants with BD and 11 age- and sex-matched control participants (CON) completed a simultaneous magnetic resonance - positron emission tomography (MR-PET) scan with [11C]Martinostat. Lower [11C]Martinostat uptake was found in the right amygdala of BD compared to CON. We assessed uptake in the dorsolateral prefrontal cortex (DLPFC) to compare previous findings of lower uptake in the DLPFC in schizophrenia and found no group differences in BD. Exploratory whole-brain voxelwise analysis showed lower [11C]Martinostat uptake in the bilateral thalamus, orbitofrontal cortex, right hippocampus, and right amygdala in BD compared to CON. Furthermore, regional [11C]Martinostat uptake was associated with emotion regulation in BD in fronto-limbic areas, which aligns with findings from previous structural, functional, and molecular neuroimaging studies in BD. Regional [11C]Martinostat uptake was associated with attention in BD in fronto-parietal and temporal regions. These findings indicate a potential role of HDACs in BD pathophysiology. In particular, HDAC expression levels may modulate attention and emotion regulation, which represent two core clinical features of BD.

Moving Toward Multicenter Therapeutic Trials in Amyotrophic Lateral Sclerosis: Feasibility of Data Pooling Using Different Translocator Protein PET Radioligands.

Neuroinflammation has been implicated in amyotrophic lateral sclerosis (ALS) and can be visualized using translocator protein (TSPO) radioligands. To become a reliable pharmacodynamic biomarker for ALS multicenter trials, TSPO radioligands have some challenges to overcome. We aimed to investigate whether multicenter data pooling of different TSPO tracers (11C-PBR28 and 18F-DPA714) is feasible, after validation of an established 11C-PBR28 PET pseudo reference analysis technique for 18F-DPA714. Methods: Seven ALS patients from Belgium (58.9 ± 6.7 y old, 5 men and 2 women), 8 healthy volunteers from Belgium (52.1 ± 15.2 y old, 3 men and 5 women), 7 ALS patients from the United States (53.4 ± 9.8 y old, 5 men and 2 women), and 7 healthy volunteers from the United States (54.6 ± 9.6 y old, 4 men and 3 women) from a previously published study underwent dynamic 18F-DPA714 (Leuven, Belgium) or 11C-PBR28 (Boston, Massachusetts) PET/MRI. For 18F-DPA714, maps of total volume of distribution (VT) were compared with SUV ratio (SUVR) images from 40 to 60 min after injection (SUVR40-60) calculated using the pseudo reference regions cerebellum, occipital cortex, and whole brain (WB) without ventricles. For 11C-PBR28, SUVR images from 60 to 90 min after injection using the WB without ventricles were calculated. Results: In line with previous studies, increased 18F-DPA714 uptake (17.0% ± 5.6%) in primary motor cortices was observed in ALS subjects, as measured by both VT and SUVR40-60 approaches. The highest sensitivity was found for SUVR calculated using the WB without ventricles (average cluster, 21.6% ± 0.1%). 18F-DPA714 VT ratio was highly correlated with the SUVR40-60 (r > 0.8, P < 0.001). A similar pattern of increased uptake (average cluster, 20.5% ± 0.5%) in the primary motor cortices was observed in ALS subjects for 11C-PBR28 SUVR calculated using the WB without ventricles. Analysis of the 18F-DPA714 and 11C-PBR28 data together resulted in a more extensive pattern of significantly increased glial activation bilaterally in the primary motor cortices. Conclusion: The same pseudo reference region analysis technique for 11C-PBR28 PET can be extended toward 18F-DPA714 PET. Therefore, in ALS, standardized analysis across these 2 tracers enables pooling of TSPO PET data across multiple centers and increases the power of TSPO as a biomarker for future therapeutic trials.

Neuroepigenetic signatures of age and sex in the living human brain.

Age- and sex-related alterations in gene transcription have been demonstrated, however the underlying mechanisms are unresolved. Neuroepigenetic pathways regulate gene transcription in the brain. Here, we measure in vivo expression of the epigenetic enzymes, histone deacetylases (HDACs), across healthy human aging and between sexes using [11C]Martinostat positron emission tomography (PET) neuroimaging (n = 41). Relative HDAC expression increases with age in cerebral white matter, and correlates with age-associated disruptions in white matter microstructure. A post mortem study confirmed that HDAC1 and HDAC2 paralogs are elevated in white matter tissue from elderly donors. There are also sex-specific in vivo HDAC expression differences in brain regions associated with emotion and memory, including the amygdala and hippocampus. Hippocampus and white matter HDAC expression negatively correlates with emotion regulation skills (n = 23). Age and sex are associated with HDAC expression in vivo, which could drive age- and sex-related transcriptional changes and impact human behavior.

Verbal Fluency Is Affected by Altered Brain Lateralization in Adults Who Were Born Very Preterm.

Language difficulties have been reported in children and adolescents who were born very preterm (<32 weeks' gestation) and associated with an atypical lateralization of language processing, i.e., increased right-hemispheric engagement. This study used functional magnetic resonance imaging (fMRI) and spherical deconvolution tractography to study the hemodynamic responses associated with verbal fluency processing (easy and hard letter trials) and verbal fluency-related white matter fiber tracts in 64 very preterm born adults and 36 adult controls (mean age: 30 years). Tractography of the arcuate fasciculus (AF) and frontal aslant tract (FAT) was performed. Tracts were quantified in terms of mean volume, hindrance modulated orientational anisotropy, and lateralization, assessed using a laterality index (LI) to indicate hemispheric dominance. During verbal fluency fMRI, very preterm participants displayed decreased hemodynamic response suppression in both the Easy > Rest and Hard > Rest conditions, compared to controls, in superior temporal gyrus (STG), insula, thalamus, and sensorimotor cortex, particularly in the right hemisphere. At the whole-group level, decreased hemodynamic response suppression in the right sensorimotor cortex was associated with worse on-line performance on the hard letter trials. Increased left-laterality in the AF was present alongside increased right hemispheric hemodynamic response suppression in controls. When only right-handed participants were considered, decreased hemodynamic response suppression in the right STG during hard letter trials was related to weaker left and right FAT white matter integrity in the preterm group only. These results show that verbal fluency is affected by altered functional lateralization in adults who were born very preterm.

Spatial gradients of healthy aging: a study of myelin-sensitive maps.

Protracted development of a brain network may entail greater susceptibility to aging decline, supported by evidence of an earlier onset of age-related changes in late-maturing anterior areas, that is, an anterior-to-posterior gradient of brain aging. Here we analyzed the spatiotemporal features of age-related differences in myelin content across the human brain indexed by magnetization transfer (MT) concentration in a cross-sectional cohort of healthy adults. We described age-related spatial gradients in MT, which may reflect the reversal of patterns observed in development. We confirmed an anterior-to-posterior gradient of age-related MT decrease and also showed a lateral-to-ventral gradient inversely mirroring the sequence of connectivity development and myelination. MT concentration in the lateral white matter regions continued to increase up to the age of 45 years and decreased moderately following a peak. In contrast, ventral white matter regions reflected life-long stable MT concentration levels, followed by a rapid decrease at a later age. We discussed our findings in relation with existing theories of brain aging, including the lack of support for the proposal that areas which mature later decline at an accelerated rate.

A dimensional approach to assessing psychiatric risk in adults born very preterm.

BACKGROUND: Individuals who were born very preterm have higher rates of psychiatric diagnoses compared with term-born controls; however, it remains unclear whether they also display increased sub-clinical psychiatric symptomatology. Hence, our objective was to utilize a dimensional approach to assess psychiatric symptomatology in adult life following very preterm birth. METHODS: We studied 152 adults who were born very preterm (before 33 weeks' gestation; gestational range 24-32 weeks) and 96 term-born controls. Participants' clinical profile was examined using the Comprehensive Assessment of At-Risk Mental States (CAARMS), a measure of sub-clinical symptomatology that yields seven subscales including general psychopathology, positive, negative, cognitive, behavioural, motor and emotional symptoms, in addition to a total psychopathology score. Intellectual abilities were examined using the Wechsler Abbreviated Scale of Intelligence. RESULTS: Between-group differences on the CAARMS showed elevated symptomatology in very preterm participants compared with controls in positive, negative, cognitive and behavioural symptoms. Total psychopathology scores were significantly correlated with IQ in the very preterm group only. In order to examine the characteristics of participants' clinical profile, a principal component analysis was conducted. This revealed two components, one reflecting a non-specific psychopathology dimension, and the other indicating a variance in symptomatology along a positive-to-negative symptom axis. K-means (k = 4) were used to further separate the study sample into clusters. Very preterm adults were more likely to belong to a high non-specific psychopathology cluster compared with controls.Conclusion and RelevanceVery preterm individuals demonstrated elevated psychopathology compared with full-term controls. Their psychiatric risk was characterized by a non-specific clinical profile and was associated with lower IQ.

Volumetric grey matter alterations in adolescents and adults born very preterm suggest accelerated brain maturation.

Previous research investigating structural neurodevelopmental alterations in individuals who were born very preterm demonstrated a complex pattern of grey matter changes that defy straightforward summary. Here we addressed this problem by characterising volumetric brain alterations in individuals who were born very preterm from adolescence to adulthood at three hierarchically related levels - global, modular and regional. We demarcated structural components that were either particularly resilient or vulnerable to the impact of very preterm birth. We showed that individuals who were born very preterm had smaller global grey matter volume compared to controls, with subcortical and medial temporal regions being particularly affected. Conversely, frontal and lateral parieto-temporal cortices were relatively resilient to the effects of very preterm birth, possibly indicating compensatory mechanisms. Exploratory analyses supported this hypothesis by showing a stronger association between lateral parieto-temporal volume and IQ in the very preterm group compared to controls. We then related these alterations to brain maturation processes. Very preterm individuals exhibited a higher maturation index compared to controls, indicating accelerated brain maturation and this was specifically associated with younger gestational age. We discuss how the findings of accelerated maturation might be reconciled with evidence of delayed maturation at earlier stages of development.

Real-Life Impact of Executive Function Impairments in Adults Who Were Born Very Preterm.

OBJECTIVES: Children and adolescents who were born very preterm (≤32 weeks' gestation) are vulnerable to experiencing cognitive problems, including in executive function. However, it remains to be established whether cognitive deficits are evident in adulthood and whether these exert a significant effect on an individual's real-lifeachievement. METHODS: Using a cross-sectional design, we tested a range of neurocognitive abilities, with a focus on executive function, in a sample of 122 very preterm individuals and 89 term-born controls born between 1979 and 1984. Associations between executive function and a range of achievement measures, indicative of a successful transition to adulthood, were examined. RESULTS: Very preterm adults performed worse compared to controls on measures of intellectual ability and executive function with moderate to large effect sizes. They also demonstrated significantly lower achievement levels in terms of years spent in education, employment status, and on a measure of functioning in work and social domains. Results of regression analysis indicated a stronger positive association between executive function and real-life achievement in the very preterm group compared to controls. CONCLUSIONS: Very preterm born adults demonstrate executive function impairments compared to full-term controls, and these are associated with lower achievement in several real-life domains. (JINS, 2017, 23, 381-389).

White matter alterations to cingulum and fornix following very preterm birth and their relationship with cognitive functions.

Very preterm birth (VPT; <32 weeks of gestation) has been associated with impairments in memory abilities and functional neuroanatomical brain alterations in medial temporal and fronto-parietal areas. Here we investigated the relationship between structural connectivity in memory-related tracts and various aspects of memory in VPT adults (mean age 19) who sustained differing degrees of perinatal brain injury (PBI), as assessed by neonatal cerebral ultrasound. We showed that the neurodevelopmental consequences of VPT birth persist into young adulthood and are associated with neonatal cranial ultrasound classification. At a cognitive level, VPT young adults showed impairments specific to effective organization of verbal information and visuospatial memory, whereas at an anatomical level they displayed reduced volume of memory-related tracts, the cingulum and the fornix, with greater alterations in those individuals who experienced high-grade PBI. When investigating the association between these tracts and memory scores, perseveration errors were associated with the volume of the fornix and dorsal cingulum (connecting medial frontal and parietal lobes). Visuospatial memory scores were associated with the volume of the ventral cingulum (connecting medial parietal and temporal lobes). These results suggest that structural connectivity alterations could underlie memory difficulties in preterm born individuals.