Publications by authors named "Jeremy Hall"

182 Publications

The Development and Internal Validation of Novel Risk Tools to Predict Subsequent Shoulder Surgery Following Proximal Humerus Fractures.

J Orthop Trauma 2021 Nov 5. Epub 2021 Nov 5.

Division of Orthopaedic Surgery, London Health Sciences Centre, London, Ontario Clinical Orthopaedic Research, St. Michael's Hospital, Toronto, Ontario Institute of Health Policy, Management and Evaluation, University of Toronto Dalla Lana School of Public Health, University of Toronto Banner Health, University of Arizona-College of Medicine, Phoenix, Arizona Li Ka Shing Centre for Healthcare Analytics Research and Training, St. Michael's Hospital, Toronto, Ontario Institute for Work Health, Toronto, Ontario.

Objective: The objectives of this study were to: 1) identify predictors of subsequent surgery following initial treatment of proximal humerus fractures (PHF); and 2) generate valid risk prediction tools to predict subsequent surgery.

Methods: We identified PHF patients ≥ 50 years from 2004 to 2015 using health datasets in Ontario, Canada. We used procedural codes to classify patients into treatment groups of: 1) surgical fixation; 2) shoulder replacement; and 3) conservative. We used procedural and diagnosis codes to capture subsequent surgery within two years post fracture. We developed regression models for two thirds of each group to identify predictors of subsequent surgery, and the regression equations to develop risk tools to predict subsequent surgery. We used the final third of each cohort to evaluate the discriminative ability of the risk tools using c-statistics.

Results: We identified 20,897 PHF patients, 2,414 treated with fixation, 1,065 with replacement, and 17,418 treated conservatively. Predictors of reoperation following fixation included bone grafting, and nail or wire fixation vs. plate fixation, while poor bone quality was associated with reoperation following initial replacement. In conservatively treated patients, more comorbidities were associated with subsequent surgery, while age 70+, and discharge home following presentation lowered the odds of subsequent surgery. The risk tools were able to discriminate with c-statistics of 0.75-0.88 (derivation) and 0.51-0.79 (validation).

Conclusion: Our risk tools showed good to strong discriminative ability for patients treated with fixation and conservatively. These data may be used as the foundation to develop a clinically informative tool.

Level Of Evidence: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.1097/BOT.0000000000002302DOI Listing
November 2021

Impairment in acquisition of conditioned fear in schizophrenia.

Neuropsychopharmacology 2021 Sep 29. Epub 2021 Sep 29.

Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.

Individuals with schizophrenia show impairments in associative learning. One well-studied, quantifiable form of associative learning is Pavlovian fear conditioning. However, to date, studies of fear conditioning in schizophrenia have been inconclusive, possibly because they lacked sufficient power. To address this issue, we pooled data from four independent fear conditioning studies that included a total of 77 individuals with schizophrenia and 74 control subjects. Skin conductance responses (SCRs) to stimuli that were paired (the CS + ) or not paired (CS-) with an aversive, unconditioned stimulus were measured, and the success of acquisition of differential conditioning (the magnitude of CS + vs. CS- SCRs) and responses to CS + and CS- separately were assessed. We found that acquisition of differential conditioned fear responses was significantly lower in individuals with schizophrenia than in healthy controls (Cohen's d = 0.53). This effect was primarily related to a significantly higher response to the CS- stimulus in the schizophrenia compared to the control group. Moreover, the magnitude of this response to the CS- in the schizophrenia group was correlated with the severity of delusional ideation (p = 0.006). Other symptoms or antipsychotic dose were not associated with fear conditioning measures. In conclusion, individuals with schizophrenia who endorse delusional beliefs may be over-responsive to neutral stimuli during fear conditioning. This finding is consistent with prior models of abnormal associative learning in psychosis.
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http://dx.doi.org/10.1038/s41386-021-01193-1DOI Listing
September 2021

Complement C3 and C3aR mediate different aspects of emotional behaviours; relevance to risk for psychiatric disorder.

Brain Behav Immun 2021 Sep 17;99:70-82. Epub 2021 Sep 17.

Neuroscience and Mental Health Research Institute, MRC Centre for Neuropsychiatric Genetic and Genomics, School of Medicine, Hadyn Ellis Building, Cardiff University, Cardiff CF24 4HQ, UK; Behavioural Genetics Group, Schools of Psychology and Medicine, Cardiff University, Cardiff CF10 3AT, UK; Hodge Centre for Neuropsychiatric Immunology, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK. Electronic address:

Complement is a key component of the immune system with roles in inflammation and host-defence. Here we reveal novel functions of complement pathways impacting on emotional reactivity of potential relevance to the emerging links between complement and risk for psychiatric disorder. We used mouse models to assess the effects of manipulating components of the complement system on emotionality. Mice lacking the complement C3a Receptor (C3aR) demonstrated a selective increase in unconditioned (innate) anxiety whilst mice deficient in the central complement component C3 (C3) showed a selective increase in conditioned (learned) fear. The dissociable behavioural phenotypes were linked to different signalling mechanisms. Effects on innate anxiety were independent of C3a, the canonical ligand for C3aR, consistent with the existence of an alternative ligand mediating innate anxiety, whereas effects on learned fear were due to loss of iC3b/CR3 signalling. Our findings show that specific elements of the complement system and associated signalling pathways contribute differentially to heightened states of anxiety and fear commonly seen in psychopathology.
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http://dx.doi.org/10.1016/j.bbi.2021.09.005DOI Listing
September 2021

Dissociable effects of complement C3 and C3aR on survival and morphology of adult born hippocampal neurons, pattern separation, and cognitive flexibility in male mice.

Brain Behav Immun 2021 Nov 14;98:136-150. Epub 2021 Aug 14.

Neuroscience and Mental Health Research Institute, MRC Centre for Neuropsychiatric Genetic and Genomics, School of Medicine, Cardiff University, Hadyn Ellis Building, Cardiff CF24 4HQ, UK; Hodge Centre for Neuropsychiatric Immunology, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK; Brain Repair and Intracranial Neurotherapeutics (BRAIN), Biomedical Research Unit, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, CF24 4HQ, UK. Electronic address:

Adult hippocampal neurogenesis (AHN) is a form of ongoing plasticity in the brain that supports specific aspects of cognition. Disruptions in AHN have been observed in neuropsychiatric conditions presenting with inflammatory components and are associated with impairments in cognition and mood. Recent evidence highlights important roles of the complement system in synaptic plasticity and neurogenesis during neurodevelopment and in acute learning and memory processes. In this work we investigated the impact of the complement C3/C3aR pathway on AHN and its functional implications for AHN-related behaviours. In C3 mice, we found increased numbers and accelerated migration of adult born granule cells, indicating that absence of C3 leads to abnormal survival and distribution of adult born neurons. Loss of either C3 or C3aR affected the morphology of immature neurons, reducing morphological complexity, though these effects were more pronounced in the absence of C3aR. We assessed functional impacts of the cellular phenotypes in an operant spatial discrimination task that assayed AHN sensitive behaviours. Again, we observed differences in the effects of manipulating C3 or C3aR, in that whilst C3aR mice showed evidence of enhanced pattern separation abilities, C3 mice instead demonstrated impaired behavioural flexibility. Our findings show that C3 and C3aR manipulation have distinct effects on AHN that impact at different stages in the development and maturation of newly born neurons, and that the dissociable cellular phenotypes are associated with specific alterations in AHN-related behaviours.
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http://dx.doi.org/10.1016/j.bbi.2021.08.215DOI Listing
November 2021

Effects of eight neuropsychiatric copy number variants on human brain structure.

Transl Psychiatry 2021 07 20;11(1):399. Epub 2021 Jul 20.

Douglas Research Centre, McGill University, Montréal, QC, Canada.

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen's d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions.
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http://dx.doi.org/10.1038/s41398-021-01490-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292542PMC
July 2021

Governance: Struggle and Strife-Or Synergy and Success-In the Trans-COVID Era.

Authors:
Jeremy L Hall

Public Adm Rev 2021 Jan-Feb;81(1):7-11. Epub 2021 Mar 11.

University of Central Florida.

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http://dx.doi.org/10.1111/puar.13347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207084PMC
March 2021

Operative Versus Nonoperative Treatment of Acute Displaced Distal Clavicle Fractures: A Multicenter Randomized Controlled Trial.

J Orthop Trauma 2021 Dec;35(12):660-666

Department of Orthopaedic Surgery, University of Arizona College of Medicine-Phoenix, Phoenix, AZ; and.

Objectives: To evaluate the differences in patient outcomes after operative or nonoperative treatment of displaced, type II distal clavicle fractures.

Design: Multicenter, prospective, randomized controlled trial.

Setting: Level I trauma centers.

Patients/participants: Patients with completely displaced type II distal clavicle fractures were included. Fifty-seven patients were randomized: 27 to the operative group and 30 to the nonoperative group.

Intervention: Patients randomized to nonoperative care received a standard shoulder sling, followed by pendulum or gentle range of motion shoulder exercises at any time as directed by the attending surgeon. Patients randomized to the operative group received plate fixation with a precontoured distal clavicular plate or a "hook" plate within 28 days from injury.

Main Outcome Measure: Disabilities of the Arm, Shoulder and Hand scores at 1 year.

Results: There were no between-group differences in Disabilities of the Arm, Shoulder and Hand or Constant scores at 1 year. More patients in the operative group went on to union (95% vs. 64%, P = 0.02) within 1 year. Twelve patients in the operative group underwent a second operation for implant removal (12/27, 44%). In the nonoperative group, 6 patients (6/30, 20%) subsequently underwent 8 operative procedures.

Conclusion: Although this study failed to demonstrate a difference in functional outcomes between operative and nonoperative treatment of Neer type II distal clavicle fractures, nonoperative management led to more complications including a moderate rate of nonunion, which often required secondary surgery to correct, a higher rate of early dissatisfaction with shoulder appearance, and a delayed return to activities in the first 6 months. Operative management provided a safe and reliable treatment option with few complications, but often required secondary implant removal, especially with hook plate fixation.

Level Of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.1097/BOT.0000000000002211DOI Listing
December 2021

Using induced pluripotent stem cells to investigate human neuronal phenotypes in 1q21.1 deletion and duplication syndrome.

Mol Psychiatry 2021 Jun 10. Epub 2021 Jun 10.

Neuroscience and Mental Health Research Institute, Hadyn Ellis Building, Cardiff University, Cardiff, United Kingdom.

Copy Number Variation (CNV) at the 1q21.1 locus is associated with a range of neurodevelopmental and psychiatric disorders in humans, including abnormalities in head size and motor deficits. Yet, the functional consequences of these CNVs (both deletion and duplication) on neuronal development remain unknown. To determine the impact of CNV at the 1q21.1 locus on neuronal development, we generated induced pluripotent stem cells from individuals harbouring 1q21.1 deletion or duplication and differentiated them into functional cortical neurons. We show that neurons with 1q21.1 deletion or duplication display reciprocal phenotype with respect to proliferation, differentiation potential, neuronal maturation, synaptic density and functional activity. Deletion of the 1q21.1 locus was also associated with an increased expression of lower cortical layer markers. This difference was conserved in the mouse model of 1q21.1 deletion, which displayed altered corticogenesis. Importantly, we show that neurons with 1q21.1 deletion and duplication are associated with differential expression of calcium channels and demonstrate that physiological deficits in neurons with 1q21.1 deletion or duplication can be pharmacologically modulated by targeting Ca channel activity. These findings provide biological insight into the neuropathological mechanism underlying 1q21.1 associated brain disorder and indicate a potential target for therapeutic interventions.
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http://dx.doi.org/10.1038/s41380-021-01182-2DOI Listing
June 2021

Haploinsufficiency of the schizophrenia and autism risk gene Cyfip1 causes abnormal postnatal hippocampal neurogenesis through microglial and Arp2/3 mediated actin dependent mechanisms.

Transl Psychiatry 2021 05 24;11(1):313. Epub 2021 May 24.

Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, UK.

Genetic risk factors can significantly increase chances of developing psychiatric disorders, but the underlying biological processes through which this risk is effected remain largely unknown. Here we show that haploinsufficiency of Cyfip1, a candidate risk gene present in the pathogenic 15q11.2(BP1-BP2) deletion may impact on psychopathology via abnormalities in cell survival and migration of newborn neurons during postnatal hippocampal neurogenesis. We demonstrate that haploinsufficiency of Cyfip1 leads to increased numbers of adult-born hippocampal neurons due to reduced apoptosis, without altering proliferation. We show this is due to a cell autonomous failure of microglia to induce apoptosis through the secretion of the appropriate factors, a previously undescribed mechanism. Furthermore, we show an abnormal migration of adult-born neurons due to altered Arp2/3 mediated actin dynamics. Together, our findings throw new light on how the genetic risk candidate Cyfip1 may influence the hippocampus, a brain region with strong evidence for involvement in psychopathology.
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http://dx.doi.org/10.1038/s41398-021-01415-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144403PMC
May 2021

Developmental Profile of Psychiatric Risk Associated With Voltage-Gated Cation Channel Activity.

Biol Psychiatry 2021 09 13;90(6):399-408. Epub 2021 Mar 13.

Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom; MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.

Background: Recent breakthroughs in psychiatric genetics have implicated biological pathways onto which genetic risk for psychiatric disorders converges. However, these studies do not reveal the developmental time point(s) at which these pathways are relevant.

Methods: We aimed to determine the relationship between psychiatric risk and developmental gene expression relating to discrete biological pathways. We used postmortem RNA sequencing data (BrainSeq and BrainSpan) from brain tissue at multiple prenatal and postnatal time points, with summary statistics from recent genome-wide association studies of schizophrenia, bipolar disorder, and major depressive disorder. We prioritized gene sets for overall enrichment of association with each disorder and then tested the relationship between the association of their constituent genes with their relative expression at each developmental stage.

Results: We observed relationships between the expression of genes involved in voltage-gated cation channel activity during early midfetal, adolescence, and early adulthood time points and association with schizophrenia and bipolar disorder, such that genes more strongly associated with these disorders had relatively low expression during early midfetal development and higher expression during adolescence and early adulthood. The relationship with schizophrenia was strongest for the subset of genes related to calcium channel activity, while for bipolar disorder, the relationship was distributed between calcium and potassium channel activity genes.

Conclusions: Our results indicate periods during development when biological pathways related to the activity of calcium and potassium channels may be most vulnerable to the effects of genetic variants conferring risk for psychiatric disorders. Furthermore, they indicate key time points and potential targets for disorder-specific therapeutic interventions.
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http://dx.doi.org/10.1016/j.biopsych.2021.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375582PMC
September 2021

Analysis of Diffusion Tensor Imaging Data From the UK Biobank Confirms Dosage Effect of 15q11.2 Copy Number Variation on White Matter and Shows Association With Cognition.

Biol Psychiatry 2021 09 3;90(5):307-316. Epub 2021 Mar 3.

Neuroscience and Mental Health Research Institute, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff, United Kingdom. Electronic address:

Background: Copy number variations at the 15q11.2 BP1-BP2 locus are present in 0.5%-1.0% of the population, and the deletion is associated with several neurodevelopmental disorders. Previously, we showed a reciprocal effect of 15q11.2 copy number variation on fractional anisotropy, with widespread increases in deletion carriers. We aim to expand these findings using a larger sample of participants (N = 29,166) and higher resolution imaging and by examining the implications for cognitive performance.

Methods: Diffusion tensor imaging measures from participants with no neurological or psychiatric diagnoses were obtained from the UK Biobank database. We compared 15q11.2 BP1-BP2 deletion (n = 102) and duplication (n = 113) carriers to a large cohort of control individuals with no neuropsychiatric copy number variants (n = 28,951). Additionally, we assessed how changes in white matter mediated the association between carrier status and cognitive performance.

Results: Deletion carriers showed increases in fractional anisotropy in the internal capsule and cingulum and decreases in the posterior thalamic radiation compared with both duplication carriers and control subjects (who had intermediate values). Compared with control subjects, deletion carriers had lower scores across cognitive tasks, which were partly influenced by white matter. Reduced fractional anisotropy in the posterior thalamic radiation partially contributed to worse cognitive performance in deletion carriers.

Conclusions: These results, together with our previous findings, provide convergent evidence for an effect of 15q11.2 BP1-BP2 on white matter microstructure, this being more pronounced in deletion carriers. Additionally, changes in white matter were found to partially mediate cognitive ability in deletion carriers, providing a link between white matter changes in 15q11.2 BP1-BP2 carriers and cognitive function.
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http://dx.doi.org/10.1016/j.biopsych.2021.02.969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343146PMC
September 2021

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.

Transl Psychiatry 2021 03 22;11(1):182. Epub 2021 Mar 22.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
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http://dx.doi.org/10.1038/s41398-021-01213-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985307PMC
March 2021

Rare Copy Number Variants Are Associated With Poorer Cognition in Schizophrenia.

Biol Psychiatry 2021 07 19;90(1):28-34. Epub 2020 Dec 19.

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom. Electronic address:

Background: Cognitive impairment in schizophrenia is a major contributor to poor outcomes, yet its causes are poorly understood. Some rare copy number variants (CNVs) are associated with schizophrenia risk and affect cognition in healthy populations, but their contribution to cognitive impairment in schizophrenia has not been investigated. We examined the effect of 12 schizophrenia CNVs on cognition in those with schizophrenia.

Methods: General cognitive ability was measured using the Measurement and Treatment Research to Improve Cognition in Schizophrenia composite z score in 875 patients with schizophrenia and in a replication sample of 519 patients with schizophrenia using Wechsler Adult Intelligence Scale Full Scale IQ. Using linear regression, we tested for association between cognition and schizophrenia CNV status, covarying for age and sex. In addition, we tested whether CNVs hitting genes in schizophrenia-enriched gene sets (loss-of-function intolerant and synaptic gene sets) were associated with cognitive impairment.

Results: A total of 23 schizophrenia CNV carriers were identified. Schizophrenia CNV carriers had lower general cognitive ability than nonschizophrenia CNV carriers in discovery (β = -0.66, 95% confidence interval [CI] = -1.31 to -0.01) and replication samples (β = -0.91, 95% CI = -1.71 to -0.11) and after meta-analysis (β = -0.76, 95% CI = -1.26 to -0.25, p = .003). CNVs hitting loss-of-function intolerant genes were associated with lower cognition (β = -0.15, 95% CI = -0.29 to -0.001, p = .048).

Conclusions: In those with schizophrenia, cognitive ability in schizophrenia CNV carriers is 0.5-1.0 standard deviations below non-CNV carriers, which may have implications for clinical assessment and management. We also demonstrate that rare CNVs hitting genes intolerant to loss-of-function variation lead to more severe cognitive impairment, above and beyond the effect of known schizophrenia CNVs.
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http://dx.doi.org/10.1016/j.biopsych.2020.11.025DOI Listing
July 2021

In Situ Placement Versus Anterior Transposition of the Ulnar Nerve for Distal Humerus Fractures Treated With Plate Fixation: A Multicenter Randomized Controlled Trial.

J Orthop Trauma 2021 09;35(9):465-471

Division of Orthopaedics, Department of Surgery, University of Western Ontario, London, ON, Canada.

Objectives: To compare clinical scores and electrodiagnostic evidence of ulnar neuropathy, between ulnar nerve mobilization and placement back in the cubital tunnel versus anterior transposition, during plate and screw fixation of a bicolumnar fracture of the distal humerus.

Design: Multicenter randomized controlled trial.

Setting: Eight tertiary care centres in Canada.

Patients: Fifty-eight patients with distal humerus fractures undergoing plate fixation of both columns were recruited and randomized.

Intervention: All patients underwent bicolumnar plate fixation for an acute, displaced fracture of the distal humerus with identification, mobilization, and protection of the ulnar nerve as part of the surgical approach. At the conclusion of the procedure, they were randomized to either (1) replacing the nerve in situ in the cubital tunnel or (2) anterior transposition.

Main Outcome Measurements: The primary outcome was the Gabel & Amadio rating scale for ulnar neuropathy. Secondary outcomes included a functional outcome score (Mayo Elbow Performance Score), disabilities of the arm, shoulder and hand instrument, 2-point discrimination, nerve conduction testing, complications, and secondary surgeries.

Results: Thirty-one patients were randomized to in situ placement and 27 to anterior transposition. The mean age was 53 years, and 60% were women. There was no difference between the 2 groups with regards to age, gender, body mass index, smoking, diabetes, injury characteristics, time to operation, length of operation, or surgical approach. There was no difference in outcome between the 2 groups at any time point with regards to Gabel & Amadio ulnar neuropathy scores, Mayo Elbow Performance Score, disabilities of the arm, shoulder and hand instrument, or 2-point discrimination. The incidence of ulnar nerve dysfunction, as measured by use of the Gabel & Amadio ulnar neuropathy score, was poor in both groups acutely; however, there was significant improvement at 12 months postoperatively (6.0-7.8, P < 0.001).

Conclusions: This study was unable to demonstrate any significant difference in outcomes when comparing ulnar nerve mobilization and in situ placement and anterior subcutaneous transposition after bicolumnar plate fixation of a distal humerus fracture. Either strategy for managing the ulnar nerve is acceptable and can be used at the discretion of the treating surgeon.

Level Of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.1097/BOT.0000000000002066DOI Listing
September 2021

Neurotrophin receptor activation rescues cognitive and synaptic abnormalities caused by hemizygosity of the psychiatric risk gene Cacna1c.

Mol Psychiatry 2021 06 17;26(6):1748-1760. Epub 2021 Feb 17.

Neuroscience and Mental Health Research Institute, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.

Genetic variation in CACNA1C, which encodes the alpha-1 subunit of Ca1.2 L-type voltage-gated calcium channels, is strongly linked to risk for psychiatric disorders including schizophrenia and bipolar disorder. To translate genetics to neurobiological mechanisms and rational therapeutic targets, we investigated the impact of mutations of one copy of Cacna1c on rat cognitive, synaptic and circuit phenotypes implicated by patient studies. We show that rats hemizygous for Cacna1c harbour marked impairments in learning to disregard non-salient stimuli, a behavioural change previously associated with psychosis. This behavioural deficit is accompanied by dys-coordinated network oscillations during learning, pathway-selective disruption of hippocampal synaptic plasticity, attenuated Ca signalling in dendritic spines and decreased signalling through the Extracellular-signal Regulated Kinase (ERK) pathway. Activation of the ERK pathway by a small-molecule agonist of TrkB/TrkC neurotrophin receptors rescued both behavioural and synaptic plasticity deficits in Cacna1c rats. These results map a route through which genetic variation in CACNA1C can disrupt experience-dependent synaptic signalling and circuit activity, culminating in cognitive alterations associated with psychiatric disorders. Our findings highlight targeted activation of neurotrophin signalling pathways with BDNF mimetic drugs as a genetically informed therapeutic approach for rescuing behavioural abnormalities in psychiatric disorder.
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http://dx.doi.org/10.1038/s41380-020-01001-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440217PMC
June 2021

The psychiatric phenotypes of 1q21 distal deletion and duplication.

Transl Psychiatry 2021 02 4;11(1):105. Epub 2021 Feb 4.

Division of Psychological Medicine and Clinical Neurosciences, Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.

Copy number variants are amongst the most highly penetrant risk factors for psychopathology and neurodevelopmental deficits, but little information about the detailed clinical phenotype associated with particular variants is available. We present the largest study of the microdeletion and -duplication at the distal 1q21 locus, which has been associated with schizophrenia and intellectual disability, in order to investigate the range of psychiatric phenotypes. Clinical and cognitive data from 68 deletion and 55 duplication carriers were analysed with logistic regression analysis to compare frequencies of mental disorders between carrier groups and controls, and linear mixed models to compare quantitative phenotypes. Both children and adults with copy number variants at 1q21 had high frequencies of psychopathology. In the children, neurodevelopmental disorders were most prominent (56% for deletion, 68% for duplication carriers). Adults had increased prevalence of mood (35% for deletion [OR = 6.6 (95% CI: 1.4-40.1)], 55% for duplication carriers [8.3 (1.4-55.5)]) and anxiety disorders (24% [1.8 (0.4-8.4)] and 55% [10.0 (1.9-71.2)]). The adult group, which included mainly genetically affected parents of probands, had an IQ in the normal range. These results confirm high prevalence of neurodevelopmental disorders associated with CNVs at 1q21 but also reveal high prevalence of mood and anxiety disorders in a high-functioning adult group with these CNVs. Because carriers of neurodevelopmental CNVs who show relevant psychopathology but no major cognitive impairment are not currently routinely receiving clinical genetic services widening of genetic testing in psychiatry may be considered.
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http://dx.doi.org/10.1038/s41398-021-01226-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862693PMC
February 2021

Global Brain Flexibility During Working Memory Is Reduced in a High-Genetic-Risk Group for Schizophrenia.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Jan 29. Epub 2021 Jan 29.

Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom; Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff, United Kingdom; MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff School of Medicine, Cardiff University, Cardiff, United Kingdom; School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.

Background: Altered functional brain connectivity has been proposed as an intermediate phenotype between genetic risk loci and clinical expression of schizophrenia. Genetic high-risk groups of healthy subjects are particularly suited for the investigation of this proposition because they can be tested in the absence of medication or other secondary effects of schizophrenia.

Methods: Here, we applied dynamic functional connectivity analysis to functional magnetic resonance imaging data to reveal the reconfiguration of brain networks during a cognitive task. We recruited healthy carriers of common risk variants using the recall-by-genotype design. We assessed 197 individuals: 99 individuals (52 female, 47 male) with low polygenic risk scores (schizophrenia risk profile scores [SCZ-PRSs]) and 98 individuals (52 female, 46 male) with high SCZ-PRSs from both tails of the SCZ-PRS distribution from a genotyped population cohort, the Avon Longitudinal Study of Parents and Children (N = 8169). We compared groups both on conventional brain activation profiles, using the general linear model of the experiment, and on the neural flexibility index, which quantifies how frequent a brain region's community affiliation changes over experimental time.

Results: Behavioral performance and standard brain activation profiles did not differ significantly between groups. High SCZ-PRS was associated with reduced flexibility index and network modularity across n-back levels. The whole-brain flexibility index and that of the frontoparietal working memory network was associated with n-back performance. We identified a dynamic network phenotype related to high SCZ-PRS.

Conclusions: Such neurophysiological markers can become important for the elucidation of biological mechanisms of schizophrenia and, particularly, the associated cognitive deficit.
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http://dx.doi.org/10.1016/j.bpsc.2021.01.007DOI Listing
January 2021

Use of the extended feasible stability region for assessing stability of perturbed walking.

Sci Rep 2021 01 13;11(1):1026. Epub 2021 Jan 13.

Department of Mechanical Engineering, University of Alberta, 9211-116 Street NW, Edmonton, AB, T6G 1H9, Canada.

Walking stability has been assessed through gait variability or existing biomechanical measures. However, such measures are unable to quantify the instantaneous risk of loss-of-balance as a function of gait parameters, body sway, and physiological and perturbation conditions. This study aimed to introduce and evaluate novel biomechanical measures for loss-of-balance under various perturbed walking conditions. We introduced the concept of 'Extended Feasible Stability Region (ExFSR)' that characterizes walking stability for the duration of an entire step. We proposed novel stability measures based on the proximity of the body's centre of mass (COM) position and velocity to the ExFSR limits. We quantified perturbed walking of fifteen non-disabled individuals and three individuals with a disability, and calculated our proposed ExFSR-based measures. 17.2% (32.5%) and 26.3% (34.0%) of the measured trajectories of the COM position and velocity during low (high) perturbations went outside the ExFSR limits, for non-disabled and disabled individuals, respectively. Besides, our proposed measures significantly correlated with measures previously suggested in the literature to assess gait stability, indicating a similar trend in gait stability revealed by them. The ExFSR-based measures facilitate our understanding on the biomechanical mechanisms of loss-of-balance and can contribute to the development of strategies for balance assessment.
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http://dx.doi.org/10.1038/s41598-020-79955-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807089PMC
January 2021

A Genetics-First Approach to Dissecting the Heterogeneity of Autism: Phenotypic Comparison of Autism Risk Copy Number Variants.

Am J Psychiatry 2021 01;178(1):77-86

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom (Chawner, Doherty, Anney, Moss, Hall, Owen, van den Bree); Cardiff University Centre for Human Developmental Science, School of Psychology, Cardiff University, Cardiff, United Kingdom (Chawner); Department of Psychology, Syracuse University, Syracuse, N.Y. (Antshel); Department of Psychiatry and Behavioral Sciences and Psychology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles (Bearden, Kushan); Departments of Psychiatry and Behavioral Sciences, University of Washington, Seattle (Bernier); Departments of Pediatrics and Medicine, Columbia University Irving Medical Center, New York (Chung); Center for Autism Research, Children's Hospital of Philadelphia (Clements, Miller, Schultz); Department of Psychology, University of Pennsylvania, Philadelphia (Clements); South West London and St. George's Mental Health National Health Service Foundation Trust, London (Curran); University Children's Hospital, Belgrade, Serbia; Faculty of Medicine, University of Belgrade, Serbia (Cuturilo); Department of Psychiatry, Brain Center, University Medical Center Utrecht, the Netherlands (Fiksinski, Vorstman); Clinical Genetics Research Program, Centre for Addiction and Mental Health, and the Dalglish Family 22q Clinic for 22q11.2 Deletion Syndrome, Toronto General Hospital, University Health Network, Toronto (Fiksinski); Department of Psychiatry, Trinity College Dublin, Ireland (Gallagher); Department of Pediatrics, Baylor College of Medicine, Houston (Goin-Kochel); Lifespan Brain Institute, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia (Gur); Department of Psychiatry, Neurodevelopment and Psychosis Section, Perelman School of Medicine, University of Pennsylvania, Philadelphia (Gur); Department of Child and Adolescent Psychiatry, Children's Hospital of Philadelphia (Gur, Schultz); Developmental Medicine, Children's Hospital Boston/Harvard Medical School, Boston (Hanson); Department of Pediatrics, University of Montreal (Jacquemont, Maillard); Centre de recherche, Centre Hospitalier Universitaire Sainte Justine, Montreal (Jacquemont); Department of Psychiatry and Behavioral Sciences, State University of New York at Upstate Medical University, Syracuse (Kates); Service des Troubles du Spectre de l'Autisme et Apparentés, Lausanne University Hospital, Lausanne, Switzerland (Maillard); Division of Human Genetics and Molecular Biology, Children's Hospital of Philadelphia (McDonald-McGinn); 22q and You Center, Children's Hospital of Philadelphia (McDonald-McGinn); Department of Pediatrics, University of Pennsylvania, Philadelphia (McDonald-McGinn, Schultz); Clinic for Psychiatry, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Serbia (Mihaljevic); Institute of Mental Health, Belgrade, Serbia, Faculty of Medicine, University of Belgrade, Serbia (Pejovic-Milovancevic); Simons Foundation, New York (Green-Snyder); Program in Genetics and Genome Biology, SickKids Research Institute, Toronto (Vorstman); Department of Psychiatry, Hospital for Sick Children, University of Toronto (Vorstman); Department of Pediatrics, Seattle Children's Hospital, Seattle (Wenger); and Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom (Hall, Owen, van den Bree).

Objective: Certain copy number variants (CNVs) greatly increase the risk of autism. The authors conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships.

Methods: This international study included 547 individuals (mean age, 12.3 years [SD=4.2], 54% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (82 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 370 22q11.2 deletion carriers, and 45 22q11.2 duplication carriers), as well as 2,027 individuals (mean age, 9.1 years [SD=4.9], 86% male) with autism of heterogeneous etiology. Assessments included the Autism Diagnostic Interview-Revised and IQ testing.

Results: The four genetic variant groups differed in autism symptom severity, autism subdomain profile, and IQ profile. However, substantial variability was observed in phenotypic outcome in individual genetic variant groups (74%-97% of the variance, depending on the trait), whereas variability between groups was low (1%-21%, depending on the trait). CNV carriers who met autism criteria were compared with individuals with heterogeneous autism, and a range of profile differences were identified. When clinical cutoff scores were applied, 54% of individuals with one of the four CNVs who did not meet full autism diagnostic criteria had elevated levels of autistic traits.

Conclusions: Many CNV carriers do not meet full diagnostic criteria for autism but nevertheless meet clinical cutoffs for autistic traits. Although profile differences between variants were observed, there is considerable variability in clinical symptoms in the same variant.
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http://dx.doi.org/10.1176/appi.ajp.2020.20010015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022239PMC
January 2021

Genetic association of FMRP targets with psychiatric disorders.

Mol Psychiatry 2021 Jul 19;26(7):2977-2990. Epub 2020 Oct 19.

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.

Genes encoding the mRNA targets of fragile X mental retardation protein (FMRP) are enriched for genetic association with psychiatric disorders. However, many FMRP targets possess functions that are themselves genetically associated with psychiatric disorders, including synaptic transmission and plasticity, making it unclear whether the genetic risk is truly related to binding by FMRP or is alternatively mediated by the sampling of genes better characterised by another trait or functional annotation. Using published common variant, rare coding variant and copy number variant data, we examined the relationship between FMRP binding and genetic association with schizophrenia, major depressive disorder and bipolar disorder. High-confidence targets of FMRP, derived from studies of multiple tissue types, were enriched for common schizophrenia risk alleles, as well as rare loss-of-function and de novo nonsynonymous variants in schizophrenia cases. Similarly, through common variation, FMRP targets were associated with major depressive disorder, and we present novel evidence of association with bipolar disorder. These relationships could not be explained by other functional annotations known to be associated with psychiatric disorders, including those related to synaptic structure and function. This study reinforces the evidence that targeting by FMRP captures a subpopulation of genes enriched for genetic association with a range of psychiatric disorders.
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http://dx.doi.org/10.1038/s41380-020-00912-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505260PMC
July 2021

Electrophysiological network alterations in adults with copy number variants associated with high neurodevelopmental risk.

Transl Psychiatry 2020 09 21;10(1):324. Epub 2020 Sep 21.

Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Maindy Road, Cardiff, CF24 4HQ, UK.

Rare copy number variants associated with increased risk for neurodevelopmental and psychiatric disorders (referred to as ND-CNVs) are characterized by heterogeneous phenotypes thought to share a considerable degree of overlap. Altered neural integration has often been linked to psychopathology and is a candidate marker for potential convergent mechanisms through which ND-CNVs modify risk; however, the rarity of ND-CNVs means that few studies have assessed their neural correlates. Here, we used magnetoencephalography (MEG) to investigate resting-state oscillatory connectivity in a cohort of 42 adults with ND-CNVs, including deletions or duplications at 22q11.2, 15q11.2, 15q13.3, 16p11.2, 17q12, 1q21.1, 3q29, and 2p16.3, and 42 controls. We observed decreased connectivity between occipital, temporal, and parietal areas in participants with ND-CNVs. This pattern was common across genotypes and not exclusively characteristic of 22q11.2 deletions, which were present in a third of our cohort. Furthermore, a data-driven graph theory framework enabled us to successfully distinguish participants with ND-CNVs from unaffected controls using differences in node centrality and network segregation. Together, our results point to alterations in electrophysiological connectivity as a putative common mechanism through which genetic factors confer increased risk for neurodevelopmental and psychiatric disorders.
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http://dx.doi.org/10.1038/s41398-020-00998-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506525PMC
September 2020

Late-Onset Radial Nerve Palsy in the Setting of Humeral Shaft Hypertrophic Nonunion: A Case Report.

JBJS Case Connect 2020 Jul-Sep;10(3):e1900582

1The CORE Institute, Phoenix, Arizona 2Department of Orthopaedic Surgery, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona 3Division of Orthopaedic Surgery, University of Toronto, Toronto, Canada 4Lakeridge Health, Ontario, Canada 5Division of Orthopaedic Surgery, St. Michael's Hospital, Toronto, Canada.

Case: A 67-year-old woman presented 9 months after a closed midshaft humerus fracture with a new onset radial nerve palsy. Radiographs demonstrated a hypertrophic nonunion. Upon exploration, the radial nerve was in continuity and entrapped in fracture callus. It was extricated from the callus, and an open reduction and plate fixation was performed. Full radial nerve function returned by 3 months.

Conclusion: We recommend that delayed onset radial nerve palsies be treated on a semiurgent basis with radial nerve exploration and decompression followed by internal fixation to achieve primary bone healing and minimize fracture callus formation.
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http://dx.doi.org/10.2106/JBJS.CC.19.00582DOI Listing
April 2021

Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study.

Mol Psychiatry 2021 Sep 27;26(9):5307-5319. Epub 2020 Jul 27.

The Centre for Neuroimaging & Cognitive Genomics (NICOG) and NCBES Galway Neuroscience Centre, National University of Ireland Galway, Galway, Ireland.

The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.
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http://dx.doi.org/10.1038/s41380-020-0820-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589646PMC
September 2021

Assessment of emotions and behaviour by the Developmental Behaviour Checklist in young people with neurodevelopmental CNVs.

Psychol Med 2020 Jul 9:1-13. Epub 2020 Jul 9.

Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK.

Background: A number of genomic conditions caused by copy number variants (CNVs) are associated with a high risk of neurodevelopmental and psychiatric disorders (ND-CNVs). Although these patients also tend to have cognitive impairments, few studies have investigated the range of emotion and behaviour problems in young people with ND-CNVs using measures that are suitable for those with learning difficulties.

Methods: A total of 322 young people with 13 ND-CNVs across eight loci (mean age: 9.79 years, range: 6.02-17.91, 66.5% male) took part in the study. Primary carers completed the Developmental Behaviour Checklist (DBC).

Results: Of the total, 69% of individuals with an ND-CNV screened positive for clinically significant difficulties. Young people from families with higher incomes (OR = 0.71, CI = 0.55-0.91, p = .008) were less likely to screen positive. The rate of difficulties differed depending on ND-CNV genotype (χ2 = 39.99, p < 0.001), with the lowest rate in young people with 22q11.2 deletion (45.7%) and the highest in those with 1q21.1 deletion (93.8%). Specific patterns of strengths and weaknesses were found for different ND-CNV genotypes. However, ND-CNV genotype explained no more than 9-16% of the variance, depending on DBC subdomain.

Conclusions: Emotion and behaviour problems are common in young people with ND-CNVs. The ND-CNV specific patterns we find can provide a basis for more tailored support. More research is needed to better understand the variation in emotion and behaviour problems not accounted for by genotype.
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http://dx.doi.org/10.1017/S0033291720002330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794095PMC
July 2020

Neuronal activity increases translocator protein (TSPO) levels.

Mol Psychiatry 2021 06 12;26(6):2025-2037. Epub 2020 May 12.

Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, Wales, UK.

The mitochondrial protein, translocator protein (TSPO), is a widely used biomarker of neuroinflammation, but its non-selective cellular expression pattern implies roles beyond inflammatory processes. In the present study, we investigated whether neuronal activity modifies TSPO levels in the adult central nervous system. First, we used single-cell RNA sequencing to generate a cellular landscape of basal TSPO gene expression in the hippocampus of adult (12 weeks old) C57BL6/N mice, followed by confocal laser scanning microscopy to verify TSPO protein in neuronal and non-neuronal cell populations. We then quantified TSPO mRNA and protein levels after stimulating neuronal activity with distinct stimuli, including designer receptors exclusively activated by designer drugs (DREADDs), exposure to a novel environment and acute treatment with the psychostimulant drug, amphetamine. Single-cell RNA sequencing demonstrated a non-selective and multi-cellular gene expression pattern of TSPO at basal conditions in the adult mouse hippocampus. Confocal laser scanning microscopy confirmed that TSPO protein is present in neuronal and non-neuronal (astrocytes, microglia, vascular endothelial cells) cells of cortical (medial prefrontal cortex) and subcortical (hippocampus) brain regions. Stimulating neuronal activity through chemogenetic (DREADDs), physiological (novel environment exposure) or psychopharmacological (amphetamine treatment) approaches led to consistent increases in TSPO gene and protein levels in neurons, but not in microglia or astrocytes. Taken together, our findings show that neuronal activity has the potential to modify TSPO levels in the adult central nervous system. These findings challenge the general assumption that altered TSPO expression or binding unequivocally mirrors ongoing neuroinflammation and emphasize the need to consider non-inflammatory interpretations in some physiological or pathological contexts.
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http://dx.doi.org/10.1038/s41380-020-0745-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440208PMC
June 2021

Are working memory and glutamate concentrations involved in early-life stress and severity of psychosis?

Brain Behav 2020 06 9;10(6):e01616. Epub 2020 May 9.

School of Psychology, National University of Ireland Galway, Galway, Ireland.

Objective: Occurrences of early-life stress (ELS) are associated with the severity of psychotic symptoms and working memory (WM) deficits in patients with psychosis (PSY). This study investigated potential mediation roles of WM behavioral performance and glutamate concentrations in prefrontal brain regions on the association between ELS and psychotic symptom severity in PSY.

Method: Forty-seven patients with PSY (established schizophrenia, n = 30; bipolar disorder, n = 17) completed measures of psychotic symptom severity. In addition, data on ELS and WM performance were collected in both patients with PSY and healthy controls (HC; n = 41). Resting-state glutamate concentrations in the bilateral dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) were also assessed with proton magnetic resonance spectroscopy for both PSY and HC groups. t tests, analyses of variance, and regression analyses were utilized.

Results: Participants with PSY reported significantly more ELS occurrences and showed poorer WM performance than HC. Furthermore, individuals with PSY displayed lower glutamate concentrations in the left DLPFC than HC. Neither ELS nor WM performance were predictive of severity of psychotic symptoms in participants with PSY. However, we found a significant negative correlation between glutamate concentrations in the left DLPFC and ELS occurrence in HC only.

Conclusion: In individuals with PSY, the current study found no evidence that the association between ELS and psychotic symptoms is mediated by WM performance or prefrontal glutamate concentrations. In HC, the association between ELS experience and glutamate concentrations may indicate a neurometabolite effect of ELS that is independent of an illness effect in psychosis.
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http://dx.doi.org/10.1002/brb3.1616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303391PMC
June 2020

Movement Disorder Phenotypes in Children With 22q11.2 Deletion Syndrome.

Mov Disord 2020 07 7;35(7):1272-1274. Epub 2020 May 7.

Neuroscience and Mental Health Research Institute, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, UK.

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http://dx.doi.org/10.1002/mds.28078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516340PMC
July 2020

Environmental enrichment rescues survival and function of adult-born neurons following early life stress.

Mol Psychiatry 2021 06 14;26(6):1898-1908. Epub 2020 Apr 14.

Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK.

Adverse experiences early in life are associated with the development of psychiatric illnesses. The hippocampus is likely to play pivotal role in generating these effects: it undergoes significant development during childhood and is extremely reactive to stress. In rodent models, stress in the pre-pubertal period impairs adult hippocampal neurogenesis (AHN) and behaviours which rely on this process. In normal adult animals, environmental enrichment (EE) is a potent promoter of AHN and hippocampal function. Whether exposure to EE during adolescence can restore normal hippocampal function and AHN following pre-pubertal stress (PPS) is unknown. We investigated EE as a treatment for reduced AHN and hippocampal function following PPS in a rodent model. Stress was administered between post-natal days (PND) 25-27, EE from PND 35 to early adulthood, when behavioural testing and assessment of AHN took place. PPS enhanced fear reactions to a conditioned stimulus (CS) following a trace fear protocol and reduced the survival of 4-week-old adult-born neurons throughout the adult hippocampus. Furthermore, we show that fewer adult-born neurons were active during recall of the CS stimulus following PPS. All effects were reversed by EE. Our results demonstrate lasting effects of PPS on the hippocampus and highlight the utility of EE during adolescence for restoring normal hippocampal function. EE during adolescence is a promising method of enhancing impaired hippocampal function resulting from early life stress, and due to multiple benefits (low cost, few side effects, widespread availability) should be more thoroughly explored as a treatment option in human sufferers of childhood adversity.
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http://dx.doi.org/10.1038/s41380-020-0718-4DOI Listing
June 2021
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