Remote neuropsychological assessment: Acceptability and feasibility of direct-to-home teleneuropsychology methodology during the COVID-19 pandemic.

OBJECTIVE: To determine the acceptability and feasibility of telephone and video-conference calls to complete cognitive assessments during the COVID-19 pandemic. METHOD: In rapid response to the pandemic, evidence-based adaptations were made to routine face-to-face (FTF) practice, delivering teleneuropsychology (TNP) within a National Health Service (NHS) Scotland neuropsychology service. Caldicott guardian approval was obtained to complete a six month study (April to October 2020) from the early stages of the first United Kingdom (UK) lockdown. Assessments were completed with patients in their own homes (direct-to-home) via remote connections. Neuropsychology clinicians, service-users and referring agents were approached for structured feedback and qualitative comment. RESULTS: Data was captured for 212 referrals assessed by seven clinical psychologists; with responses from 70 (33%) service-users and 14 (58%) referring agents. 94% of referrals were assessed remotely and discharged. TNP reduced defaulted appointment discharge rates. Gender, socioeconomic deprivation and age did not affect access to information technology (IT) equipment.Clinicians agreed that remote assessment allowed them to complete initial interview (96%) and formulate (77%) cases appropriately. Service-users agreed they were comfortable with equipment (84%), the process was straightforward (74%), and would recommend TNP to others (68%). Referring agents were satisfied with the service provided (100%). Limitations included evidence-based remote test availability, technical issues and home distractions. CONCLUSIONS: Study findings evidence the acceptability and efficiency of TNP; increasing service accessibility, while reducing infection risk, defaulted appointments and travel. The results advocate for a post-pandemic mixed model of service delivery encompassing both FTF and TNP approaches.

The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder.

BACKGROUND: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects. METHODS: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects. RESULTS: FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < -0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects. CONCLUSIONS: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.

Effects of environmental risks and polygenic loading for schizophrenia on cortical thickness.

There are established differences in cortical thickness (CT) in schizophrenia (SCZ) and bipolar (BD) patients when compared to healthy controls (HC). However, it is unknown to what extent environmental or genetic risk factors impact on CT in these populations. We have investigated the effect of Environmental Risk Scores (ERS) and Polygenic Risk Scores for SCZ (PGRS-SCZ) on CT. Structural MRI scans were acquired at 3T for patients with SCZ or BD (n=57) and controls (n=41). Cortical reconstructions were generated in FreeSurfer (v5.3). The ERS was created by determining exposure to cannabis use, childhood adverse events, migration, urbanicity and obstetric complications. The PGRS-SCZ were generated, for a subset of the sample (Patients=43, HC=32), based on the latest PGC GWAS findings. ANCOVAs were used to test the hypotheses that ERS and PGRS-SCZ relate to CT globally, and in frontal and temporal lobes. An increase in ERS was negatively associated with CT within temporal lobe for patients. A higher PGRS-SCZ was also related to global cortical thinning for patients. ERS effects remained significant when including PGRS-SCZ as a fixed effect. No relationship which survived FDR correction was found for ERS and PGRS-SCZ in controls. Environmental risk for SCZ was related to localised cortical thinning in patients with SCZ and BD, while increased PGRS-SCZ was associated with global cortical thinning. Genetic and environmental risk factors for SCZ appear therefore to have differential effects. This provides a mechanistic means by which different risk factors may contribute to the development of SCZ and BD.

Balanced translocation linked to psychiatric disorder, glutamate, and cortical structure/function.

Rare genetic variants of large effect can help elucidate the pathophysiology of brain disorders. Here we expand the clinical and genetic analyses of a family with a (1;11)(q42;q14.3) translocation multiply affected by major psychiatric illness and test the effect of the translocation on the structure and function of prefrontal, and temporal brain regions. The translocation showed significant linkage (LOD score 6.1) with a clinical phenotype that included schizophrenia, schizoaffective disorder, bipolar disorder, and recurrent major depressive disorder. Translocation carriers showed reduced cortical thickness in the left temporal lobe, which correlated with general psychopathology and positive psychotic symptom severity. They showed reduced gyrification in prefrontal cortex, which correlated with general psychopathology severity. Translocation carriers also showed significantly increased activation in the caudate nucleus on increasing verbal working memory load, as well as statistically significant reductions in the right dorsolateral prefrontal cortex glutamate concentrations. These findings confirm that the t(1;11) translocation is associated with a significantly increased risk of major psychiatric disorder and suggest a general vulnerability to psychopathology through altered cortical structure and function, and decreased glutamate levels.

The cortical thickness phenotype of individuals with DISC1 translocation resembles schizophrenia.

BACKGROUND: The disrupted in schizophrenia 1 (DISC1) gene locus was originally identified in a Scottish pedigree with a high incidence of psychiatric disorders that is associated with a balanced t(1;11)(q42.1;q14.3) chromosomal translocation. Here, we investigated whether members of this family carrying the t(1;11)(q42.1;q14.3) translocation have a common brain-related phenotype and whether this phenotype is similar to that observed in schizophrenia (SCZ), using multivariate pattern recognition techniques. METHODS: We measured cortical thickness, cortical surface area, subcortical volumes, and regional cerebral blood flow (rCBF) in healthy controls (HC) (n = 24), patients diagnosed with SCZ (n = 24), patients diagnosed with bipolar disorder (BP) (n = 19), and members of the original Scottish family (n = 30) who were either carriers (T+) or noncarriers (T-) of the DISC1 translocation. Binary classification models were developed to assess the differences and similarities across groups. RESULTS: Based on cortical thickness, 72% of the T- group were assigned to the HC group, 83% of the T+ group were assigned to the SCZ group, and 45% of the BP group were classified as belonging to the SCZ group, suggesting high specificity of this measurement in predicting brain-related phenotypes. Shared brain-related phenotypes between SCZ and T+ individuals were found for cortical thickness only. Finally, a classification accuracy of 73% was achieved when directly comparing the pattern of cortical thickness of T+ and T- individuals. CONCLUSION: Together, the results of this study suggest that the DISC1 translocation may increase the risk of psychiatric disorders in this pedigree by affecting neurostructural phenotypes such as cortical thickness. FUNDING: This work was supported by the National Health Service Research Scotland, the Scottish Translational Medicine Research Collaboration, the Innovative Medicines Initiative (IMI), the Engineering and Physical Sciences Research Council (EPSRC), The Wellcome Trust, the National Institute of Health Research (NIHR), and Pfizer.

Hippocampal, amygdala and nucleus accumbens volume in first-episode schizophrenia patients and individuals at high familial risk: A cross-sectional comparison.

It is unknown whether brain changes occur prior to onset of schizophrenia or after it develops. Prospective familial high risk studies provide a good method to investigate this. In the Edinburgh High Risk Study, structural MRI scans of 150 young individuals at familial high risk of schizophrenia, 34 patients with first-episode schizophrenia and 36 matched controls were obtained. Of the high risk participants with scans suitable for analysis, 17 developed schizophrenia after the scans were taken, whilst 57 experienced isolated or sub-clinical psychotic symptoms, and 70 remained well. We used Freesurfer to extract volumetric measurements of the hippocampus, amygdala and nucleus accumbens with the aim of assessing whether any alterations found were present in all those at high risk, or selectively in the high risk cohort based on future clinical outcome, or only in those experiencing their first-episode of psychosis. We found no significant differences in any examined regions between controls and those at high risk, or between those at high risk who later developed schizophrenia and those who remained well. However, patients with first-episode schizophrenia demonstrated significant volumetric reductions in the bilateral hippocampus, left amygdala, and right nucleus accumbens compared to high risk individuals and healthy controls, which were not significantly associated with the intake of anti-psychotic medication or duration of illness. We found that patients had significantly smaller left amygdalae and bilateral hippocampus compared to HR[ill]. Our findings suggest that volumetric reductions of the hippocampus, amygdala and nucleus accumbens occur early in the first-episode of psychosis. The apparent absence of high risk versus control differences we found using Freesurfer is at odds with our previous studies conducted on the same sample, and possible methodological reasons for these apparent discrepancies are discussed.

Cortical Surface Area Differentiates Familial High Risk Individuals Who Go on to Develop Schizophrenia.

BACKGROUND: Schizophrenia is associated with structural brain abnormalities that may be present before disease onset. It remains unclear whether these represent general vulnerability indicators or are associated with the clinical state itself. METHODS: To investigate this, structural brain scans were acquired at two time points (mean scan interval 1.87 years) in a cohort of individuals at high familial risk of schizophrenia (n = 142) and control subjects (n = 36). Cortical reconstructions were generated using FreeSurfer. The high-risk cohort was subdivided into individuals that remained well during the study, individuals that had transient psychotic symptoms, and individuals that subsequently became ill. Baseline measures and longitudinal change in global estimates of thickness and surface area and lobar values were compared, focusing on overall differences between high-risk individuals and control subjects and then on group differences within the high-risk cohort. RESULTS: Longitudinally, control subjects showed a significantly greater reduction in cortical surface area compared with the high-risk group. Within the high-risk group, differences in surface area at baseline predicted clinical course, with individuals that subsequently became ill having significantly larger surface area than individuals that remained well during the study. For thickness, longitudinal reductions were most prominent in the frontal, cingulate, and occipital lobes in all high-risk individuals compared with control subjects. CONCLUSIONS: Our results suggest that larger surface areas at baseline may be associated with mechanisms that go above and beyond a general familial disposition. A relative preservation over time of surface area, coupled with a thinning of the cortex compared with control subjects, may serve as vulnerability markers of schizophrenia.

The Behavioural Inhibition System, anxiety and hippocampal volume in a non-clinical population.

BACKGROUND: Animal studies have suggested that the hippocampus may play an important role in anxiety as part of the Behavioural Inhibition System (BIS), which mediates reactivity to threat and punishment and can predict an individual's response to anxiety-relevant cues in a given environment. The aim of the present structural magnetic resonance imaging (MRI) study was to examine the relationship between individual differences in BIS and hippocampal structure, since this has not received sufficient attention in non-clinical populations. Thirty healthy right-handed participants with no history of alcohol or drug abuse, neurological or psychiatric disorders, or traumatic brain injury were recruited (16 male, 14 female, age 18 to 32 years). T1-weighted structural MRI scans were used to derive estimates of total intracranial volume, and hippocampal and amygdala gray matter volume using FreeSurfer. To relate brain structure to Gray's BIS, participants completed the Sensitivity to Punishment questionnaire. They also completed questionnaires assessing other measures potentially associated with hippocampal volume (Beck Depression Inventory, Negative Life Experience Survey), and two other measures of anxiety (Spielberger Trait Anxiety Inventory and the Beck Anxiety Inventory). RESULTS: We found that high scores on the Sensitivity to Punishment scale were positively associated with hippocampal volume, and that this phenomenon was lateralized to the right side. In other words, greater levels of behavioural inhibition (BIS) were positively associated with right hippocampal volume. CONCLUSIONS: Our data suggest that hippocampal volume is related to the cognitive and affective dimensions of anxiety indexed by the Sensitivity to Punishment, and support the idea that morphological differences in the hippocampal formation may be associated with behavioural inhibition contributions to anxiety.

The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data.

The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.