Hippocampal subfield volumes in treatment resistant depression and serial ketamine treatment.

Introduction: Subanesthetic ketamine is a rapidly acting antidepressant that has also been found to improve neurocognitive performance in adult patients with treatment resistant depression (TRD). Provisional evidence suggests that ketamine may induce change in hippocampal volume and that larger pre-treatment volumes might be related to positive clinical outcomes. Here, we examine the effects of serial ketamine treatment on hippocampal subfield volumes and relationships between pre-treatment subfield volumes and changes in depressive symptoms and neurocognitive performance. Methods: Patients with TRD (N = 66; 31M/35F; age = 39.5 ± 11.1 years) received four ketamine infusions (0.5 mg/kg) over 2 weeks. Structural MRI scans, the National Institutes of Health Toolbox (NIHT) Cognition Battery, and Hamilton Depression Rating Scale (HDRS) were collected at baseline, 24 h after the first and fourth ketamine infusion, and 5 weeks post-treatment. The same data was collected for 32 age and sex matched healthy controls (HC; 17M/15F; age = 35.03 ± 12.2 years) at one timepoint. Subfield (CA1/CA3/CA4/subiculum/molecular layer/GC-ML-DG) volumes corrected for whole hippocampal volume were compared across time, between treatment remitters/non-remitters, and patients and HCs using linear regression models. Relationships between pre-treatment subfield volumes and clinical and cognitive outcomes were also tested. All analyses included Bonferroni correction. Results: Patients had smaller pre-treatment left CA4 (p = 0.004) and GC.ML.DG (p = 0.004) volumes compared to HC, but subfield volumes remained stable following ketamine treatment (all p > 0.05). Pre-treatment or change in hippocampal subfield volumes over time showed no variation by remission status nor correlated with depressive symptoms (p > 0.05). Pre-treatment left CA4 was negatively correlated with improved processing speed after single (p = 0.0003) and serial ketamine infusion (p = 0.005). Left GC.ML.DG also negatively correlated with improved processing speed after single infusion (p = 0.001). Right pre-treatment CA3 positively correlated with changes in list sorting working memory at follow-up (p = 0.0007). Discussion: These results provide new evidence to suggest that hippocampal subfield volumes at baseline may present a biomarker for neurocognitive improvement following ketamine treatment in TRD. In contrast, pre-treatment subfield volumes and changes in subfield volumes showed negligible relationships with ketamine-related improvements in depressive symptoms.

Schizophrenia Polygenic Risk During Typical Development Reflects Multiscale Cortical Organization.

Background: Schizophrenia is widely recognized as a neurodevelopmental disorder. Abnormal cortical development in otherwise typically developing children and adolescents may be revealed using polygenic risk scores for schizophrenia (PRS-SCZ). Methods: We assessed PRS-SCZ and cortical morphometry in typically developing children and adolescents (3-21 years, 46.8% female) using whole-genome genotyping and T1-weighted magnetic resonance imaging (n = 390) from the PING (Pediatric Imaging, Neurocognition, and Genetics) cohort. We contextualized the findings using 1) age-matched transcriptomics, 2) histologically defined cytoarchitectural types and functionally defined networks, and 3) case-control differences of schizophrenia and other major psychiatric disorders derived from meta-analytic data of 6 ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) working groups, including a total of 12,876 patients and 15,670 control participants. Results: Higher PRS-SCZ was associated with greater cortical thickness, which was most prominent in areas with heightened gene expression of dendrites and synapses. PRS-SCZ-related increases in vertexwise cortical thickness were mainly distributed in association cortical areas, particularly the ventral attention network, while relatively sparing koniocortical type cortex (i.e., primary sensory areas). The large-scale pattern of cortical thickness increases related to PRS-SCZ mirrored the pattern of cortical thinning in schizophrenia and mood-related psychiatric disorders derived from the ENIGMA consortium. Age group models illustrate a possible trajectory from PRS-SCZ-associated cortical thickness increases in early childhood toward thinning in late adolescence, with the latter resembling the adult brain phenotype of schizophrenia. Conclusions: Collectively, combining imaging genetics with multiscale mapping, our work provides novel insight into how genetic risk for schizophrenia affects the cortex early in life.

White matter microstructural perturbations after total sleep deprivation in depression.

Background: Total sleep deprivation (TSD) transiently reverses depressive symptoms in a majority of patients with depression. How TSD modulates diffusion tensor imaging (DTI) measures of white matter (WM) microstructure, which may be linked with TSD's rapid antidepressant effects, remains uncharacterized. Methods: Patients with depression (N = 48, mean age = 33, 26 women) completed diffusion-weighted imaging and Hamilton Depression Rating (HDRS) and rumination scales before and after >24 h of TSD. Healthy controls (HC) (N = 53, 23 women) completed the same assessments at baseline, and after receiving TSD in a subset of HCs (N = 15). Tract based spatial statistics (TBSS) investigated voxelwise changes in fractional anisotropy (FA) across major WM pathways pre-to-post TSD in patients and HCs and between patients and HCs at baseline. Post hoc analyses tested for TSD effects for other diffusion metrics, and the relationships between change in diffusion measures with change in mood and rumination symptoms. Results: Significant improvements in mood and rumination occurred in patients with depression (both p < 0.001), but not in HCs following TSD. Patients showed significant (p < 0.05, corrected) decreases in FA values in multiple WM tracts, including the body of the corpus callosum and anterior corona radiata post-TSD. Significant voxel-level changes in FA were not observed in HCs who received TSD (p > 0.05). However, differential effects of TSD between HCs and patients were found in the superior corona radiata, frontal WM and the posterior thalamic radiation (p < 0.05, corrected). A significant (p < 0.05) association between change in FA and axial diffusivity within the right superior corona radiata and improvement in rumination was found post-TSD in patients. Conclusion: Total sleep deprivation leads to rapid microstructural changes in WM pathways in patients with depression that are distinct from WM changes associated with TSD observed in HCs. WM tracts including the superior corona radiata and posterior thalamic radiation could be potential biomarkers of the rapid therapeutic effects of TSD. Changes in superior corona radiata FA, in particular, may relate to improvements in maladaptive rumination.

Neurocognitive effects of subanesthetic serial ketamine infusions in treatment resistant depression.

INTRODUCTION: Ketamine treatment prompts a rapid antidepressant response in treatment-resistant depression (TRD). We performed an exploratory investigation of how ketamine treatment in TRD affects different cognitive domains and relates to antidepressant response. METHODS: Patients with TRD (N = 66; 30 M/35F; age = 39.5 ± 11.1 years) received four ketamine infusions (0.5 mg/kg). Neurocognitive function and depressive symptoms were assessed at baseline, 24 h after the first and fourth ketamine infusion, and 5 weeks following end of treatment. Mixed effect models tested for changes in seven neurocognitive domains and antidepressant response, with post-hoc pairwise comparisons between timepoints, including follow-up. Relationships between change in neurocognitive function and antidepressant response over the course of treatment were tested with Pearson's correlation and mediation analyses. Associations between baseline neurocognitive performance and antidepressant response were tested with Pearson's correlation. RESULTS: Significant improvements in inhibition, working memory, processing speed, and overall fluid cognition were observed after the first and fourth ketamine infusion. Improvements in processing speed and overall fluid cognition persisted through follow-up. Significant improvements in depressive symptoms reverted towards baseline at follow-up. Baseline working memory and change in inhibition were moderately correlated with antidepressant response, however, improvements in neurocognitive performance were statistically independent from antidepressant response. CONCLUSION: Antidepressant ketamine leads to improved neurocognitive function, which persist for at least 5 weeks. Neurocognitive improvements observed appear independent of antidepressant response, suggesting ketamine may target overlapping but distinct functional brain systems. Limitations Research investigating repeated serial ketamine treatments is important to determine cognitive safety. This study is a naturalistic design and does not include placebo.

Neuroimaging-Derived Biomarkers of the Antidepressant Effects of Ketamine.

Major depressive disorder is a highly prevalent psychiatric disorder. Despite an extensive range of treatment options, about a third of patients still struggle to respond to available therapies. In the last 20 years, ketamine has gained considerable attention in the psychiatric field as a promising treatment of depression, particularly in patients who are treatment resistant or at high risk for suicide. At a subanesthetic dose, ketamine produces a rapid and pronounced reduction in depressive symptoms and suicidal ideation, and serial treatment appears to produce a greater and more sustained therapeutic response. However, the mechanism driving ketamine's antidepressant effects is not yet well understood. Biomarker discovery may advance knowledge of ketamine's antidepressant action, which could in turn translate to more personalized and effective treatment strategies. At the brain systems level, neuroimaging can be used to identify functional pathways and networks contributing to ketamine's therapeutic effects by studying how it alters brain structure, function, connectivity, and metabolism. In this review, we summarize and appraise recent work in this area, including 51 articles that use resting-state and task-based functional magnetic resonance imaging, arterial spin labeling, positron emission tomography, structural magnetic resonance imaging, diffusion magnetic resonance imaging, or magnetic resonance spectroscopy to study brain and clinical changes 24 hours or longer after ketamine treatment in populations with unipolar or bipolar depression. Though individual studies have included relatively small samples, used different methodological approaches, and reported disparate regional findings, converging evidence supports that ketamine leads to neuroplasticity in structural and functional brain networks that contribute to or are relevant to its antidepressant effects.

Genome-wide mapping of brain phenotypes in extended pedigrees with strong genetic loading for bipolar disorder.

Bipolar disorder is a highly heritable illness, associated with alterations of brain structure. As such, identification of genes influencing inter-individual differences in brain morphology may help elucidate the underlying pathophysiology of bipolar disorder (BP). To identify quantitative trait loci (QTL) that contribute to phenotypic variance of brain structure, structural neuroimages were acquired from family members (n = 527) of extended pedigrees heavily loaded for bipolar disorder ascertained from genetically isolated populations in Latin America. Genome-wide linkage and association analysis were conducted on the subset of heritable brain traits that showed significant evidence of association with bipolar disorder (n = 24) to map QTL influencing regional measures of brain volume and cortical thickness. Two chromosomal regions showed significant evidence of linkage; a QTL on chromosome 1p influencing corpus callosum volume and a region on chromosome 7p linked to cortical volume. Association analysis within the two QTLs identified three SNPs correlated with the brain measures.

Neurodegenerative disease biomarkers Aß1-40, Aß1-42, tau, and p-tau181 in the vervet monkey cerebrospinal fluid: Relation to normal aging, genetic influences, and cerebral amyloid angiopathy.

Background: The Caribbean vervet monkey (Chlorocebus aethiops sabaeus) is a potentially valuable animal model of neurodegenerative disease. However, the trajectory of aging in vervets and its relationship to human disease is incompletely understood. Methods: To characterize biomarkers associated with neurodegeneration, we measured cerebrospinal fluid (CSF) concentrations of Aß1-40, Aß1-42, total tau, and p-tau181 in 329 members of a multigenerational pedigree. Linkage and genome-wide association were used to elucidate a genetic contribution to these traits. Results: Aß1-40 concentrations were significantly correlated with age, brain total surface area, and gray matter thickness. Levels of p-tau181 were associated with cerebral volume and brain total surface area. Among the measured analytes, only CSF Aß1-40 was heritable. No significant linkage (LOD > 3.3) was found, though suggestive linkage was highlighted on chromosomes 4 and 12. Genome-wide association identified a suggestive locus near the chromosome 4 linkage peak. Conclusions: Overall, these results support the vervet as a non-human primate model of amyloid-related neurodegeneration, such as Alzheimer's disease and cerebral amyloid angiopathy, and highlight Aß1-40 and p-tau181 as potentially valuable biomarkers of these processes.

JAKMIP1, a Novel Regulator of Neuronal Translation, Modulates Synaptic Function and Autistic-like Behaviors in Mouse.

Autism spectrum disorder (ASD) is a heritable, common neurodevelopmental disorder with diverse genetic causes. Several studies have implicated protein synthesis as one among several of its potential convergent mechanisms. We originally identified Janus kinase and microtubule-interacting protein 1 (JAKMIP1) as differentially expressed in patients with distinct syndromic forms of ASD, fragile X syndrome, and 15q duplication syndrome. Here, we provide multiple lines of evidence that JAKMIP1 is a component of polyribosomes and an RNP translational regulatory complex that includes fragile X mental retardation protein, DEAD box helicase 5, and the poly(A) binding protein cytoplasmic 1. JAKMIP1 loss dysregulates neuronal translation during synaptic development, affecting glutamatergic NMDAR signaling, and results in social deficits, stereotyped activity, abnormal postnatal vocalizations, and other autistic-like behaviors in the mouse. These findings define an important and novel role for JAKMIP1 in neural development and further highlight pathways regulating mRNA translation during synaptogenesis in the genesis of neurodevelopmental disorders.

Brain structure-function associations in multi-generational families genetically enriched for bipolar disorder.

Recent theories regarding the pathophysiology of bipolar disorder suggest contributions of both neurodevelopmental and neurodegenerative processes. While structural neuroimaging studies indicate disease-associated neuroanatomical alterations, the behavioural correlates of these alterations have not been well characterized. Here, we investigated multi-generational families genetically enriched for bipolar disorder to: (i) characterize neurobehavioural correlates of neuroanatomical measures implicated in the pathophysiology of bipolar disorder; (ii) identify brain-behaviour associations that differ between diagnostic groups; (iii) identify neurocognitive traits that show evidence of accelerated ageing specifically in subjects with bipolar disorder; and (iv) identify brain-behaviour correlations that differ across the age span. Structural neuroimages and multi-dimensional assessments of temperament and neurocognition were acquired from 527 (153 bipolar disorder and 374 non-bipolar disorder) adults aged 18-87 years in 26 families with heavy genetic loading for bipolar disorder. We used linear regression models to identify significant brain-behaviour associations and test whether brain-behaviour relationships differed: (i) between diagnostic groups; and (ii) as a function of age. We found that total cortical and ventricular volume had the greatest number of significant behavioural associations, and included correlations with measures from multiple cognitive domains, particularly declarative and working memory and executive function. Cortical thickness measures, in contrast, showed more specific associations with declarative memory, letter fluency and processing speed tasks. While the majority of brain-behaviour relationships were similar across diagnostic groups, increased cortical thickness in ventrolateral prefrontal and parietal cortical regions was associated with better declarative memory only in bipolar disorder subjects, and not in non-bipolar disorder family members. Additionally, while age had a relatively strong impact on all neurocognitive traits, the effects of age on cognition did not differ between diagnostic groups. Most brain-behaviour associations were also similar across the age range, with the exception of cortical and ventricular volume and lingual gyrus thickness, which showed weak correlations with verbal fluency and inhibitory control at younger ages that increased in magnitude in older subjects, regardless of diagnosis. Findings indicate that neuroanatomical traits potentially impacted by bipolar disorder are significantly associated with multiple neurobehavioural domains. Structure-function relationships are generally preserved across diagnostic groups, with the notable exception of ventrolateral prefrontal and parietal association cortex, volumetric increases in which may be associated with cognitive resilience specifically in individuals with bipolar disorder. Although age impacted all neurobehavioural traits, we did not find any evidence of accelerated cognitive decline specific to bipolar disorder subjects. Regardless of diagnosis, greater global brain volume may represent a protective factor for the effects of ageing on executive functioning.

Multisystem component phenotypes of bipolar disorder for genetic investigations of extended pedigrees.

IMPORTANCE: Genetic factors contribute to risk for bipolar disorder (BP), but its pathogenesis remains poorly understood. A focus on measuring multisystem quantitative traits that may be components of BP psychopathology may enable genetic dissection of this complex disorder, and investigation of extended pedigrees from genetically isolated populations may facilitate the detection of specific genetic variants that affect BP as well as its component phenotypes. OBJECTIVE: To identify quantitative neurocognitive, temperament-related, and neuroanatomical phenotypes that appear heritable and associated with severe BP (bipolar I disorder [BP-I]) and therefore suitable for genetic linkage and association studies aimed at identifying variants contributing to BP-I risk. DESIGN, SETTING, AND PARTICIPANTS: Multigenerational pedigree study in 2 closely related, genetically isolated populations: the Central Valley of Costa Rica and Antioquia, Colombia. A total of 738 individuals, all from Central Valley of Costa Rica and Antioquia pedigrees, participated; among them, 181 have BP-I. MAIN OUTCOMES AND MEASURES: Familial aggregation (heritability) and association with BP-I of 169 quantitative neurocognitive, temperament, magnetic resonance imaging, and diffusion tensor imaging phenotypes. RESULTS: Of 169 phenotypes investigated, 126 (75%) were significantly heritable and 53 (31%) were associated with BP-I. About one-quarter of the phenotypes, including measures from each phenotype domain, were both heritable and associated with BP-I. Neuroimaging phenotypes, particularly cortical thickness in prefrontal and temporal regions as well as volume and microstructural integrity of the corpus callosum, represented the most promising candidate traits for genetic mapping related to BP based on strong heritability and association with disease. Analyses of phenotypic and genetic covariation identified substantial correlations among the traits, at least some of which share a common underlying genetic architecture. CONCLUSIONS AND RELEVANCE: To our knowledge, this is the most extensive investigation of BP-relevant component phenotypes to date. Our results identify brain and behavioral quantitative traits that appear to be genetically influenced and show a pattern of BP-I association within families that is consistent with expectations from case-control studies. Together, these phenotypes provide a basis for identifying loci contributing to BP-I risk and for genetic dissection of the disorder.