Benefits of subthalamic nucleus deep brain stimulation on visually-guided saccades depend on stimulation side and classic paradigm in Parkinson's disease.

OBJECTIVE: We aimed to gain further insight into previously reported beneficial effects of subthalamic nucleus deep brain stimulation (STN-DBS) on visually-guided saccades by examining the effects of unilateral compared to bilateral stimulation, paradigm, and target eccentricity on saccades in individuals with Parkinson's disease (PD). METHODS: Eleven participants with PD and STN-DBS completed the visually-guided saccade paradigms with OFF, RIGHT, LEFT, and BOTH stimulation. Rightward saccade performance was evaluated for three paradigms and two target eccentricities. RESULTS: First, we found that BOTH and LEFT increased gain, peak velocity, and duration compared to OFF stimulation. Second, we found that BOTH and LEFT stimulation decreased latency during the gap and step paradigms but had no effect on latency during the overlap paradigm. Third, we found that RIGHT was not different compared to OFF at benefiting rightward saccade performance. CONCLUSIONS: Left unilateral and bilateral stimulation both improve the motor outcomes of rightward visually-guided saccades. Additionally, both improve latency, a cognitive-motor outcome, but only in paradigms when attention does not require disengagement from a present stimulus. SIGNIFICANCE: STN-DBS primarily benefits motor and cognitive-motor aspects of visually-guided saccades related to reflexive attentional shifting, with the latter only evident when the fixation-related attentional system is not engaged.

Peripheral inflammation is associated with impairments of inhibitory behavioral control and visual sensorimotor function in psychotic disorders.

Elevated markers of peripheral inflammation are common in psychosis spectrum disorders and have been associated with brain anatomy, pathology, and physiology as well as clinical outcomes. Preliminary evidence suggests a link between inflammatory cytokines and C-reactive protein (CRP) with generalized cognitive impairments in a subgroup of individuals with psychosis. Whether these patients with elevated peripheral inflammation demonstrate deficits in specific cognitive domains remains unclear. To examine this, seventeen neuropsychological and sensorimotor tasks and thirteen peripheral inflammatory and microvascular markers were quantified in a subset of B-SNIP consortium participants (129 psychosis, 55 healthy controls). Principal component analysis was conducted across the inflammatory markers, resulting in five inflammation factors. Three discrete latent cognitive domains (Visual Sensorimotor, General Cognitive Ability, and Inhibitory Behavioral Control) were characterized based on the neurobehavioral battery and examined in association with inflammation factors. Hierarchical clustering analysis identified cognition-sensitive high/low inflammation subgroups. Among persons with psychotic disorders but not healthy controls, higher inflammation scores had significant associations with impairments of Inhibitory Control (R2 = 0.100, p-value = 2.69e-4, q-value = 0.004) and suggestive associations with Visual Sensorimotor function (R2 = 0.039, p-value = 0.024, q-value = 0.180), but not with General Cognitive Ability (R2 = 0.015, p-value = 0.162). Greater deficits in Inhibitory Control were observed in the high inflammation patient subgroup, which represented 30.2 % of persons with psychotic disorders, as compared to the low inflammation psychosis subgroup. These findings indicate that inflammation dysregulation may differentially impact specific neurobehavioral domains across psychotic disorders, particularly performance on tasks requiring ongoing behavioral monitoring and control.

Profile of Embedded Validity Indicators in Criminal Defendants with Verified Valid Neuropsychological Test Performance.

OBJECTIVE: Few studies have examined the use of embedded validity indicators (EVIs) in criminal-forensic practice settings, where judgements regarding performance validity can carry severe consequences for the individual and society. This study sought to examine how various EVIs perform in criminal defendant populations, and determine relationships between EVI scores and intrapersonal variables thought to influence performance validity. METHOD: Performance on 16 empirically established EVI cutoffs were examined in a sample of 164 criminal defendants with valid performance who were referred for forensic neuropsychological evaluation. Subsequent analyses examined the relationship between EVI scores and intrapersonal variables in 83 of these defendants. RESULTS: Half of the EVIs (within the Wechsler Adult Intelligence Scale Digit Span Total, Conners' Continuous Performance Test Commissions, Wechsler Memory Scale Logical Memory I and II, Controlled Oral Word Association Test, Trail Making Test Part B, and Stroop Word and Color) performed as intended in this sample. The EVIs that did not perform as intended were significantly influenced by relevant intrapersonal variables, including below-average intellectual functioning and history of moderate-severe traumatic brain injury and neurodevelopmental disorder. CONCLUSIONS: This study identifies multiple EVIs appropriate for use in criminal-forensic settings. However, based on these findings, practitioners may wish to be selective in choosing and interpreting EVIs for forensic evaluations of criminal court defendants.

Reduced task-evoked pupillary response in preparation for an executive cognitive control response among individuals across the psychosis spectrum.

Task-evoked pupillary response (TEPR) is a measure of physiological arousal modulated by cognitive demand. Healthy individuals demonstrate greater TEPR prior to correct versus error antisaccade trials and correct antisaccade versus visually guided saccade (VGS) trials. The relationship between TEPR and antisaccade performance in individuals with psychotic disorders and their relatives has not been investigated. Probands with schizophrenia, schizoaffective disorder, psychotic bipolar disorder, their first-degree relatives, and controls from the B-SNIP study completed antisaccade and VGS tasks. TEPR prior to execution of responses on these tasks was evaluated among controls compared to probands and relatives according to diagnostic groups and neurobiologically defined subgroups (biotypes). Controls demonstrated greater TEPR on antisaccade correct versus error versus VGS trials. TEPR was not differentiated between antisaccade correct versus error trials in bipolar or schizophrenia probands, though was greater on antisaccade compared to prosaccade trials. There was no modulation of TEPR in schizoaffective probands. Relatives of schizophrenia and schizoaffective probands and those with elevated psychosis spectrum traits failed to demonstrate differential TEPR on antisaccade correct versus error trials. No proband or relative biotypes demonstrated differential TEPR on antisaccade correct versus error trials, and only proband biotype 3 and relative biotypes 3 and 2 demonstrated greater TEPR on antisaccade versus VGS trials. Our findings suggest that aberrant modulation of preparatory activity prior to saccade execution contributes to impaired executive cognitive control across the psychosis spectrum, including nonpsychotic relatives with elevated clinical risk. Reduced pupillary modulation under cognitive challenge may thus be a biomarker for the psychosis phenotype.

Medication adversely impacts visually-guided eye movements in Parkinson's disease.

OBJECTIVE: We examined whether previous inconsistent findings about the effect of anti-Parkinsonian medication on visually-guided saccades (VGS) were due to the use of different paradigms, which change the timing of fixation offset and target onset, or different target eccentricities. METHODS: Thirty-three participants with Parkinson's disease (PD) completed the VGS tasks OFF and ON medication, along with 13 healthy controls. Performance on 3 paradigms (gap, step, and overlap) and 2 target eccentricities was recorded. We used mixed models to determine the effect of medication, paradigm, and target eccentricity on saccade latency, gain, and peak velocity. RESULTS: First, we confirmed known paradigm effects on latency, and target eccentricity effects on gain and peak velocity in participants with PD. Second, latency was positively associated with OFF medication Movement Disorders Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score in PD. Third, medication prolonged latency for the larger target eccentricity across the 3 paradigms, while decreasing gain and peak velocity in the step paradigm across target eccentricities. CONCLUSIONS: Medication adversely affected and was not therapeutically beneficial for VGS. Previous inconsistencies may have resulted from chosen target eccentricity. SIGNIFICANCE: The negative medication effect on VGS may be clinically significant, as many activities in daily life require oculomotor control, inhibitory control, and visually-guided shifts of attention.

Shape features of working memory-related deep-brain regions differentiate high and low community functioning in schizophrenia.

We have previously shown that schizophrenia (SCZ) participants with high community functioning demonstrate better verbal working memory (vWM) performance relative to those with low community functioning. In the present study, we investigated whether neuroanatomical differences in regions supporting vWM also exist between schizophrenia groups that vary on community functioning. Utilizing magnetic resonance imaging, shape features of deep-brain nuclei known to be involved in vWM were calculated in samples of high functioning (HF-SCZ, n = 23) and low functioning schizophrenia participants (LF-SCZ, n = 18), as well as in a group of healthy control participants (CON, n = 45). Large deformation diffeomorphic metric mapping was employed to characterize surface anatomy of the caudate nucleus, globus pallidus, hippocampus, and thalamus. Statistical analyses involved linear mixed-effects models and vertex-wise contrast mapping to assess between-group differences in structural shape features, and Pearson correlations to evaluate relationships between shape metrics and vWM performance. We found significant between-group main effects in deep-brain surface anatomy across all structures. Post-hoc comparisons revealed HF-SCZ and LF-SCZ groups significantly differed on both caudate and hippocampal shape, however, significant correlations with vWM were only observed in hippocampal shape for both SCZ groups. Specifically, more abnormal hippocampal deformation was associated with lower vWM suggesting hippocampal shape is both a neural substrate for vWM deficits and a potential biomarker to predict or monitor the efficacy of cognitive rehabilitation. These findings add to a growing body of literature related to functional outcomes in schizophrenia by demonstrating unique shape patterns across the spectrum of community functioning in SCZ.

The Epistemic Fallacy: Unintended Consequences of Empirically Treating (Clinically Diagnosed) Chronic Lyme Disease in a Soldier.

OBJECTIVE: We document a military patient presenting with a diffuse set of symptoms suggestive of chronic Lyme disease (CLD) and the subsequent empiric treatment and health complications arising therein. The lay medical community, spurred by the internet, has ascribed these diffuse symptoms to various illnesses including CLD without confirmatory serological evidence of any underlying disease. With a growing community of patient advocates, CLD has become an illness with broad and highly generalized list of clinical symptoms and an absence of agreed-upon confirmatory laboratory tests. Further complicating matters, diagnostic criteria and treatment protocols differ between the Infectious Diseases Society of America and the International Lyme and Associated Diseases Society guidelines. Clinicians also face serious challenges in diagnosing and treating patients who present with generalized symptoms and close to 50 diagnostic tests for Lyme disease available in North America. Further complicating the picture for military patients seeking medical confirmation of a disease and resolution of their symptoms, medical fitness boards use putative diagnoses as prima faciae evidence in disability. Here a military patient with a long list of complaints that defy any clear or easy diagnosis and treatment is discussed. However, these symptoms taken together with selectively summed notes in the medical record in the absence of convincing and clear laboratory confirmation are suggestive of CLD and its complications, but no resolution was ultimately reached. With the presumptive determination of a medical disability due to CLD by the medical board, the medical dismissal of this service member from active duty occurred.

Impact of polygenic risk for coronary artery disease and cardiovascular medication burden on cognitive impairment in psychotic disorders.

BACKGROUND: Cognitive impairment is a core deficit across psychotic disorders, the causes and therapeutics of which remain unclear. Epidemiological observations have suggested associations between cognitive dysfunction in psychotic disorders and cardiovascular risk factors, but an underlying etiology has not been established. METHODS: Neuropsychological performance using the Brief Assessment of Cognition in Schizophrenia (BACS) was assessed in 616 individuals of European ancestry (403 psychosis, 213 controls). Polygenic risk scores for coronary artery disease (PRSCAD) were quantified for each participant across 13 p-value thresholds (PT 0.5-5e-8). Cardiovascular and psychotropic medications were categorized for association analyses. Each PRSCAD was examined in relation to the BACS and the optimized PT was confirmed with five-fold cross-validation and independent validation. Functional enrichment analyses were used to identify biological mechanisms linked to PRSCAD-cognition associations. Multiple regression analyses examined PRSCAD under the optimal PT and medication burden in relation to the BACS composite and subtest scores. RESULTS: Higher PRSCAD was associated with lower BACS composite scores (p = 0.001) in the psychosis group, primarily driven by the Verbal Memory subtest (p < 0.001). Genes linked to multiple nervous system related processes and pathways were significantly enriched in PRSCAD. After controlling for PRSCAD, a greater number of cardiovascular medications was also correlated with worse BACS performance in patients with psychotic disorders (p = 0.029). CONCLUSIONS: Higher PRSCAD and taking more cardiovascular medications were both significantly associated with cognitive impairment in psychosis. These findings indicate that cardiovascular factors may increase the risk for cognitive dysfunction and related functional outcomes among individuals with psychotic disorders.

Differentiating Perpetrators of Intimate Partner Violence From Other Violent Offenders Using a Statistical Learning Model: The Role of Cognition and Life History Variables.

Intimate partner violence (IPV) is a widespread crime that victimizes over 4-million women per year in the United States and results in significant monetary cost and unmeasured physical and psychological consequences for victims. Specialized IPV offender treatment programs demonstrate limited effectiveness, which may be due to an insufficient understanding of the factors that differentiate between IPV perpetrators and non-IPV violent offenders. In this study, we utilized classification and regression tree (CART) analysis to identify combinations of factors that best discriminate IPV perpetrators from non-IPV violent offenders. We also compared cognitive abilities between IPV perpetrators and non-IPV violent offenders using standardized neurocognitive tests. CART analysis presented two pathways for identifying offenders as IPV perpetrators: (a) extensive nonviolent criminal history and (b) moderate-to-severe expression of interpersonal traits of psychopathy without attentional deficits. In addition, a third pathway identified non-IPV violent offenders: (c) low levels of interpersonal psychopathic traits and no history of neurodevelopmental diagnosis. IPV perpetrators demonstrated intact cognition relative to test norms, and study groups did not significantly differ on cognitive performance. These findings suggest that individuals with multiple arrests for nonviolent crime or individuals with interpersonal traits of psychopathy without attentional difficulties may be at enhanced risk for IPV perpetration.

Eye Movements Detect Differential Change after Participation in Male Collegiate Collision versus Non-Collision Sports.

Although neuroimaging studies of collision (COLL) sport athletes demonstrate alterations in brain structure and function from pre- to post-season, reliable tools to detect behavioral/cognitive change relevant to functional networks associated with participation in collision sports are lacking. This study evaluated the use of eye-movement testing to detect change in cognitive and sensorimotor processing among male club collegiate athletes after one season of participation in collision sports of variable exposure. We predicted that COLL (High Dose [hockey], n = 8; Low Dose [rugby], n = 9) would demonstrate longer reaction times (antisaccade and memory-guided saccade [MGS] latencies), increased inhibitory errors (antisaccade error rate), and poorer spatial working memory (MGS spatial accuracy) at post-season, relative to pre-season, whereas non-collision collegiate athletes (NON-COLL; n = 17) would remain stable. We also predicted that whereas eye-movement performance would detect pre- to post-season change, ImPACT (Immediate Post-Concussion Assessment and Cognitive Test) performance would remain stable. Our data showed that NON-COLL had shorter (improved performance) post- versus pre-season antisaccade and MGS latencies, whereas COLL groups showed stable, longer, or attenuated reduction in latency (ps ≤ 0.001). Groups did not differ in antisaccade error rate. On the MGS task, NON-COLL demonstrated improved spatial accuracy over time, whereas COLL groups showed reduced spatial accuracy (p < 0.05, uncorrected). No differential change was observed on ImPACT. This study provides preliminary evidence for eye-movement testing as a sensitive marker of subtle changes in attentional control and working memory resulting from participation in sports with varying levels of subconcussive exposure.

Deficits in generalized cognitive ability, visual sensorimotor function, and inhibitory control represent discrete domains of neurobehavioral deficit in psychotic disorders.

Psychotic disorders are characterized by impaired cognition, yet some reports indicate specific deficits extend beyond reduced general cognitive ability. This study utilized exploratory and confirmatory factor analytic methods to evaluate the latent structure of a broad neurocognitive battery used in the Bipolar-Schizophrenia Network of Intermediate Phenotypes (B-SNIP) study, which included neuropsychological and neurophysiological measures in psychotic disorder probands and their unaffected first-degree relatives. Findings indicate that the factor structure of data from this set of assessments is more complex than the unitary factor of global cognitive ability underlying the Brief Assessment of Cognition in Schizophrenia (BACS). In addition to assessing generalized cognitive ability, two other factors were identified: visual sensorimotor function and inhibitory behavioral control. This complex cognitive architecture, derived in controls, generalized to patients across the psychosis spectrum and to their unaffected relatives. These findings highlight the need for a more differentiated assessment of neurobehavioral functions in studies designed to test for diagnostically specific biomarkers, endophenotypes for gene discovery and beneficial effects of therapeutics on cognitive function.

Genome-wide association study accounting for anticholinergic burden to examine cognitive dysfunction in psychotic disorders.

Identifying genetic contributors to cognitive impairments in psychosis-spectrum disorders can advance understanding of disease pathophysiology. Although CNS medications are known to affect cognitive performance, they are often not accounted for in genetic association studies. In this study, we performed a genome-wide association study (GWAS) of global cognitive performance, measured as composite z-scores from the Brief Assessment of Cognition in Schizophrenia (BACS), in persons with psychotic disorders and controls (N = 817; 682 cases and 135 controls) from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Analyses accounting for anticholinergic exposures from both psychiatric and non-psychiatric medications revealed five significantly associated variants located at the chromosome 3p21.1 locus, with the top SNP rs1076425 in the inter-alpha-trypsin inhibitor heavy chain 1 (ITIH1) gene (P = 3.25×E-9). The inclusion of anticholinergic burden improved association models (P < 0.001) and the number of significant SNPs identified. The effect sizes and direction of effect of the top variants remained consistent when investigating findings within individuals receiving specific antipsychotic drugs and after accounting for antipsychotic dose. These associations were replicated in a separate study sample of untreated first-episode psychosis. The chromosome 3p21.1 locus was previously reported to have association with the risk for psychotic disorders and cognitive performance in healthy individuals. Our findings suggest that this region may be a psychosis risk locus that is associated with cognitive mechanisms. Our data highlight the general point that the inclusion of medication exposure information may improve the detection of gene-cognition associations in psychiatric genetic research.

Preliminary Report: Localized Cerebral Blood Flow Mediates the Relationship between Progesterone and Perceived Stress Symptoms among Female Collegiate Club Athletes after Mild Traumatic Brain Injury.

Female athletes are under-studied in the field of concussion research, despite evidence of higher injury prevalence and longer recovery time. Hormonal fluctuations caused by the natural menstrual cycle (MC) or hormonal contraceptive (HC) use impact both post-injury symptoms and neuroimaging findings, but the relationships among hormone, symptoms, and brain-based measures have not been jointly considered in concussion studies. In this preliminary study, we compared cerebral blood flow (CBF) measured with arterial spin labeling between concussed female club athletes 3-10 days after mild traumatic brain injury (mTBI) and demographic, HC/MC matched controls (CON). We tested whether CBF statistically mediates the relationship between progesterone serum levels and post-injury symptoms, which may support a hypothesis for progesterone's role in neuroprotection. We found a significant three-way relationship among progesterone, CBF, and perceived stress score (PSS) in the left middle temporal gyrus for the mTBI group. Higher progesterone was associated with lower (more normative) PSS, as well as higher (more normative) CBF. CBF mediates 100% of the relationship between progesterone and PSS (Sobel p value = 0.017). These findings support a hypothesis for progesterone having a neuroprotective role after concussion and highlight the importance of controlling for the effects of sex hormones in future concussion studies.

Brain Perfusion Bridges Virtual-Reality Spatial Behavior to TPH2 Genotype for Head Acceleration Events.

Neuroimaging demonstrates that athletes of collision sports can suffer significant changes to their brain in the absence of concussion, attributable to head acceleration event (HAE) exposure. In a sample of 24 male Division I collegiate football players, we examine the relationships between tryptophan hydroxylase 2 (TPH2), a gene involved in neurovascular function, regional cerebral blood flow (rCBF) measured by arterial spin labeling, and virtual reality (VR) motor performance, both pre-season and across a single football season. For the pre-season, TPH2 T-carriers showed lower rCBF in two left hemisphere foci (fusiform gyrus/thalamus/hippocampus and cerebellum) in association with higher (better performance) VR Reaction Time, a dynamic measure of sensory-motor reactivity and efficiency of visual-spatial processing. For TPH2 CC homozygotes, higher pre-season rCBF in these foci was associated with better performance on VR Reaction Time. A similar relationship was observed across the season, where TPH2 T-carriers showed improved VR Reaction Time associated with decreases in rCBF in the right hippocampus/amygdala, left middle temporal lobe, and left insula/putamen/pallidum. In contrast, TPH2 CC homozygotes showed improved VR Reaction Time associated with increases in rCBF in the same three clusters. These findings show that TPH2 T-carriers have an abnormal relationship between rCBF and the efficiency of visual-spatial processing that is exacerbated after a season of high-impact sports in the absence of diagnosable concussion. Such gene-environment interactions associated with behavioral changes after exposure to repetitive HAEs have been unrecognized with current clinical analytical tools and warrant further investigation. Our results demonstrate the importance of considering neurovascular factors along with traumatic axonal injury to study long-term effects of repetitive HAEs.

Multivariate relationships between peripheral inflammatory marker subtypes and cognitive and brain structural measures in psychosis.

Elevations in peripheral inflammatory markers have been reported in patients with psychosis. Whether this represents an inflammatory process defined by individual or subgroups of markers is unclear. Further, relationships between peripheral inflammatory marker elevations and brain structure, cognition, and clinical features of psychosis remain unclear. We hypothesized that a pattern of plasma inflammatory markers, and an inflammatory subtype established from this pattern, would be elevated across the psychosis spectrum and associated with cognition and brain structural alterations. Clinically stable psychosis probands (Schizophrenia spectrum, n = 79; Psychotic Bipolar disorder, n = 61) and matched healthy controls (HC, n = 60) were assessed for 15 peripheral inflammatory markers, cortical thickness, subcortical volume, cognition, and symptoms. A combination of unsupervised exploratory factor analysis and hierarchical clustering was used to identify inflammation subtypes. Levels of IL6, TNFα, VEGF, and CRP were significantly higher in psychosis probands compared to HCs, and there were marker-specific differences when comparing diagnostic groups. Individual and/or inflammatory marker patterns were associated with neuroimaging, cognition, and symptom measures. A higher inflammation subgroup was defined by elevations in a group of 7 markers in 36% of Probands and 20% of HCs. Probands in the elevated inflammatory marker group performed significantly worse on cognitive measures of visuo-spatial working memory and response inhibition, displayed elevated hippocampal, amygdala, putamen and thalamus volumes, and evidence of gray matter thickening compared to the proband group with low inflammatory marker levels. These findings specify the nature of peripheral inflammatory marker alterations in psychotic disorders and establish clinical, neurocognitive and neuroanatomic associations with increased inflammatory activation in psychosis. The identification of a specific subgroup of patients with inflammatory alteration provides a potential means for targeting treatment with anti-inflammatory medications.

Differential Change in Oculomotor Performance among Female Collegiate Soccer Players versus Non-Contact Athletes from Pre- to Post-Season.

Sensitive and reliable tools are needed to evaluate potential behavioral and cognitive changes following head impact exposure in contact and collision sport participation. We evaluated change in oculomotor testing performance among female, varsity, collegiate athletes following variable exposure to head impacts across a season. Female, collegiate, contact sport (soccer, CONT) and non-contact sport (NON-CONT) athletes were assessed pre-season and post-season. Soccer athletes were grouped according to total season game headers into low dose (≤40 headers; CONT-Low Dose) or high dose (>40 headers; CONT-High Dose) groups. Performance on pro-saccade (reflexive visual response), anti-saccade (executive inhibition), and memory-guided saccade (MGS, spatial working memory) computer-based laboratory tasks were assessed. Primary saccade measures included latency/reaction time, inhibition error rate (anti-saccade only), and spatial accuracy (MGS only). NON-CONT (n = 20), CONT-Low Dose (n = 17), and CONT-High Dose (n = 7) groups significantly differed on pre-season versus post-season latency on tasks with executive functioning demands (anti-saccade and MGS, p ≤ 0.001). Specifically, NON-CONT and CONT-Low Dose demonstrated shorter (i.e., faster) anti-saccade (1.84% and 2.68%, respectively) and MGS (5.74% and 2.76%, respectively) latencies from pre-season to post-season, whereas CONT-High Dose showed 1.40% average longer anti-saccade, and 0.74% shorter MGS, latencies. NON-CONT and CONT-Low Dose demonstrated reduced (i.e., improved) inhibition error rate on the anti-saccade task at post-season versus pre-season, whereas CONT-High Dose demonstrated relative stability (p = 0.021). The results of this study suggest differential exposure to subconcussive head impacts in collegiate female athletes is associated with differential change in reaction time and inhibitory control performances on executive saccadic oculomotor testing.

Catechol-O-methyltransferase genotype differentially contributes to the flexibility and stability of cognitive sets in patients with psychotic disorders and their first-degree relatives.

Dopaminergic activity in prefrontal cortex is modulated by the low (Met) and high (Val) activity of the rs4680 Val158Met single nucleotide polymorphism (SNP) in the Catechol-O-Methyltransferase (COMT) gene. While this has been related to working memory maintenance in patients with schizophrenia, the familial pattern, impact across the psychosis spectrum, and the role of this genotype on other aspects of behavior, such as cognitive flexibility, remains unclear. The relationship between COMT Val158Met genotype and both cognitive stability and flexibility were assessed using the Penn Conditional Exclusion Test (PCET) in healthy controls (n = 241), patients with psychotic disorders (n = 542), and their first-degree relatives (n = 613) from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium. Higher rates of perseverative errors (poor flexibility) were associated with the low-activity COMT genotype (Met allele carriers) in probands compared to their first-degree relatives with the same genotype. Probands and first-degree relatives homozygous for the high-activity COMT enzyme (Val/Val) showed elevated rates of regressive errors (poor stability) compared to controls. Conversely, heterozygous relatives had comparable regressive error rates to controls, with probands showing elevated errors in comparison. These findings suggest that impaired suppression of learned response patterns and reduced stability of mental sets may be a familial intermediate cognitive phenotype related to Val COMT allele genotype.

The effect of high vs. low dose lurasidone on eye movement biomarkers of prefrontal abilities in treatment-resistant schizophrenia.

OBJECTIVE: Eye movement (EM) measures can serve as biomarkers to evaluate pharmacological effects on brain systems involved in cognition. In recent onset schizophrenia, antipsychotic treatment can improve attentional control on the antisaccade task and exacerbate working memory impairment on the memory guided saccade task; effects in treatment-resistant schizophrenia (TRS) are less clear. This study evaluated the effects of high versus low dose lurasidone on EM performance in TRS. METHODS: TRS patients completed EM testing: 1) at baseline, on existing medication regimen (n = 42), 2) after 6 weeks of low dose (80 mg) lurasidone (n = 38), 3) after 12 weeks following randomization to low (80 mg) or high dose (240 mg) lurasidone (n = 27), and 4) after 24 weeks of treatment (n = 23). EM testing included prosaccade, antisaccade, and memory guided saccade tasks. RESULTS: Six weeks of lurasidone resulted in increased prosaccade saccade latency and reduced antisaccade errors, with no change in memory guided saccade accuracy. After randomization, prosaccade and antisaccade latencies increased in only the high dose group, with no change in antisaccade errors in both groups. Memory guided saccade error increased in the high dose group and remained stable in the low dose group. CONCLUSION: Among TRS, stabilization on low dose lurasidone was associated with improved executive control of attention reflected by reduced antisaccade errors. High dose lurasidone resulted in prolonged speed of reflexive and executive shifts of attention and reduced spatial working memory relative to low dose. These findings indicate that EM measures are helpful biomarkers of dose-dependent antipsychotic treatment effects on executive cognitive abilities in TRS.

Brain Perfusion Mediates the Relationship Between miRNA Levels and Postural Control.

Transcriptomics, regional cerebral blood flow (rCBF), and a virtual reality-based spatial motor task were integrated using mediation analysis in a novel demonstration of "imaging omics." Data collected in National Collegiate Athletic Association (NCAA) Division I football athletes cleared for play before in-season training showed significant relationships in 1) elevated levels of miR-30d and miR-92a to elevated putamen rCBF, 2) elevated putamen rCBF to compromised Balance scores, and 3) compromised Balance scores to elevated microRNA (miRNA) levels. rCBF acted as a consistent mediator variable (Sobel's test P < 0.05) between abnormal miRNA levels and compromised Balance scores. Given the involvement of these miRNAs in inflammation and immune function and that vascular perfusion is a component of the inflammatory response, these findings support a chronic inflammatory model in these athletes with 11 years of average football exposure. rCBF, a systems biology measure, was necessary for miRNA to affect behavior.

NRXN1 is associated with enlargement of the temporal horns of the lateral ventricles in psychosis.

Schizophrenia, Schizoaffective, and Bipolar disorders share behavioral and phenomenological traits, intermediate phenotypes, and some associated genetic loci with pleiotropic effects. Volumetric abnormalities in brain structures are among the intermediate phenotypes consistently reported associated with these disorders. In order to examine the genetic underpinnings of these structural brain modifications, we performed genome-wide association analyses (GWAS) on 60 quantitative structural brain MRI phenotypes in a sample of 777 subjects (483 cases and 294 controls pooled together). Genotyping was performed with the Illumina PsychChip microarray, followed by imputation to the 1000 genomes multiethnic reference panel. Enlargement of the Temporal Horns of Lateral Ventricles (THLV) is associated with an intronic SNP of the gene NRXN1 (rs12467877, P = 6.76E-10), which accounts for 4.5% of the variance in size. Enlarged THLV is associated with psychosis in this sample, and with reduction of the hippocampus and enlargement of the choroid plexus and caudate. Eight other suggestively significant associations (P < 5.5E-8) were identified with THLV and 5 other brain structures. Although rare deletions of NRXN1 have been previously associated with psychosis, this is the first report of a common SNP variant of NRXN1 associated with enlargement of the THLV in psychosis.