Diffusion imaging markers of bipolar versus general psychopathology risk in youth at-risk.

Bipolar disorder (BD) is highly heritable. Thus, studies in first-degree relatives of individuals with BD could lead to the discovery of objective risk markers of BD. Abnormalities in white matter structure reported in at-risk individuals could play an important role in the pathophysiology of BD. Due to the lack of studies with other at-risk offspring, however, it remains unclear whether such abnormalities reflect BD-specific or generic risk markers for future psychopathology. Using a tract-profile approach, we examined 18 major white matter tracts in 38 offspring of BD parents, 36 offspring of comparison parents with non-BD psychopathology (depression, attention-deficit/hyperactivity disorder), and 41 offspring of healthy parents. Both at-risk groups showed significantly lower fractional anisotropy (FA) in left-sided tracts (cingulum, inferior longitudinal fasciculus, forceps minor), and significantly greater FA in right-sided tracts (uncinate fasciculus and inferior longitudinal fasciculus), relative to offspring of healthy parents (P < 0.05). These abnormalities were present in both healthy and affected youth in at-risk groups. Only offspring (particularly healthy offspring) of BD parents showed lower FA in the right superior longitudinal fasciculus relative to healthy offspring of healthy parents (P < 0.05). We show, for the first time, important similarities, and some differences, in white matter structure between offspring of BD and offspring of non-BD parents. Findings suggest that lower left-sided and higher right-sided FA in tracts important for emotional regulation may represent markers of risk for general, rather than BD-specific, psychopathology. Lower FA in the right superior longitudinal fasciculus may protect against development of BD in offspring of BD parents.

Motor system dysfunction in the schizophrenia diathesis: Neural systems to neurotransmitters.

Motor control is a ubiquitous aspect of human function, and from its earliest origins, abnormal motor control has been proposed as being central to schizophrenia. The neurobiological architecture of the motor system is well understood in primates and involves cortical and sub-cortical components including the primary motor cortex, supplementary motor area, dorsal anterior cingulate cortex, the prefrontal cortex, the basal ganglia, and cerebellum. Notably all of these regions are associated in some manner to the pathophysiology of schizophrenia. At the molecular scale, both dopamine and γ-Aminobutyric Acid (GABA) abnormalities have been associated with working memory dysfunction, but particularly relating to the basal ganglia and the prefrontal cortex respectively. As evidence from multiple scales (behavioral, regional and molecular) converges, here we provide a synthesis of the bio-behavioral relevance of motor dysfunction in schizophrenia, and its consistency across scales. We believe that the selective compendium we provide can supplement calls arguing for renewed interest in studying the motor system in schizophrenia. We believe that in addition to being a highly relevant target for the study of schizophrenia related pathways in the brain, such focus provides tractable behavioral probes for in vivo imaging studies in the illness. Our assessment is that the motor system is a highly valuable research domain for the study of schizophrenia.

Reward-related neural activity and structure predict future substance use in dysregulated youth.

BACKGROUND: Identifying youth who may engage in future substance use could facilitate early identification of substance use disorder vulnerability. We aimed to identify biomarkers that predicted future substance use in psychiatrically un-well youth. METHOD: LASSO regression for variable selection was used to predict substance use 24.3 months after neuroimaging assessment in 73 behaviorally and emotionally dysregulated youth aged 13.9 (s.d. = 2.0) years, 30 female, from three clinical sites in the Longitudinal Assessment of Manic Symptoms (LAMS) study. Predictor variables included neural activity during a reward task, cortical thickness, and clinical and demographic variables. RESULTS: Future substance use was associated with higher left middle prefrontal cortex activity, lower left ventral anterior insula activity, thicker caudal anterior cingulate cortex, higher depression and lower mania scores, not using antipsychotic medication, more parental stress, older age. This combination of variables explained 60.4% of the variance in future substance use, and accurately classified 83.6%. CONCLUSIONS: These variables explained a large proportion of the variance, were useful classifiers of future substance use, and showed the value of combining multiple domains to provide a comprehensive understanding of substance use development. This may be a step toward identifying neural measures that can identify future substance use disorder risk, and act as targets for therapeutic interventions.

Predicting clinical outcome from reward circuitry function and white matter structure in behaviorally and emotionally dysregulated youth.

Behavioral and emotional dysregulation in childhood may be understood as prodromal to adult psychopathology. Additionally, there is a critical need to identify biomarkers reflecting underlying neuropathological processes that predict clinical/behavioral outcomes in youth. We aimed to identify such biomarkers in youth with behavioral and emotional dysregulation in the Longitudinal Assessment of Manic Symptoms (LAMS) study. We examined neuroimaging measures of function and white matter in the whole brain using 80 youth aged 14.0 (s.d.=2.0) from three clinical sites. Linear regression using the LASSO (Least Absolute Shrinkage and Selection Operator) method for variable selection was used to predict severity of future behavioral and emotional dysregulation measured by the Parent General Behavior Inventory-10 Item Mania Scale (PGBI-10M)) at a mean of 14.2 months follow-up after neuroimaging assessment. Neuroimaging measures, together with near-scan PGBI-10M, a score of manic behaviors, depressive behaviors and sex, explained 28% of the variance in follow-up PGBI-10M. Neuroimaging measures alone, after accounting for other identified predictors, explained ~1/3 of the explained variance, in follow-up PGBI-10M. Specifically, greater bilateral cingulum length predicted lower PGBI-10M at follow-up. Greater functional connectivity in parietal-subcortical reward circuitry predicted greater PGBI-10M at follow-up. For the first time, data suggest that multimodal neuroimaging measures of underlying neuropathologic processes account for over a third of the explained variance in clinical outcome in a large sample of behaviorally and emotionally dysregulated youth. This may be an important first step toward identifying neurobiological measures with the potential to act as novel targets for early detection and future therapeutic interventions.

Neural dysfunction in ADHD with Reading Disability during a word rhyming Continuous Performance Task.

BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a heterogeneous, neurodevelopmental disorder which co-occurs often with Reading Disability (RD). ADHD with and without RD consistently have higher inattentive ratings compared with typically developing controls, with co-occurring ADHD and RD also demonstrating impaired phonological processing. Accordingly, inattention has been associated with greater phonological impairment, though the neural correlates of the association are poorly understood from a functional neuroimaging perspective. It was postulated that only the co-occurring subgroup would demonstrate hypoactivation of posterior, left hemispheric, reading-related areas and, to a lesser extent, alterations in right hemispheric, attention areas compared with controls. METHODS: A novel word rhyming Continuous Performance Task assesses functional activation differences in phonology- and attention-related areas between three groups: ten boys with ADHD and RD, fourteen boys with ADHD without RD, and fourteen typically developing controls. Subjects respond to words that rhyme with a target word as mono- and disyllabic, English words are visually presented over 90s blocks. RESULTS: Behavioral performance was not different between groups. Some hypoactivation of left hemispheric, reading-related areas was apparent in ADHD and RD, but not ADHD without RD, compared with controls. Right hemispheric, attention areas showed alterations in both ADHD subgroups relative to controls; however, the differences for each subgroup were dissimilar. CONCLUSIONS: The dorsal decoding subnetwork may not be grossly compromised in ADHD with Reading Disability. The role of cognitive impairments, including the level of inattention, on phonology requires clarification from a neuroimaging perspective.

Behavioral and emotional dysregulation trajectories marked by prefrontal-amygdala function in symptomatic youth.

BACKGROUND: Neuroimaging measures of behavioral and emotional dysregulation can yield biomarkers denoting developmental trajectories of psychiatric pathology in youth. We aimed to identify functional abnormalities in emotion regulation (ER) neural circuitry associated with different behavioral and emotional dysregulation trajectories using latent class growth analysis (LCGA) and neuroimaging. METHOD: A total of 61 youth (9-17 years) from the Longitudinal Assessment of Manic Symptoms study, and 24 healthy control youth, completed an emotional face n-back ER task during scanning. LCGA was performed on 12 biannual reports completed over 5 years of the Parent General Behavior Inventory 10-Item Mania Scale (PGBI-10M), a parental report of the child's difficulty regulating positive mood and energy. RESULTS: There were two latent classes of PGBI-10M trajectories: high and decreasing (HighD; n=22) and low and decreasing (LowD; n=39) course of behavioral and emotional dysregulation over the 12 time points. Task performance was >89% in all youth, but more accurate in healthy controls and LowD versus HighD (p<0.001). During ER, LowD had greater activity than HighD and healthy controls in the dorsolateral prefrontal cortex, a key ER region, and greater functional connectivity than HighD between the amygdala and ventrolateral prefrontal cortex (p's<0.001, corrected). CONCLUSIONS: Patterns of function in lateral prefrontal cortical-amygdala circuitry in youth denote the severity of the developmental trajectory of behavioral and emotional dysregulation over time, and may be biological targets to guide differential treatment and novel treatment development for different levels of behavioral and emotional dysregulation in youth.

Adolescent risk pathways toward schizophrenia: sustained attention and the brain.

Schizophrenia is a complex epigenetic puzzle, the antecedents of which are presumed to lie in neurodevelopmental dysmaturation. This dysmaturation has an impact on children and adolescents at genetic risk for schizophrenia. In this framework, normative mechanisms of brain development that are highly dynamic in adolescence are likely to be disrupted in the at-risk adolescent brain. It is likely that what is affected is the integrity of brain networks that sub-serve fundamental domains of function such as sustained attention. Notably, expansion in proficiency in sustained attention that is characteristic of typical development is likely to be compromised in adolescents at risk for schizophrenia. This confluence of at-risk adolescents and neuro-behavioral domains of inquiry is discussed. We outline the evidence for developmental antecedents of schizophrenia, and their bases in systems and molecular mechanisms in the brain. Then we juxtapose these results against neuro-behavioral evidence of attention deficits in high-risk populations, and fMRI evidence of dysfunctional responses in critical brain regions. We end by advocating the application of systems-based approaches toward understanding the progression of network dysfunction in the adolescent risk-state.

Pathological effects of cortical architecture on working memory in schizophrenia.

Neural connectivity of the prefrontal cortex is essential to working memory. Reduction of prefrontal connectivity and abnormal prefrontal dopamine modulation are common characteristics associated with schizophrenia. Two experiments separately modeled the effects of exaggerated pruning and of synaptic depression to imitate schizophrenic performance in a prefrontal neural network. In the first model, effects of cortical pruning were simulated with a set of scale-free networks of neurons and compared with empirical results from the Sternberg working memory task. The second set of simulations were based on the synaptic theory of working memory. Simulations of this model measured memory duration in relation to synaptic facilitation and depression constants and in relation to the level of neural connectivity. In the first set of simulations, modulating levels of cortical pruning resulted in a gain or loss in accuracy and speed of memory recollection. In the second set of simulations, increased facilitation time constants and decreased inhibitory time constants resulting in longer memory durations, and overly connected networks resulted in very low memory durations. In the first model, the decline in memory performance can be attributed to the emergence of pathological memory behavior brought about by the warping of the basins of attraction. Collectively, the simulations demonstrate that a reduction of prefrontal cortical hubs can lead to schizophrenia like performance in neural networks, and may account for pathological working memory in the disorder.

Abnormalities of the corpus callosum in first episode, treatment naive schizophrenia.

BACKGROUND: Structural alterations in the association cortices as well as in the corpus callosum (CC) have been described in schizophrenia, and have been considered to reflect developmental abnormalities. Areas of primary and association cortices have been topographically mapped in the CC. OBJECTIVE: To investigate whether, in schizophrenia, there are alterations in CC subdivisions that connect association, but not primary, cortices, and also to see if the normative, developmentally mediated increase in CC size with age is absent in this disorder. METHODS: The midsagittal magnetic resonance imaging scans of 31 first episode, neuroleptic naive, schizophrenic patients, 12 non-schizophrenic, psychotic patients, and 31 healthy controls were compared. The total area of CC as well as that of anterior, middle and posterior genu, body, isthmus, and anterior, middle, and posterior splenii were measured. RESULTS: Patients with schizophrenia as a group had a smaller CC, anterior genu, anterior body, isthmus, and anterior splenium than normal controls. Furthermore, the age related increase in CC size seen in normal subjects was absent in the patients. CONCLUSIONS: The observed reductions in size in selected regions of CC suggest a reduction in axonal connections between the heteromodal association cortices, which typically involve small diameter fibres. Furthermore, the absence of an age related increase in CC size in patients with schizophrenia suggests a neurodevelopmental abnormality that may extend into adolescence and early adulthood.

Mental rotation of objects retrieved from memory: a functional MRI study of spatial processing.

This functional MRI study examined how people mentally rotate a 3-dimensional object (an alarm clock) that is retrieved from memory and rotated according to a sequence of auditory instructions. We manipulated the geometric properties of the rotation, such as having successive rotation steps around a single axis versus alternating between 2 axes. The latter condition produced much more activation in several areas. Also, the activation in several areas increased with the number of rotation steps. During successive rotations around a single axis, the activation was similar for rotations in the picture plane and rotations in depth. The parietal (but not extrastriate) activation was similar to mental rotation of a visually presented object. The findings indicate that a large-scale cortical network computes different types of spatial information by dynamically drawing on each of its components to a differential, situation-specific degree.

Oculomotor delayed response abnormalities in young offspring and siblings at risk for schizophrenia.

Individuals with schizophrenia are know to demonstrate cognitive and behavioral difficulties, particularly alterations in executive functions, including working memory. It is unclear whether these deficits reflect trait-related vulnerability to schizophrenia indicators and can be assessed by studying nonpsychotic relatives of patients with schizophrenia. In this study, we used an oculomotor delayed response (ODR) paradigm to examine spatial working memory in 37 "high-risk" child and adolescent offspring and siblings (age range=6-25 years) of patients with schizophrenia or schizoaffective disorder. Compared with 37 age- and sex-matched healthy controls (age range=6-23 years), high-risk subjects showed nonsignificantly greater errors in the ODR task at longer delay intervals. Statistical analyses suggested that performance improved with age in healthy control subjects, whereas it worsened with age in high-risk subjects. In both groups, the ODR errors were generally associated with poorer sustained attention (Continuous Performance Test: visuospatial d prime), somewhat poorer executive function (Wisconsin Card Sorting Test), and elevated Heinrichs-Buchanan neurological soft signs scores. These findings indicate the presence of spatial working memory abnormalities in individuals at risk for schizophrenia. Furthermore, these abnormalities may be progressive in nature. The ODR task is a valuable indicator of prefrontal cortical function and spatial working memory and may be a potentially valuable marker for familial risk of schizophrenia.

Collaborative activity between parietal and dorso-lateral prefrontal cortex in dynamic spatial working memory revealed by fMRI.

Functional MRI was used to determine how the constituents of the cortical network subserving dynamic spatial working memory respond to two types of increases in task complexity. Participants mentally maintained the most recent location of either one or three objects as the three objects moved discretely in either a two- or three-dimensional array. Cortical activation in the dorsolateral prefrontal (DLPFC) and the parietal cortex increased as a function of the number of object locations to be maintained and the dimensionality of the display. An analysis of the response characteristics of the individual voxels showed that a large proportion were activated only when both the variables imposed the higher level of demand. A smaller proportion were activated specifically in response to increases in task demand associated with each of the independent variables. A second experiment revealed the same effect of dimensionality in the parietal cortex when the movement of objects was signaled auditorily rather than visually, indicating that the additional representational demands induced by 3-D space are independent of input modality. The comodulation of activation in the prefrontal and parietal areas by the amount of computational demand suggests that the collaboration between areas is a basic feature underlying much of the functionality of spatial working memory.

Postprandial low-density lipoproteins in type 2 diabetes are oxidized more extensively than fasting diabetes and control samples.

This study examined the kinetics of low-density lipoprotein (LDL) oxidation in the fasting and postprandial states of diabetic and control subjects to determine if LDL oxidation may contribute to accelerated atherosclerosis in diabetes. We compared in vitro oxidation of LDL from 12 control and 13 Type 2 diabetic subjects in the fasting and postprandial states. The extent of oxidation was assessed by length of lag phase, formation of conjugated dienes (CD), lipid peroxides, thiobarbituric acid reactive substances (TBARS), and percentage reduction in free amine groups. Diabetic subjects were significantly older and heavier. Comparisons between control and diabetic subjects in the postprandial state showed that the lag phase was significantly shorter in diabetic subjects than controls (P = 0.005), TBARS were significantly higher (P = 0.006), and levels of CD were higher at 60, 65, and 70 min (P < 0.01). In the fasting state, however, these comparisons were not significant. In diabetic subjects, postprandial samples had a significantly shorter lag phase (P = 0.003), higher TBARS (P = 0.006), and higher levels of CD at 60, 65 (P < 0.001), and 70 min (P = 0.0013) compared to fasting samples. Elevated levels of serum triglycerides in diabetic subjects were negatively correlated to lag phase, in fasting (P = 0.06) and postprandial states (P = 0.002). We conclude that accelerated oxidation of LDL seen in postprandial states in diabetes may be a critical contributor to cardiovascular risks. Elevated levels of serum triglycerides may contribute to the rapid oxidation of LDL seen in diabetic subjects.

Antioxidant supplementation effects on low-density lipoprotein oxidation for individuals with type 2 diabetes mellitus.

OBJECTIVE: This study compared susceptibility to oxidation of low-density lipoproteins (LDL) of non-diabetic and diabetic (Type 2) men and examined the response of diabetic men to antioxidant supplementation (alpha-tocopherol, beta-carotene and ascorbate). RESEARCH DESIGN AND METHODS: Twenty adult non-diabetic and 20 diabetic men were recruited. Oxidation of LDL was assessed by four different assay systems, and the extent of oxidation was assessed by four different measurements. Diabetic men received eight weeks of placebo ("baseline"), twelve weeks of antioxidant supplements ("treated") and eight weeks of placebo ("post-treatment"). Supplements provided 24 mg of beta-carotene, 1000 mg of ascorbate and 800 IU of alpha-tocopherol daily. RESULTS: With Cu oxidation at 37 degrees C, thiobarbituric reactive substances (TBARS) formation was significantly higher (p=0.032) and loss of free amine groups was significantly greater (p=0.013) in the LDL from diabetic subjects than controls. Antioxidant supplementation of diabetic subjects significantly decreased all parameters of LDL oxidation with Cu at 30 degrees C and 37 degrees C. At 30 degrees C the lag phase increased from 55 to 129 minutes (p<0.0001); conjugated diene formation decreased from 1.23 to 0.62 OD units (p<0.0001); TBARS formation decreased from 78 to 33 nmoles MDA/mg LDL protein (p<0.0001); and free amine loss decreased from 41 to 12% (p<0.0001). With Cu oxidation at 37 degrees C, similar changes occurred. CONCLUSIONS: These studies indicate that the LDL from diabetic subjects are more susceptible to oxidation than LDL from non-diabetic subjects. Supplementation of diabetic subjects with antioxidant vitamins significantly decreases susceptibility of LDL to oxidation by Cu. These studies are consistent with epidemiological and intervention studies suggesting that antioxidant vitamin use significantly decreases risk for coronary heart disease.

Selective effects of different antioxidants on oxidation of lipoproteins from rats.

Lipoprotein oxidation may contribute to development of atherosclerosis, and supplementation with antioxidants may reduce risk for atherosclerotic events. Genistein, a major isoflavone from soy protein, and catechins from green tea have important antioxidant properties. This study compared the effects of various diets containing antioxidant-rich foods or supplements on serum lipids and lipoprotein oxidation of male Sprague-Dawley rats. The control diet used was devoid of vitamin E. Test diets included these ingredients: green tea powder, 20 g/kg; beta-carotene, 250 mg/kg; a low isoflavone soy protein isolate; a genistein-rich soy protein isolate; and vitamin E, 4000 mg/kg. Ten-week-old rats were acclimatized for 1 week on a special custom diet without vitamin E. Following randomization and allocation to different diet groups, rats were fed the test diets for 3 weeks. Blood was drawn by cardiac puncture, and the plasma was separated by centrifugation. The VLDL-LDL fraction was isolated by ultracentrifugation. Oxidation kinetics of the VLDL-LDL fraction were determined by measuring the lag phase and formation of conjugated dienes, lipid peroxides, and TBARS. The vitamin E diet (P < 0.001) and high-genistein diet profoundly decreased all parameters of lipoprotein oxidation. The following alterations were noted with the high-genistein diet compared to the control diet: the lag phase was 49% longer (P=0.002); conjugated diene formation was decreased by 28% (P=0.01); lipid peroxide formation was decreased 31% (P=0.0059); and TBARS production was 35% lower (P=0.019). The low-isoflavone diet increased the lag phase by 43% (P=0.0019) but did not significantly alter other measures of oxidation. Green tea increased only the lag phase by 33% (P=0.012) compared to the control diet. Beta-Carotene had no significant effect on the oxidation of lipoproteins. The effect of genistein-rich soy protein isolates on lipoprotein oxidation in vitro suggests that either soy isoflavones or other antioxidants derived from soy protein, like vitamin E, may be transported in these lipoproteins. The minimal effects of the isoflavone-poor soy protein isolate suggests that either the small amount of isoflavones present have a potent effect or other components of soy protein are exerting these effects. Further studies are required to examine these results.

Symmetry and asymmetry of human spatial memory.

Six experiments investigated the limiting conditions on and the causes of asymmetries in estimates of euclidean distance. Participants estimated distances between locations on recently learned maps or between buildings on their college campus. Estimates between landmarks and neighboring nonlandmarks were often asymmetric, but estimates between other pairs of locations were typically symmetric. These and other results were inconsistent with the predictions of models that attribute asymmetries to stimulus or to retrieval bias. A contextual scaling model of asymmetry is proposed. According to this model, asymmetries in proximity judgments are caused by general principles of human memory and judgment: (a) Stimuli differ in the contexts they establish in working memory and (b) magnitude estimates are scaled by the context in which they are made.

Clinical and biochemical studies in an American child with sialuria.

Sialuria is a rare inborn error of sialic acid (NeuAc) metabolism resulting from failure of CMP-NeuAc to adequately feedback inhibit the rate-limiting enzyme in sialic acid synthesis, UDP N-acetylglucosamine (UDP-GlcNAc) 2-epimerase. We describe the fourth reported sialuria patient, T.W., whose clinical features include developmental delay, coarse facies, and massive urinary excretion of sialic acid. Biochemical studies of T.W. fibroblasts revealed a 200-fold increase in free NeuAc content compared with normal. Bound NeuAc was only slightly elevated. The free NeuAc was predominantly in the cytosol fraction of fibroblasts after differential centrifugation, with only 4% of the free NeuAc content in other (nuclear, granular, and microsomal) cellular compartments. CMP-NeuAc inhibited UDP-GlcNAc 2-epimerase by 80% in normal fibroblasts but inhibited the epimerase of T.W. (sialuria) cells by only 13%. Cytidine feeding of sialuria fibroblasts decreased the intracellular free NeuAc content by 47%; this was accompanied by a fourfold increase in CMP-NeuAc, which may be sufficient to feedback inhibit the mutant epimerase and reduce free NeuAc production. Cytoplasmic pH was determined by the pH sensitive fluorescent indicator 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein, pentaacetoxymethylester (BCECF/AM) using the H+ equilibration method. The intracellular pH of sialuria fibroblasts, 7.18 +/- 0.04, was not found to be significantly different from that of normal cells (7.19 +/- 0.08).