Deficits in Docosahexaenoic Acid Accrual during Adolescence Reduce Rat Forebrain White Matter Microstructural Integrity: An in vivo Diffusion Tensor Imaging Study.

Neuropsychiatric disorders that frequently initially emerge during adolescence are associated with deficits in the omega-3 (n-3) fatty acid docosahexaenoic acid (DHA), elevated proinflammatory signaling, and regional reductions in white matter integrity (WMI). This study determined the effects of altering brain DHA accrual during adolescence on WMI in the rat brain by diffusion tensor imaging (DTI), and investigated the potential mediating role of proinflammatory signaling. During periadolescent development, male rats were fed a diet deficient in n-3 fatty acids (DEF, n = 20), a fish oil-fortified diet containing preformed DHA (FO, n = 20), or a control diet (CON, n = 20). In adulthood, DTI scans were performed and brain WMI was determined using voxelwise tract-based spatial statistics (TBSS). Postmortem fatty acid composition, peripheral (plasma IL-1ß, IL-6, and C-reactive protein [CRP]) and central (IL-1ß and CD11b mRNA) proinflammatory markers, and myelin basic protein (MBP) mRNA expression were determined. Compared with CON rats, forebrain DHA levels were lower in DEF rats and higher in FO rats. Compared with CON rats, DEF rats exhibited greater radial diffusivity (RD) and mean diffusivity in the right external capsule, and greater axial diffusivity in the corpus callosum genu and left external capsule. DEF rats also exhibited greater RD than FO rats in the right external capsule. Forebrain MBP expression did not differ between groups. Compared with CON rats, central (IL-1ß and CD11b) and peripheral (IL-1ß and IL-6) proinflammatory markers were not different in DEF rats, and DEF rats exhibited lower CRP levels. These findings demonstrate that deficits in adolescent DHA accrual negatively impact forebrain WMI, independently of elevated proinflammatory signaling.

Brain white matter development is associated with a human-specific haplotype increasing the synthesis of long chain fatty acids.

The genetic and molecular pathways driving human brain white matter (WM) development are only beginning to be discovered. Long chain polyunsaturated fatty acids (LC-PUFAs) have been implicated in myelination in animal models and humans. The biosynthesis of LC-PUFAs is regulated by the fatty acid desaturase (FADS) genes, of which a human-specific haplotype is strongly associated with ω-3 and ω-6 LC-PUFA concentrations in blood. To investigate the relationship between LC-PUFA synthesis and human brain WM development, we examined whether this FADS haplotype is associated with age-related WM differences across the life span in healthy individuals 9-86 years of age (n = 207). Diffusion tensor imaging was performed to measure fractional anisotropy (FA), a putative measure of myelination, of the cerebral WM tracts. FADS haplotype status was determined with a single nucleotide polymorphism (rs174583) that tags this haplotype. Overall, normal age-related WM differences were observed, including higher FA values in early adulthood compared with childhood, followed by lower FA values across older age ranges. However, individuals homozygous for the minor allele (associated with lower LC-PUFA concentrations) did not display these normal age-related WM differences (significant age × genotype interactions, p(corrected) < 0.05). These findings suggest that LC-PUFAs are involved in human brain WM development from childhood into adulthood. This haplotype and LC-PUFAs may play a role in myelin-related disorders of neurodevelopmental origin.

The accumbofrontal tract: Diffusion tensor imaging characterization and developmental change from childhood to adulthood.

The presence of an anatomical connection between the orbitofrontal cortex and ventral striatum, forming a so-called reward network, is well established across species. This connection has important implications for reward processing and is relevant to a number of neuropsychiatric disorders. Moreover, white matter (WM) is known to continue to mature across adolescence and into early adulthood, and developmental change in the reward network is an important component of models of decision making and risk taking. Despite the importance of this connection, the underlying WM has only recently been characterized in humans histologically, and not yet in-vivo using brain imaging. Here, we implemented diffusion tensor imaging (DTI) in a large cross-sectional sample of 295 healthy individuals ages 8-68 to further characterize the WM of this connection and its development from childhood into adulthood. We demonstrate that the accumbofrontal tract, connecting the orbitofrontal cortex and nucleus accumbens, can be identified using standard DTI sequences. Using Poisson modeling, we show that the accumbofrontal tract undergoes significant change across the lifespan, with males showing a higher and earlier peak compared to females. Moreover, the change occurs in a pattern consistent with developmental models of decision-making. These findings support the hypothesis that developmental differences in WM integrity may be a contributing factor to the observed risk taking that occurs in adolescence. The accumbofrontal tract is not yet included in standard WM atlases, but may be important for inclusion in studies investigating fronto-striatal networks, as well as in investigations of substance abuse and decision making.

Age-associated alterations in corpus callosum white matter integrity in bipolar disorder assessed using probabilistic tractography.

OBJECTIVES: Atypical age-associated changes in white matter integrity may play a role in the neurobiology of bipolar disorder, but no studies have examined the major white matter tracts using nonlinear statistical modeling across a wide age range in this disorder. The goal of this study was to identify possible deviations in the typical pattern of age-associated changes in white matter integrity in patients with bipolar disorder across the age range of 9-62 years. METHODS: Diffusion tensor imaging was performed in 57 (20 male and 37 female) patients with a diagnosis of bipolar disorder and 57 (20 male and 37 female) age- and sex-matched healthy volunteers. Mean diffusivity and fractional anisotropy were computed for the genu and splenium of the corpus callosum, two projection tracts, and five association tracts using probabilistic tractography. RESULTS: Overall, patients had lower fractional anisotropy and higher mean diffusivity compared to healthy volunteers across all tracts (while controlling for the effects of age and age(2) ). In addition, there were greater age-associated increases in mean diffusivity in patients compared to healthy volunteers within the genu and splenium of the corpus callosum beginning in the second and third decades of life. CONCLUSIONS: Our findings provide evidence for alterations in the typical pattern of white matter development in patients with bipolar disorder compared to healthy volunteers. Changes in white matter development within the corpus callosum may lead to altered inter-hemispheric communication that is considered integral to the neurobiology of the disorder.

Independent component analysis of resting state activity in pediatric obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is an often severely disabling illness with onset generally in childhood or adolescence. Little is known, however, regarding the pattern of brain resting state activity in OCD early in the course of illness. We therefore examined differences in brain resting state activity in patients with pediatric OCD compared with healthy volunteers and their clinical correlates. Twenty-three pediatric OCD patients and 23 healthy volunteers (age range 9-17), matched for sex, age, handedness, and IQ completed a resting state functional magnetic resonance imaging exam at 3T. Patients completed the Children's Yale Brown Obsessive Scale. Data were decomposed into 36 functional networks using spatial group independent component analysis (ICA) and logistic regression was used to identify the components that yielded maximum group separation. Using ICA we identified three components that maximally separated the groups: a middle frontal/dorsal anterior cingulate network, an anterior/posterior cingulate network, and a visual network yielding an overall group classification of 76.1% (sensitivity = 78.3% and specificity = 73.9%). Independent component expression scores were significantly higher in patients compared with healthy volunteers in the middle frontal/dorsal anterior cingulate and the anterior/posterior cingulate networks, but lower in patients within the visual network. Higher expression scores in the anterior/posterior cingulate network correlated with greater severity of compulsions among patients. These findings implicate resting state fMRI abnormalities within the cingulate cortex and related control regions in the pathogenesis and phenomenology of OCD early in the course of the disorder and prior to extensive pharmacologic intervention.

Longitudinal investigation of the relationship between omega-3 polyunsaturated fatty acids and neuropsychological functioning in recent-onset psychosis: A randomized clinical trial.

Alterations in polyunsaturated fatty acids (PUFAs), including omega-3 and omega-6, have been implicated in the pathophysiology of psychotic disorders, but little is known about their associations with neuropsychological functioning. The present study includes 46 recent-onset psychosis patients who participated in a larger (n = 50) double blind, placebo-controlled randomized clinical trial comparing 16 weeks of treatment with either risperidone + fish oil (FO) (EPA 740 mg and DHA 400 mg daily) or risperidone + placebo and completed neuropsychological assessments at the baseline timepoint. We investigated the relationship between baseline omega-3 (i.e., eicosapentaenoic acid, EPA; docosapentaenoic acid, DPA and docosahexaenoic acid, DHA) and omega-6 (i.e., arachidonic acid, AA) PUFA with baseline MATRICS Consensus Cognitive Battery (MCCB) and Brief Psychiatric Rating Scale (BPRS) scores. Twenty-five patients had neuropsychological data available at 16 weeks following participation in the clinical trial, which included 12 patients assigned to risperidone + FO and 13 patients assigned to risperidone + placebo. At baseline both higher DHA and EPA correlated significantly with better social cognition after controlling for functioning on other neuropsychological domains, total BPRS score, AA level and substance use. Also, at baseline higher AA correlated significantly with hostility/uncooperativeness after controlling for DHA + EPA + DPA, overall neuropsychological functioning and substance use. Patients treated with risperidone + FO demonstrated a significant longitudinal increase in social cognition that was significantly higher at 16 weeks compared to patients treated with risperidone + placebo. DHA also correlated significantly with social cognition at the 16-week timepoint. This study provides novel evidence for a differential role of omega-3 vs. omega-6 PUFA in neuropsychological deficits and symptoms in recent-onset psychosis and its treatment.

A 16-week randomized placebo-controlled trial investigating the effects of omega-3 polyunsaturated fatty acid treatment on white matter microstructure in recent-onset psychosis patients concurrently treated with risperidone.

We examined the impact of treatment with fish oil (FO), a rich source of omega-3 polyunsaturated fatty acids (n-3 PUFA), on white matter in 37 recent-onset psychosis patients receiving risperidone in a double-blind placebo-controlled randomized clinical trial. Patients were scanned at baseline and randomly assigned to receive 16-weeks of treatment with risperidone + FO or risperidone + placebo. Eighteen patients received follow-up MRIs (FO, n = 10/Placebo, n = 8). Erythrocyte levels of n-3 PUFAs eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and docosapentaenoic acid (DPA) were obtained at both time points. We employed Free Water Imaging metrics representing the extracellular free water fraction (FW) and fractional anisotropy of the tissue (FA-t). Analyses were conducted using Tract-Based-Spatial-Statistics and nonparametric permutation-based tests with family-wise error correction. There were significant positive correlations of FA-t with DHA and DPA among all patients at baseline. Patients treated with risperidone + placebo demonstrated reductions in FA-t and increases in FW, whereas patients treated with risperidone + FO exhibited no significant changes in FW and FA-t reductions were largely attenuated. The correlations of DPA and DHA with baseline FA-t support the hypothesis that n-3 PUFA intake or biosynthesis are associated with white matter abnormalities in psychosis. Adjuvant FO treatment may partially mitigate against white matter alterations observed in recent-onset psychosis patients following risperidone treatment.

Cannabis use and callosal white matter structure and integrity in recent-onset schizophrenia.

Adolescent-onset cannabis use, compared with adult-onset use, has been associated with a higher risk for developing symptoms of schizophrenia-like psychotic disorders. To test the hypothesis that onset of cannabis use in early adolescence in male schizophrenia patients is associated with abnormalities in white matter structure and integrity, we used high resolution structural and diffusion tensor brain images to compare three groups of patients: those who started regular use of cannabis (1) before the age of 15 years (early-onset cannabis users, n = 10) or (2) at the age of 17 years or later (late-onset cannabis users, n = 8), and (3) those who were cannabis naïve (n = 8). To verify patient findings, we also compared white matter integrity of the three patient groups with that of a healthy control group (n = 10). Cannabis naïve patients showed reduced white matter density and reduced fractional anisotropy, an indicator for white matter integrity, in the splenium of the corpus callosum compared with patients with early-onset cannabis use. In the same brain area, cannabis naïve patients showed reduced fractional anisotropy compared with healthy controls. Our results suggest that the age of onset of cannabis use is not an identifying characteristic for white matter abnormalities in schizophrenia patients; however, our results might indicate a more vulnerable brain structure in cannabis naïve schizophrenia patients.

White matter connectivity and psychosis in ultra-high-risk subjects: a diffusion tensor fiber tracking study.

This study assessed with diffusion tensor imaging (DTI) whether ultra-high-risk subjects who later develop a psychotic disorder (UHR-P) show abnormalities in association white matter fiber tracts as compared to UHR subjects who do not convert to psychosis (UHR-NP) and healthy controls. Participants comprised 17 male UHR subjects and 10 male healthy controls, who received baseline DTI scans before clinical follow-up. The uncinate and arcuate fasciculi, anterior and dorsal cingulate, and subdivisions of the corpus callosum were calculated and visualized, and tract-specific measurements were performed. At 24-month follow-up seven UHR subjects had developed a first psychotic episode. Fractional anisotropy in baseline DTI scans, including left-right asymmetry measures, did not differ between the groups. Thus, DTI measures of these association white matter tracts were not biological markers of psychosis in our UHR sample. Abnormalities of these fiber tracts may develop around or after onset of psychosis. However, further DTI studies in UHR subjects are needed in larger samples.

Subjective effects of cannabis before the first psychotic episode.

OBJECTIVE: The aim of the present study was to gain more insight into the positive and negative effects of cannabis in the prodromal phase of schizophrenia and in the ultra-high-risk (UHR) state for psychosis. METHOD: A theory-driven questionnaire was used to examine subjective effects in the prodromal phase in male subjects with a recent onset of schizophrenia or related disorder (n = 52) and in the UHR state in help-seeking male subjects screened for being at UHR for psychosis (n = 17); both groups were compared to cannabis-using controls from the general population (n=52). RESULTS: Recent-onset patients and UHR subjects reported feeling more anxious, depressed and suspicious immediately after cannabis use. Some patients also reported feeling less depressed after cannabis use. Recent-onset patients reported increased visual and acoustic hallucinations, and confusion after cannabis use. Of the recent-onset patients 37% reported that their very first psychotic symptoms occurred during cannabis intoxication. Long-term effects of cannabis reported more often by both patient groups were depression, less control over thoughts and social problems. CONCLUSIONS: These results suggest that schizophrenia patients in the prodromal phase and subjects at UHR for psychosis are more sensitive to some negative effects of cannabis, in particular psychotic effects, compared to cannabis users from the general population. Although limited by the retrospective design in the recent-onset patients, the present study adds qualitative evidence to longitudinal studies that suggest that cannabis is a component cause in the onset of the first psychotic episode. Further studies are needed on the objective and subjective effects of cannabis in UHR subjects.

A potential role for adjunctive omega-3 polyunsaturated fatty acids for depression and anxiety symptoms in recent onset psychosis: Results from a 16 week randomized placebo-controlled trial for participants concurrently treated with risperidone.

Omega-3 treatment studies for multi-episode schizophrenia or clinical high risk for conversion to psychosis states have had variable, and often negative, results. To examine adjunctive omega-3 treatment for recent onset psychosis, participants aged 15-40 years with recent onset schizophrenia-spectrum (n = 46) or bipolar (n = 4) disorders and current psychotic symptoms were treated for 16 weeks with risperidone and randomly-assigned omega-3 (EPA 740 mg and DHA 400 mg daily) or matching placebo. The primary outcome measure was the Brief Psychiatric Rating Scale (BPRS) total score. Mean lifetime antipsychotic exposure was 18.1 days. Length of time in treatment, risperidone dose and number of omega-3/placebo capsules taken did not differ between conditions. Longitudinal analysis of the total BPRS score revealed a trend level (p = 0.0826) treatment effect favoring omega-3 treatment. Lorazepam was an allowed concomitant medication. Among the subgroup (N = 23) who did not receive lorazepam, the treatment effect on BPRS total scores favoring omega-3 was significant (p = 0.0406) and factor scores analyses revealed a substantial decrease in depression-anxiety with omega-3 but no change with placebo (treatment-by-time interaction, p = 0.0184). Motor side effects did not differ between conditions. Analysis of Systematic Assessment for Treatment Emergent Events assessments revealed fewer adverse events overall with omega-3 compared with placebo with the largest differences between conditions (all favoring omega-3) on confusion, anxiety, depression, irritability, and tiredness/fatigue. These results suggest that omega-3 adjuvant treatment is a potential option for depression and anxiety symptoms of people with recent onset psychosis. Further research is needed to confirm this potential. Clinical trial registration: NCT01786239.

White matter fibertracking in first-episode schizophrenia, schizoaffective patients and subjects at ultra-high risk of psychosis.

There is increasing evidence of white matter pathology in schizophrenia. The aim of this study was to examine whether white matter abnormalities found with diffusion tensor imaging (DTI) in previous schizophrenia studies are present in the early phase of the illness. DTI was performed at 3 T on 10 male patients with a first (n = 8) or second (n = 2) psychotic episode of schizophrenia or schizoaffective disorder, 10 male patients at ultra-high risk of psychosis with (pre)psychotic symptoms and 10 healthy controls. Fibertracts found to be abnormal in other DTI studies (uncinate and arcuate fasciculus, anterior and dorsal cingulum, subdivisions of the corpus callosum) were calculated and visualized; tract-specific measurements (fractional anisotropy and trace) were performed. No differences were found between the healthy subjects and the 2 patient groups. These preliminary findings suggest that there is no white matter pathology of these association tracts detectable with DTI in the early stages of schizophrenic illness in males. Our findings are in contrast with DTI abnormalities found in some other first-episode studies. This discrepancy in findings may be related to differences in subject characteristics and DTI methodology. Possible effects of age, gender, level of education and illicit substance use on DTI findings in schizophrenia are discussed.

Functional Activation During a Cognitive Control Task in Healthy Youth Specific to Externalizing or Internalizing Behaviors.

BACKGROUND: Externalizing behaviors are negative behaviors expressed outwardly, including rule breaking, aggression, and risk taking; internalizing behaviors are expressed inwardly, including depression, withdrawal, and anxiety. Such behavior can cause problems in early life and predict difficulties across the lifespan. There is evidence for a relationship between executive function and both externalizing and internalizing. However, although these behaviors occur along a spectrum, there is little neuroimaging research on this relationship in typically developing youth. METHODS: We assessed 41 youth (10-19 years of age) using the Multi-Source Interference Task during functional magnetic resonance imaging and related the findings to self-reported externalizing and internalizing scores as measured by the Youth Self-Report. We performed a general linear model using FSL software; externalizing, internalizing, age, and sex were included in the model. RESULTS: Compared to the control condition, the more difficult Multi-Source Interference Task interference condition was associated with greater engagement of the frontoparietal cognitive control system and decreased engagement of regions in the default mode network, based on a cluster threshold of Z > 3.1 (p = .01). When we examined regions uniquely associated with either internalizing or externalizing, we found that within the same group of subjects, higher externalizing behavior was associated with hyperactivity in the parietal lobe; in contrast, higher internalizing behavior was associated with increased activation in the medial prefrontal cortex. CONCLUSIONS: These findings suggest that externalizing and internalizing may be associated with altered, but different, patterns of activation during cognitive control. This has implications for our understanding of the relationship between cognitive control and behavioral problems in youth.

Relationship among interthalamic adhesion size, thalamic anatomy and neuropsychological functions in healthy volunteers.

The interthalamic adhesion (ITA) is an understudied neuroanatomical structure that forms a bridge of tissue connecting the thalamus of each hemisphere across the midline whose functional significance remains largely unknown. The likelihood of ITA absence has been reported in some studies to be increased in males, but findings have been inconsistent. We used magnetic resonance imaging to investigate the size and absence of the ITA and their relationship to thalamic volume, putative indices of white matter integrity (fractional anisotropy and mean diffusivity) within the anterior thalamic radiation and neuropsychological functions in 233 (129 M/104 F) healthy volunteers (age range 8-68). To ensure high reliability in this study two operators independently rated the absence of the ITA and measured its size for all individuals. The ITA was absent in 4% of all individuals with no sex differences in its absence. Females had greater ITA size compared to males overall with both groups demonstrating nonlinear age-associated changes across the age range examined. ITA size among females correlated significantly with thalamus volume and lower mean diffusivity in the anterior thalamic radiation. Path modeling indicated that ITA size statistically mediated the relationship between age and attention among females. Our findings provide evidence for sex differences in ITA size across the lifespan, which are associated with the surrounding thalamic anatomy and neuropsychological functions.

White Matter Abnormalities Associated With Subsyndromal Psychotic-Like Symptoms Predict Later Social Competence in Children and Adolescents.

INTRODUCTION: Recent data suggest that healthy children and adolescents who report psychotic-like experiences (PLEs) evidence abnormalities in white matter (WM). To date, no study has examined whether WM abnormalities associated with PLEs are predictive of outcome at a later time-point. The present study examined whether abnormalities in WM associated with PLEs in children and adolescents at a baseline assessment were predictive of social functioning at a 12-month follow-up. SUBJECTS AND METHODS: Healthy children and adolescents aged 8-18 years (N = 56) were recruited from the community and received a diffusion tensor imaging exam and a clinical exam at baseline. Voxel-wise statistical analysis of fractional anisotropy (FA), using Tract-Based Spatial Statistics, and probabilistic tractography were used to identify WM abnormalities associated with PLEs at baseline. These abnormalities were then examined for association to social problems and social competence in 28 participants at 12-month follow-up. RESULTS: Lower FA in regions proximal to the superior longitudinal fasciculus (SLF) and corticospinal tract bilaterally as well as in the left inferior fronto-occipital fasciculus and inferior longitudinal fasciculus were associated with higher levels of PLEs at baseline. Moreover, baseline FA in the SLF, but not baseline severity of PLEs, was significantly predictive of social competence at a 12-month follow-up. In contrast, baseline severity of PLEs, but not baseline FA in the SLF, predicted social problems at 12-month follow-up. DISCUSSION: These findings suggest that alterations in WM, which are associated with symptoms of psychosis well below the threshold of clinical significance, may have significant ramifications for later social development.

Polyunsaturated fatty acid biostatus, phospholipase A2 activity and brain white matter microstructure across adolescence.

Adolescence is a period of major brain white matter (WM) changes, and membrane lipid metabolism likely plays a critical role in brain WM myelination. Long-chain polyunsaturated fatty acids (LC-PUFAs) are essential components of cell membranes including oligodendrocytes, and LC-PUFA release and turnover in membranes is regulated by phospholipase A2 enzymes. To investigate the role of membrane lipid metabolism in healthy WM myelination across adolescence, the present study examined the relationship between membrane LC-PUFA biostatus, phospholipase A2 activity, and brain WM microstructure in healthy subjects aged 9-20years (n=30). Diffusion tensor imaging (DTI) was performed to measure average fractional anisotropy (FA) and diffusivity (indices sensitive to WM myelination) of nine major cerebral WM tracts. Blood samples were collected to measure erythrocyte membrane fatty acid concentrations and plasma intracellular phospholipase A2 activity (inPLA2). Plasma inPLA2 activity showed a significant U-curved association with WM radial diffusivity, and an inverted U-curved association with WM FA, independent of age. A significant positive linear correlation was observed between docosahexaenoic acid concentration and axial diffusivity in the corpus callosum. These findings suggest that there may be optimal physiological inPLA2 activity levels associated with healthy WM myelination in late childhood and adolescence. Myelination may be mediated by cleavage of docosahexaenoic acid from membrane phospholipids by inPLA2. These findings have implications for our understanding of the role of LC-PUFA homeostasis in myelin-related neurodevelopmental disorders.

Age and Sex Effects on White Matter Tracts in Psychosis from Adolescence through Middle Adulthood.

There is controversy regarding specificity of white matter abnormalities in psychosis, their deviation from healthy aging, and the influence of sex on these measures. We used diffusion tensor imaging to characterize putative white matter microstructure in 224 patients with psychosis and healthy volunteers across the age range of 15-64 years. Sixty-five younger (age <30 years; 47M/18F) patients with psychosis (all experiencing a first episode of illness) and 48 older (age ⩾30 years; 30M/18F) patients were age-matched to younger and older healthy volunteer groups (N=63 (40M/23F) and N=48 (29M/19F), respectively). The trajectories of two inter-hemispheric (splenium and genu), two projection (cortico-pontine and anterior thalamic), and five bilateral association (inferior fronto-occipital, inferior longitudinal, superior longitudinal, cingulum, and uncinate) tracts were quantified using tractography to derive measures of fractional anisotropy and mean, axial, and radial diffusivity. Fractional anisotropy was significantly lower in the inferior longitudinal fasciculus and superior longitudinal fasciculus in all patients compared with all healthy volunteers, with comparable effect sizes observed in both the younger and older patients compared with their respective healthy volunteer groups. Moreover, age-associated differences in fractional anisotropy within these tracts were comparable between groups across the age span. In addition, female patients had significantly lower fractional anisotropy across all tracts compared with female controls regardless of age. Our findings demonstrate comparable putative white matter abnormalities in two independent samples of patients with psychosis and argue against their progression in patients. These data further highlight the novel and potentially underappreciated role of sex in understanding white matter dysfunction in the neurobiology of psychosis.

White matter development in the early stages of psychosis.

Schizophrenia has been conceptualized as a disorder of both neurodevelopment and a disorder of connectivity. One important aspect of the neurodevelopmental hypothesis is that schizophrenia is no longer thought to have discrete illness time points, but rather a long trajectory of brain changes, spanning many years, across a series of stages of the disease including the prodrome, first episode, and chronic period. As the disease progresses, there is a complex relationship between age related changes and disease related changes. Therefore, neural changes, and specifically white matter based connectivity changes, in schizophrenia may be best conceptualized based on a lifespan trajectory. In this selective review, we discuss healthy changes in white matter integrity that occur with age, as well as changes that occur across illness stages. We further propose a set of models that might explain lifespan changes in white matter integrity in schizophrenia, with the conclusion that the evidence most strongly supports a pattern of disrupted maturation during adolescence, with the potential for later changes that may be a result of disease neurotoxicity, abnormal or excessive aging effects, as well as medication, cohort or other effects. Thus, when considering white matter integrity in psychosis, it is critical to consider age in addition to other contributing factors including disease specific effects. Discovery of the factors driving healthy white matter development across the lifespan and deviations from the normal developmental trajectory may provide insights relevant to the discovery of early treatment interventions.

Evidence from structural and diffusion tensor imaging for frontotemporal deficits in psychometric schizotypy.

BACKGROUND: Previous studies of nonclinical samples exhibiting schizotypal traits have provided support for the existence of a continuous distribution of psychotic symptoms in the general population. Few studies, however, have examined the neural correlates of psychometric schizotypy using structural and diffusion tensor imaging (DTI). METHODS: Healthy volunteers between the ages of 18 and 68 were recruited from the community and assessed using the Schizotypal Personality Questionnaire and received structural and DTI exams. Participants with high (N = 67) and low (N = 71) psychometric schizotypy were compared on gray and white matter volume, and cortical thickness in frontal and temporal lobe regions and on fractional anisotropy (FA) within 5 association tracts traversing the frontal and temporal lobes. RESULTS: Higher levels of schizotypy were associated with lower overall volumes of gray matter in both the frontal and temporal lobes and lower gray matter thickness in the temporal lobe. Regionally specific effects were evident in both white matter and gray matter volume of the rostral middle frontal cortex and gray matter volume in the pars orbitalis. Moreover, relative to individuals who scored low, those who scored high in schizotypy had lower FA in the inferior fronto-occipital fasciculus as well as greater asymmetry (right > left) in the uncinate fasciculus. CONCLUSIONS: These findings are broadly consistent with recent data on the neurobiological correlates of psychometric schizotypy as well as findings in schizotypal personality disorder and schizophrenia and suggest that frontotemporal lobe dysfunction may represent a core component of the psychosis phenotype.

Adding insult to injury: childhood and adolescent risk factors for psychosis predict lower fractional anisotropy in the superior longitudinal fasciculus in healthy adults.

Although epidemiological studies provide strong support for demographic and environmental risk factors in psychotic disorders, few data examine how these risk factors relate to the putative aberrant neurodevelopment associated with illness. The present study examined how the accumulation of risk factors including low IQ, low parental socioeconomic status (SES), history of adolescent cannabis use and childhood trauma, and high levels of subclinical psychotic-like experiences (PLEs) contributed to aberrant neurodevelopmental outcomes in 112 otherwise healthy adults recruited from the community. Participants were studied with diffusion tensor imaging (DTI), and voxel-wise statistical analysis of fractional anisotropy (FA) using tract-based spatial statistics (TBSS) was used to examine the relation between cumulative risk (CR) for psychosis and white matter (WM) integrity across the whole brain. Analyses revealed that higher CR was significantly associated with lower FA in a cluster in the left superior longitudinal fasciculus (SLF). These results suggest that risk factors previously associated with psychotic disorders are associated with WM integrity even in otherwise healthy adults and may provide insight into how previously identified risk factors contribute to the structural brain abnormalities associated with psychotic illness. Prospective longitudinal studies examining the effect of risk factors on the developmental trajectory of brain WM are warranted.