Prefrontal executive function associated coupling relates to Huntington's disease stage.

Huntington's disease (HD) is a neurodegenerative disease caused by cytosine-adenine-guanine (CAG)-repeat expansion in the huntingtin (HTT) gene. Early changes that may precede clinical manifestation of movement disorder include executive dysfunction. The aim of this study was to identify functional network correlates of impaired higher cognitive functioning in relation to HD stage. Blood-oxygenation-level-dependent (BOLD) functional-magnetic resonance imaging (fMRI) and structural-MRI were performed in 53 subjects with the HD-mutation (41 prodromals, 12 early affected) and 52 controls. Disease stage was estimated for each subject with HD-mutation based on age, length of the CAG-repeat expansion mutation and also putaminal atrophy. The Tower of London test was administered with three levels of complexity during fMRI as a challenge of executive function. Functional brain networks of interest were identified based on cortical gray matter voxel-clusters with significantly enhanced task-related functional coupling to the medial prefrontal cortex (MPFC) area. While prodromal HD-subjects showed similar performance levels as controls, multivariate analysis of task-related functional coupling to the MPFC identified reduced connectivity in prodromal and early manifest HD-subjects for a cluster including mainly parts of the left premotor area. Secondary testing indicated a significant moderator effect for task complexity on group differences and on the degree of correlation to measures of HD stage. Our data suggest that impaired premotor-MPFC coupling reflects HD stage related dysfunction of cognitive systems involved in executive function and may be present in prodromal HD-subjects that are still cognitively normal. Additional longitudinal studies may reveal temporal relationships between impaired task-related premotor-MPFC coupling and other brain changes in HD.

Total white matter hyperintensity volume in bipolar disorder patients and their healthy relatives.

OBJECTIVES: White matter hyperintensities (WMH) are more common in subjects with bipolar disorder (BP) than in healthy subjects (HS). Few studies have examined the effect of the diagnostic type of bipolar illness on WMH burden, and none have approached this question through a direct measurement of the volume of affected white matter in relationship to familiality. In this pilot study, we utilized a volumetric measurement of WMH to investigate the relationship between the total volume of WMH and the familiality and type of BP. METHODS: Forty-five individuals with bipolar I disorder (BP-I) with psychotic features, BP-I without psychotic features, or bipolar II disorder (BP-II), seven of their unaffected relatives, and 32 HS were recruited for participation. T-2 weighted magnetic resonance imaging scans were obtained on all subjects, and the total volume of all WMH for each subject was measured in cubic centimeters. The significance of difference between groups was tested using ANOVA with post-hoc adjustment for multiple comparisons. Further, we used logistic regression to test for trends between symptom load and total WMH volume. RESULTS: The mean total volume of WMH in BP-I patients with psychotic features was significantly higher (p < 0.05) than that of HS. Further, we observed a positive linear trend by familiality and type of affectedness when comparing mean total WMH volume of HS, unaffected family members, subjects with BP-II, and BP-I with and without a history of psychosis (p < 0.05). CONCLUSIONS: Based on a quantitative technique, WMH burden appears to be associated with familiality and type of BP. The significance of these findings remains to be fully elucidated.

Multicenter reliability of diffusion tensor imaging.

A number of studies are now collecting diffusion tensor imaging (DTI) data across sites. While the reliability of anatomical images has been established by a number of groups, the reliability of DTI data has not been studied as extensively. In this study, five healthy controls were recruited and imaged at eight imaging centers. Repeated measures were obtained across two imaging protocols allowing intra-subject and inter-site variability to be assessed. Regional measures within white matter were obtained for standard rotationally invariant measures: fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity. Intra-subject coefficient of variation (CV) was typically <1% for all scalars and regions. Inter-site CV increased to ~1%-3%. Inter-vendor variation was similar to inter-site variability. This variability includes differences in the actual implementation of the sequence.

Depressive symptoms in prodromal Huntington's Disease correlate with Stroop-interference related functional connectivity in the ventromedial prefrontal cortex.

Huntington's Disease (HD) is a neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) triplet repeat-expansion in the Huntingtin (HTT) gene. Diagnosis of HD is classically defined by the presence of motor symptoms; however, cognitive and depressive symptoms frequently precede motor manifestations, and may occur early in the prodromal phase. There are sparse data so far on functional brain correlates of depressive symptoms in prodromal HD. A Stroop color-naming test was administered to 32 subjects in the prodromal phase of HD and 52 expansion-negative controls while performing functional magnetic resonance imaging at 3Tesla. Networks of functional connectivity were identified using group independent component analysis, followed by an analysis of functional network interactions. A contrast of temporal regression-based beta-weights was calculated as a reflection of Stroop-interference related activity and correlated with Center for Epidemiologic Studies Depression (CES-D) scores. For secondary analysis, patients were stratified into two subgroups by median split of CAG repeat-length. Stroop performance was independent of HTT mutation-carrier status and CES-D score. Stroop-interference-related activity of the ventromedial prefrontal cortex-node of the default-mode network, calculated by temporal-regression beta-weights, was more highly correlated with depressive symptoms in subjects in the prodromal phase of HD than in controls, differing significantly. The strength of this correlation and its difference from controls increased when a subgroup of patients with longer CAG repeat lengths was analyzed. These findings suggest that depressive symptoms in prodromal HD subjects may reflect altered functional brain network activity in the context of early HD-related brain alterations.

Diffuse abnormality of low to moderately organized white matter in schizophrenia.

Increasing evidence suggests that abnormal white matter is central to the pathophysiology and, potentially, the pathogenesis of schizophrenia (SCZ). The spatial distribution of observed abnormalities and the type of white matter involved remain to be elucidated. Seventeen chronically ill individuals with SCZ and 17 age- and gender-matched controls were studied using a 3T magnetic resonance imaging diffusion tensor imaging protocol designed to examine the abnormalities of white matter by region and by level of architectural infrastructure as assessed by fractional anisotropy (FA) in native space. After assessing whole-brain FA, FA was divided into quartiles, capturing all brain regions with FA values from 0 to 0.25, 0.25 to 0.5, 0.5 to 0.75, and 0.75 to 1.0. Mean whole-brain FA was 4.6% smaller in the SCZ group than in healthy controls. This difference was largely accounted for by FA values from the second quartile (between 0.25 and 0.5). Second quartile FA was decreased in all 130 brain regions of the template in the SCZ group, with the difference reaching statistical significance in 41 regions. Correspondingly, the amount of brain tissue with an FA of ∼0.4 was significantly reduced in the SCZ group, while the amount of brain tissue falling in the lowest quartile of FA was increased. These findings strongly imply a diffuse loss of white matter integrity in SCZ. Our finding that the loss of integrity disproportionately involves white matter of low to moderate organization suggests an approach to the specificity of white matter abnormalities in SCZ based on microstructure rather than spatial distribution.

Neurobiology of schizophrenia.

With its hallucinations, delusions, thought disorder, and cognitive deficits, schizophrenia affects the most basic human processes of perception, emotion, and judgment. Evidence increasingly suggests that schizophrenia is a subtle disorder of brain development and plasticity. Genetic studies are beginning to identify proteins of candidate genetic risk factors for schizophrenia, including dysbindin, neuregulin 1, DAOA, COMT, and DISC1, and neurobiological studies of the normal and variant forms of these genes are now well justified. We suggest that DISC1 may offer especially valuable insights. Mechanistic studies of the properties of these candidate genes and their protein products should clarify the molecular, cellular, and systems-level pathogenesis of schizophrenia. This can help redefine the schizophrenia phenotype and shed light on the relationship between schizophrenia and other major psychiatric disorders. Understanding these basic pathologic processes may yield novel targets for the development of more effective treatments.

Regional white matter change in pre-symptomatic Huntington's disease: a diffusion tensor imaging study.

The pathology of Huntington's disease (HD) is characterized by diffuse brain atrophy, with the most substantial neuronal loss occurring in the caudate and putamen. Recent evidence suggests that there may be more widespread neuronal degeneration with significant involvement of extrastriate structures, including white matter. In this study of pre-symptomatic carriers of the HD genetic mutation, we have used diffusion tensor imaging to examine the integrity and organization of white matter in a group of individuals who previously demonstrated abnormalities in response to a functional magnetic resonance imaging paradigm. Our results indicate that, before the onset of manifest HD, there are regional decreases in fractional anisotropy, indicating early white matter disorganization.

Functional MRI study of a serial reaction time task in Huntington's disease.

The aim of this study was to investigate pathophysiological changes at an early stage of clinical Huntington's disease (HD) using a functional magnetic resonance imaging (fMRI) study and a serial reaction time task paradigm. Mildly affected and presymptomatic HD subjects (n = 8) and healthy normal controls (NC, n = 12) were studied. A group behavioral effect of implicit learning was seen only in the control population. Individual statistical parametric mapping (SPM) analysis showed more consistent activation of the caudate nucleus and putamen in the NC group. In the HD group, the group average SPM showed significant activation in the right head of caudate nucleus, as well as bilateral thalami, left middle temporal, right superior temporal, right superior frontal, right middle and inferior frontal and right postcentral gyri. In the comparison of between-group differences (NC-HD), reduced activation in the HD group relative to NC was observed in the right middle frontal, left middle occipital, left precuneus, and left middle frontal gyri. The variable striatal activity in the Huntington's group suggests early functional loss possibly associated with previously demonstrated early atrophy of these same neural structures.

Functional brain changes in presymptomatic Huntington's disease.

Evidence suggests early structural brain changes in individuals with the Huntington's disease (HD) genetic mutation who are presymptomatic for the movement symptoms of the illness. The aim of this study was to investigate the presence of functional brain changes in this same population using functional magnetic resonance imaging. Subjects and matched controls underwent an functional magnetic resonance imaging "interference" protocol, a task known to be mediated in part by corticostriatal circuitry. In the setting of normal cognitive performance, presymptomatic HD subjects had significantly and specifically less activation in the left anterior cingulate cortex (BA 24, 32) compared with matched controls.