Subgenual cingulate volumes in offspring of bipolar parents and in sporadic bipolar patients.

Decreased volumes of subgenual cingulate (SGC) have been reported primarily among familial bipolar patients, which is one of the hallmarks of an endophenotype. In order to investigate specificity of SGC volume abnormalities to familial mood disorders and to test whether SGC volumes represent an endophenotype for BD, we measured SGC volumes in young affected and unaffected relatives of bipolar patients (high-risk design) and in sporadic bipolar patients. We included 20 unaffected, 15 affected offspring of bipolar I or bipolar II parents, 18 controls, and 19 sporadic bipolar patients between 15 and 30 years of age. SGC volumes were measured on 1.5 T 3D anatomical MRI images using standard methods. We also combined the effect sizes from all published studies of sporadic patients with mood disorders (N = 61) and controls (N = 84) using random-effect models. We found comparable SGC volumes among unaffected, affected offspring of BD parents and controls (F = 0.7, df = 2; 50, P = 0.47). Likewise no SGC abnormalities were found between sporadic bipolar and control subjects (F = 2.31, df = 1; 34, P = 0.14). When combining all available data from sporadic patients, there were no differences in left (SDM 0.19, 95% CI -0.13 to 0.51) or right (SDM -0.11, 95% CI -0.47 to 0.26) SGC volumes between sporadic bipolar patients and controls. The limitations of the study are cross-sectional design and inclusion of both bipolar I and bipolar II probands. In conclusion, SGC volume abnormalities were absent in unaffected, affected relatives of bipolar patients as well as sporadic bipolar patients and thus did not meet criteria for endophenotype.

Longitudinal Volumetric Assessment of Ventricular Enlargement in Pet Dogs Trained for Functional Magnetic Resonance Imaging (fMRI) Studies.

BACKGROUND: Recent studies suggest that clinically sound ventriculomegaly in dogs could be a preliminary form of the clinically significant hydrocephalus. We evaluated changes of ventricular volumes in awake functional magnetic resonance imaging (fMRI) trained dogs with indirectly assessed cognitive abilities over time (thus avoiding the use of anaesthetics, which can alter the pressure). Our research question was whether ventricular enlargement developing over time would have any detrimental effect on staying still while being scanned; which can be extrapolated to the ability to pay attention and to exert inhibition. METHODS: Seven healthy dogs, 2-8 years old at the baseline scan and 4 years older at rescan, participated in a rigorous and gradual training for staying motionless (<2 mm) in the magnetic resonance (MR) scanner without any sedation during 6 minute-long structural MR sequences. On T1 structural images, volumetric analyses of the lateral ventricles were completed by software guided semi-automated tissue-type segmentations performed with FMRIB Software Library (FSL, Analysis Group, Oxford, UK). RESULTS AND CONCLUSION: We report significant enlargement for both ventricles (left: 47.46 %, right: 46.07 %) over time while dogs retained high levels of attention and inhibition. The results suggest that even considerable ventricular enlargement arising during normal aging does not necessarily reflect observable pathological changes in behavior.

Amygdala and hippocampal volumes in relatives of patients with bipolar disorder: a high-risk study.

OBJECTIVE: Bipolar disorders (BD) have a strong genetic underpinning, yet no biological vulnerability markers for BD have yet been identified. To test whether amygdala or hippocampal volumes represent an endophenotype for BD, we measured mesiotemporal volumes in young affected and unaffected relatives of patients with BD (high-risk design). METHOD: High-risk participants (aged 15 to 30 years) were recruited from families multiply affected with BD. They included 20 affected and 26 unaffected offspring of parents with primary mood disorders, matched by age and sex with 31 control subjects without a personal or family history of psychiatric disorders. Amygdala and hippocampal volumes were measured on 1.5 Tesla 3-dimensional anatomical magnetic resonance images using standard methods. RESULTS: We found comparable amygdala and hippocampal volumes among unaffected relatives, affected high-risk patients, and control subjects. The exclusion of 6 medicated patients did not change the results. There were no differences between participants with family history of BD I, compared with participants with family history of BD II, or between subjects with family history of BD with psychotic symptoms, compared with subjects with family history of BD without psychotic symptoms. CONCLUSIONS: Hippocampal and amygdala volume abnormalities were absent in unaffected and affected relatives of patients with BD and thus did not meet criteria for endophenotype.

Subgenual cingulate volumes in affected and unaffected offspring of bipolar parents.

BACKGROUND: Bipolar disorders (BD) have a strong genetic underpinning, yet no biological vulnerability markers for BD have been identified. Decreased volumes of subgenual cingulate (SGC) were replicated in familial bipolar patients. Presence of abnormality in unaffected subjects at genetic risk for an illness needs to be established before SGC volumes can be used as an endophenotype. This is the first study of SGC volumes in affected and unaffected subjects at familial risk for mood disorders. METHOD: High-risk participants were recruited from families multiply affected with BD. The high-risk sample included 13 affected and 13 unaffected offspring of bipolar I parents, who were matched by age and sex with 31 controls without a personal or family history of psychiatric disorders. The expanded sample consisted of 24 unaffected, 19 affected subjects all with a first or second degree relative suffering from BD I or II. The age range for all subjects was 15-30 years. Subgenual cingulate volumes were measured on 1.5 T 3D anatomical MRI images using standard methods. RESULTS: We found comparable SGC volumes among unaffected, affected offspring of BD I parents and controls. Likewise no SGC abnormalities were found in the expanded sample of subjects with BD I or II relatives. Left SGC volumes in all groups were smaller than right SGC volumes without laterality by group interaction. The exclusion of 5 medicated subjects did not change the results. LIMITATIONS: Cross sectional design, inclusion of both bipolar I and bipolar II probands. CONCLUSIONS: Subgenual cingulate volume abnormalities were absent in unaffected or affected relatives of bipolar patients and thus did not meet criteria for endophenotype.

Sex-Based Differences in Multiple Sclerosis (MS): Part II: Rising Incidence of Multiple Sclerosis in Women and the Vulnerability of Men to Progression of this Disease.

It is well known that a number of autoimmune diseases including multiple sclerosis (MS) predominantly affect women and there has been much attention directed toward understanding why this is the case. Past research has revealed a number of sex differences in autoimmune responses that can account for the female bias in MS. However, much less is known about why the incidence of MS has increased exclusively in women over the past half century. The recency of this increase suggests that changing environmental or lifestyle factors are interacting with biological sex to increase MS risk predominantly in females. Indeed, a number of recent studies have identified sex-specific differences in the effect of environmental factors on MS incidence. The first part of this chapter will overview this evidence and will discuss the possible scenarios of how the environment may be interacting with autoimmune mechanisms to contribute to the preferential rise in MS incidence in women. Despite the strong female bias in MS incidence, culminating evidence from natural history studies, and imaging and pathology studies suggests that males who develop MS may exhibit a more rapid decline in disability and cognitive functioning than women. Very little is known about the biological basis of this more rapid deterioration, but some insights have been provided by studies in rodent models of demyelination/remyelination. The second part of this chapter will overview the evidence that males with relapsing-onset MS undergo a more rapid progression of disease than females and will discuss potential biological mechanisms that account for this sex difference.

Smaller volumes of caudate nuclei in prepubertal children with ADHD: impact of age.

OBJECTIVE: Age-related abnormalities in caudate volumes have been reported to differ across the periods of childhood and puberty in children with ADHD. This study assessed caudate volumetric abnormalities across two narrow age clusters within the childhood period. METHOD: Three-dimensional manual tracings of the head and body of the caudate nucleus and of the cerebrum were acquired from 26 medication-naïve boys with a diagnosis of ADHD (ages 5.9-10.8 years), and 24 age-matched normal controls. RESULTS: Boys with ADHD had smaller total caudate volumes relative to controls, F(1,48)=4.29, p=0.04. Adjustment of caudate volumes with respect to age demonstrated that this group difference was driven solely by participants in the 5.9-7.3 year range, F(1, 46)=5.64, p=0.022, with an effect size of d=0.69. No Group effect was found in older participants, F(1, 46)=0.82, p=0.37. CONCLUSIONS: These novel findings suggest a different pattern of caudate volume abnormalities across narrow age clusters prior to puberty in boys with ADHD. Anatomical differences in brain structures related to ADHD in prepubertal children should be evaluated with respect to the changing developmental trajectory of brain regions within this period of rapid brain growth.

White matter hyperintensities: from medical comorbidities to bipolar disorders and back.

White matter hyperintensities (WMHs) are among the most replicated neuroimaging findings in studies of patients with bipolar disorders (BD). Despite the high rates of WMHs, their role and etiology in BD are not well understood. WMHs occur in multiple other conditions frequently co-morbid with BD. From the available studies it seems that WMHs are not a primary risk factor/endophenotype for BD. More likely, these lesions indicate the presence of medical co-morbidities with specific links to BD. Furthermore, the etiology of the WMHs in BD may represent different processes depending on age. In certain forms of BD, such as pediatric BD, WMHs may represent co-morbidity with developmental disorders. High frequency of migraine in BD and high prevalence of WMHs in migraine may suggest that a substantial proportion of WMHs in early adulthood to midlife BD subjects may be related to co-morbidity with migraine. Among elderly subjects with BD, or those with late-onset BD, WMHs are likely related to the presence of cardiovascular/metabolic disorders. With further research WMHs may enhance our knowledge about various pathological pathways involved in BD, help in decreasing the etiological heterogeneity of BD, and become useful as markers of severity or subtype of BD.

White matter hyperintensities in affected and unaffected late teenage and early adulthood offspring of bipolar parents: a two-center high-risk study.

BACKGROUND: White matter hyperintensities (WMHs) are among the most replicated neuroimaging findings in bipolar disorder (BD). It is not clear whether these lesions are an artifact of comorbid conditions, or whether they are directly associated with the disorder, or even represent biological risk factor for BD. METHODS: To test whether WMHs meet criteria for an endophenotype of BD, we conducted a high-risk design study and recruited 35 affected, 44 unaffected relatives of bipolar probands (age range 15-30 years), matched by age and sex with 49 healthy controls without any personal or family history of psychiatric disorders. The presence of WMHs was determined from Fluid Attenuated Inversion Recovery (FLAIR) scans acquired on a 1.5 Tesla scanner using a validated semi-quantitative scale. RESULTS: We found mostly low grade WMHs in all groups. The proportion of WMH-positive subjects was comparable between the unaffected high-risk, affected familial and control groups. CONCLUSION: White matter hyperintensities did not meet criteria for an endophenotype of BD. Bipolar disorder in young subjects without comorbid conditions was not associated with increased rate of WMHs.

Amygdala volumes in mood disorders--meta-analysis of magnetic resonance volumetry studies.

BACKGROUND: The amygdala plays an important role in the regulation of emotions and has been implicated in the pathophysiology of mood disorders. Studies of amygdala volumes in mood disorders have been conflicting, with findings of increased, decreased and unchanged amygdala volumes in patients relative to controls. We present the largest meta-analysis of amygdala volumes in mood disorders and the first one to investigate modifying effects of clinical, demographic and methodological variables. METHODS: We reviewed 40 magnetic resonance imaging studies investigating amygdala volumes in patients with unipolar or bipolar disorders. For meta-analysis we used standardized differences in means (SDM) and random effect models. In the search for sources of heterogeneity, we subdivided the studies based on diagnosis, setting, age, medication status, sex, duration of illness, slice thickness, interrater reliability of tracing and anatomical definitions used. RESULTS: The volumes of the left and right amygdala in bipolar (N=215) or unipolar (N=409) patients were comparable to controls. Bipolar children and adolescents had significantly smaller left amygdala volumes relative to controls (SDM=-0.34, 95%CI=-0.65; -0.04, z=-2.20, p=0.03), whereas bipolar adults showed a trend for left amygdala volume increases (SDM=0.46, 95%CI=-0.03; 0.96, z=1.83, p=0.07). Unipolar inpatients had significantly larger left (SDM=0.35, 95%CI=0.03; 0.67, z=-2.17, p=0.03) amygdala volumes than controls, with no significant amygdala volume changes in unipolar outpatients. LIMITATIONS: Heterogeneity of included studies. CONCLUSIONS: The absence of overall differences in amygdala volumes, in the presence of significant and sometimes mirror changes in patient subgroups, demonstrates marked heterogeneity among mood disorders. Amygdala volume abnormalities may not be associated with mood disorders per se, but rather may underlie only some dimensions of illness or represent artifacts of medication or comorbid conditions.

Striatal volumes in affected and unaffected relatives of bipolar patients--high-risk study.

BACKGROUND: Striatal volume changes reported in bipolar disorders could represent artifacts of medication or comorbid conditions, or illness related changes, either biological predispositions or consequences of illness burden. We conducted volumetric high-risk study to investigate whether striatal volume changes represent primary biological risk factor for bipolar disorders. METHODS: High-risk (HR) participants (age range 15-30 years) were recruited from families multiply affected with bipolar disorders. They included 20 affected and 26 unaffected offspring of parents with primary mood disorders, matched by age and sex with 31 controls without a personal or family history of psychiatric disorders. Striatal volumes were measured on 1.5T 3D anatomical MRI images using standard methods. RESULTS: There was a significant difference between groups (affected, unaffected HR and control subjects) in caudate volumes (F=3.50, DF=2; 74 and p=0.04) in absence of putamen volume changes. The caudate volumes were largest in unaffected HR subjects without differences between affected and control or affected and unaffected HR subjects. The maximum changes were found in the head of the caudate. Controlling for non-independence of observations in multiple subjects per family yielded non-significant differences. CONCLUSIONS: Despite the biological plausibility, partial agreement with previous studies and nominal statistical significance, controlling for non-independence of observations within families changed the increased caudate volumes among unaffected subjects to non-significant. We thus present these findings as negative, pending further replication. Striatal volume abnormalities did not meet criteria for endophenotype in this study.

Pituitary volumes in relatives of bipolar patients: high-risk study.

BACKGROUND: Increased, decreased, as well as unchanged pituitary volumes have been reported in bipolar disorders (BD). It is unclear, whether abnormal pituitary volumes increase vulnerability for BD (primary vulnerability marker), or are secondary to burden of illness. To address this question, we performed the first high-risk study of pituitary volumes in affected and unaffected relatives of bipolar subjects. METHOD: High-risk participants (age range 15-30 years) were recruited from families multiply affected with BD and included 24 unaffected, 19 affected subjects with first or second degree bipolar I or II relative, matched by age and sex with 31 controls without a personal or family history of psychiatric disorders. Pituitary volumes were measured on 1.5 T 3D anatomical MRI images using standard methods. RESULTS: We found comparable pituitary volumes among unaffected, affected relatives of bipolar patients and controls. There were no differences in pituitary volumes between male and female subjects nor was there any sex by group interaction. Analyzing 26 participants with bipolar I parent or excluding 5 medicated subjects did not change the results. There were no differences between subjects from families containing bipolar I versus families containing only bipolar II subjects. CONCLUSIONS: The lack of abnormalities in unaffected and also affected subjects early in the course of illness in our study, as well as previous investigations of bipolar and familial unipolar children and adolescents, suggest that pituitary volume abnormalities are unlikely to be a primary risk factor for mood disorders.