Neurochemical deficits in the cerebellar vermis in child offspring of parents with bipolar disorder

Singh MK, Spielman D, Libby A, Adams E, Acquaye T, Howe M, Kelley R, Reiss A, Chang KD. Neurochemical deficits in the cerebellar vermis in child offspring of parents with bipolar disorder.
Bipolar Disord 2011: 13: 189–197. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objectives: We aimed to compare concentrations of N‐acetyl aspartate, myo‐inositol, and other neurometabolites in the cerebellar vermis of offspring at risk for bipolar disorder (BD) and healthy controls to examine whether changes in these neuronal metabolite concentrations occur in at‐risk offspring prior to the onset of mania. Methods: A total of 22 children and adolescents aged 9–17 years with a familial risk for bipolar I or II disorder [at‐risk offspring with non‐bipolar I disorder mood symptoms (AR)], and 25 healthy controls (HC) were examined using proton magnetic resonance spectroscopy at 3T to study metabolite concentrations in an 8‐cc voxel in the cerebellar vermis. Results: Decreased myo‐inositol and choline concentrations in the vermis were seen in the AR group compared to HC (p < 0.01). Conclusions: Decreased cellular metabolism and interference with second messenger pathways may be present in the cerebellar vermis in youth at risk for BD as evident by decreased myo‐inositol and choline concentrations in this region. These results may be limited by a cross‐sectional design, co‐occurring diagnoses, and medication exposure. Longitudinal studies are necessary to determine whether early neurochemical changes can predict the development of mania. Improved methods for identifying children with certain neurochemical vulnerabilities may inform preventive and early intervention strategies prior to the onset of mania.     

非典型症状与双相障碍

概述：双相障碍（Bipolar Disorder,BD）临床症状多样,容易被误诊为抑郁症（Major depressive disorder, MDD）。非典型症状（Atypical Features,ATFs）是一个有用的指标,可以从抑郁状态中识别出双相障碍,有助于双相障碍与抑郁症的鉴别诊断。本文就非典型症状与双相障碍的相关性问题进行讨论。     

Cerebellar ataxia in youths at risk for bipolar disorder

Objective:  Structural, biochemical, and functional cerebellar abnormalities occur in individuals with or at-risk for developing bipolar disorder (BD), but the clinical implications of these abnormalities are unknown. The present study examined cerebellar function in youths who were at familial risk for BD by comparing ataxia battery scores of youths with a bipolar parent to those of healthy youths.
Methods:  Trained raters administered an ataxia battery, consisting of three tasks, to children (aged 8–12 years) with at least one parent with BD type I (BDI) who themselves did not have BDI (at-risk or AR group, n = 21) and healthy comparison children (aged 8–12 years) with parents free of DSM-IV Axis I psychopathology (HC group, n = 23).
Results:  AR youths performed worse than HC youths on the Sharpened Romberg test (subjects standing heel-to-toe) and standing on one foot with eyes open ( p  < 0.02).
Conclusions:  The results indicate that youths at familial risk for BD have more difficulty performing a Sharpened Romberg test than a HC group, suggesting that midline cerebellar dysfunction may be a biomarker for the future development of BD. Further studies examining the relationships among youths at risk for BD, coordination abnormalities, and cerebellar dysfunction are needed.     

Increased right amygdala volume in lithium‐treated patients with bipolar I disorder

Usher J, Menzel P, Schneider‐Axmann T, Kemmer C, Reith W, Falkai P, Gruber O, Scherk H. Increased right amygdala volume in lithium‐treated patients with bipolar I disorder. Objective: The amygdala plays a major role in processing emotional stimuli. Fourteen studies using structural magnetic resonance imaging (MRI) have examined the amygdala volume in paediatric and adult patients with bipolar disorder (BD) compared with healthy controls (HC) and reported inconsistent findings. Lithium has been found to increase grey matter volume, and first evidence points towards an effect on regional brain volume such as the amygdala. Method: We examined the amygdala volume of euthymic patients with BD treated with lithium (n = 15), without lithium (n = 24) and HC (n = 41) using structural MRI. Results: Patients treated with lithium exhibited in comparison to HC a larger right absolute (+17.9%, P = 0.015) and relative (+18%, P = 0.017) amygdala volume. There was no significant difference in amygdala volume between patients without lithium treatment and HC. Conclusion: Lithium appears to have a sustained effect on a central core region of emotional processing and should therefore be considered in studies examining BD.     

抑郁症门诊患者中未识别出的双相障碍者的临床特征（英文）

背景双相障碍常未被识别或被误诊为单相抑郁。明确未被识别或被误诊的双相障碍者的临床特征有助于减少错误分类。目的调查门诊抑郁症患者中未被识别的双相障碍者的比例,并分析未被识别的双相障碍者的临床特征。方法使用32项轻躁狂症状清单（Hypomania Checklist-32,HCL-32）、心境障碍问卷（Mood Disorder Questionnaire,MDQ）和简明国际神经精神访谈（Mini International Neuropsychiatric Interview,MINI）对目前被诊断为抑郁症的100例门诊患者进行调查。对被重新诊断为双相障碍与仍然被诊断为抑郁症的患者的临床特征进行比较分析。结果共有29例（29%）抑郁症门诊患者被诊断为双相障碍;其中双相Ⅰ型6例,双相Ⅱ型23例。与未更改诊断的抑郁症者相比,被重新诊断为双相障碍者年龄轻、起病早、发病次数多、受教育程度高,多为复发性抑郁且多伴精神病性症状。多因素Logistic回归分析显示年龄（OR=0.55,95%CI=0.34~0.89）和精神病性症状（OR=9.12,95%CI=1.56~53.26）是双相障碍的独立危险因素。结论在门诊抑郁症患者中未被识别的双相障碍比例较高,尤其是双相Ⅱ型。与单相抑郁相比,诊断为抑郁症而为未被识别的双相障碍者年龄轻,更可能伴有精神病性症状。     

Progressive neurostructural changes in adolescent and adult patients with bipolar disorder

Lisy ME, Jarvis KB, DelBello MP, Mills NP, Weber WA, Fleck D, Strakowski SM, Adler CM. Progressive neurostructural changes in adolescent and adult patients with bipolar disorder.
Bipolar Disord 2011: 13: 396–405. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objectives: Several lines of evidence suggest that bipolar disorder is associated with progressive changes in gray matter volume (GMV), particularly in brain structures involved in emotional regulation and expression. The majority of these studies however, have been cross‐sectional in nature. In this study we compared baseline and follow‐up scans in groups of bipolar disorder and healthy subjects. We hypothesized bipolar disorder subjects would demonstrate significant GMV changes over time. Methods: A total of 58 bipolar disorder and 48 healthy subjects participated in structural magnetic resonance imaging (MRI). Subjects were rescanned 3–34 months after their baseline MRI. MRI images were segmented, normalized to standard stereotactic space, and compared voxel‐by‐voxel using statistical parametrical mapping software (SPM2). A model was developed to investigate differences in GMV at baseline, and associated with time and episodes, as well as in comparison to healthy subjects. Results: We observed increases in GMV in bipolar disorder subjects across several brain regions at baseline and over time, including portions of the prefrontal cortex as well as limbic and subcortical structures. Time‐related changes differed to some degree between adolescent and adult bipolar disorder subjects. The interval between scans positively correlated with GMV increases in bipolar disorder subjects in portions of the prefrontal cortex, and both illness duration and number of depressive episodes were associated with increased GMV in subcortical and limbic structures. Conclusions: Our findings support suggestions that widely observed progressive neurofunctional changes in bipolar disorder patients may be related to structural brain abnormalities in anterior limbic structures. Abnormalities largely involve regions previously noted to be integral to emotional expression and regulation, and appear to vary by age.     

Structural abnormalities of ventrolateral and orbitofrontal cortex in patients with familial bipolar disorder

Objectives: Abnormalities of ventral prefrontal function have been widely reported in bipolar disorder, but reports of structural abnormalities in the same region are less consistent. We examined the presence and location of ventral prefrontal abnormalities in a large sample of individuals with bipolar disorder and their relationship to gender, psychotic symptoms, and age. Methods: Structural magnetic resonance imaging brain scans were carried out on 66 individuals with bipolar disorder, type I, and 66 controls. Voxel‐based morphometry was used to examine differences in grey and white matter density between the groups and their relationship with a lifetime occurrence of psychotic symptoms and age. Results: Reductions in grey matter density were seen in the left and right lateral orbital gyri and the right inferior frontal gyrus, while white matter density reductions were seen in the corona radiata and the left temporal stem. In contrast, hallucinations and positive symptoms were associated with grey matter reduction in the left middle temporal gyrus. Age was more strongly associated with the right inferior frontal gyrus grey matter reductions in the bipolar group than in the controls, but not with any other finding. Conclusion: Abnormalities of the ventral prefrontal cortex are likely to be involved in the aetiopathology of bipolar disorder, while hallucinations appear to be more closely associated with temporal lobe abnormality, extending earlier work in schizophrenia. Further prospective studies are required to comprehensively address the trajectory of these findings.     

Caudate volume measurement in older adults with bipolar disorder

BACKGROUND: Decreased caudate volumes have been noted in unipolar depressed subjects, especially in the elderly and those with cognitive impairment. No differences have been noted in initial studies of multi-aged bipolar subjects; however, this region has not been examined in older bipolar subjects. METHODS: We examined the caudate nuclei volumes of 36 older bipolar subjects (mean age 58) and 35 older controls (mean age 62) using logistic regression analyses to control for age and gender differences. Differences between late- and early-onset (age-of-onset before age 45) bipolar subjects were also examined, as well as the effect of length of illness. RESULTS: The right caudate was noted to be smaller in older bipolar subjects compared with older controls when controlled for sex and age (p = 0.0448). No differences were noted in overall brain volume nor lateral ventricular volume between the bipolar and control subjects. Late-onset bipolar subjects had a decrease in brain volume (p = 0.035) compared with early-onset bipolar subjects. Late-onset bipolar subjects had a decrease in the right (p = 0.044) and total (p = 0.04) caudate size compared with older controls. CONCLUSIONS: Right caudate volume is decreased in older bipolar subjects compared to controls. Bipolar subjects with late-onset illness have significantly decreased right and total caudate volumes compared to controls. This is affected by neither the length of illness nor the age of onset. Late-onset bipolar subjects have decreased total brain volume compared with early-onset bipolar subjects.     

Alterations of the cerebellum and basal ganglia in bipolar disorder mood states detected by quantitative T1ρ mapping

Objectives

Quantitative mapping of T1 relaxation in the rotating frame (T1ρ) is a magnetic resonance imaging technique sensitive to pH and other cellular and microstructural factors, and is a potentially valuable tool for identifying brain alterations in bipolar disorder. Recently, this technique identified differences in the cerebellum and cerebral white matter of euthymic patients vs healthy controls that were consistent with reduced pH in these regions, suggesting an underlying metabolic abnormality. The current study built upon this prior work to investigate brain T1ρ differences across euthymic, depressed, and manic mood states of bipolar disorder.

Methods

Forty participants with bipolar I disorder and 29 healthy control participants matched for age and gender were enrolled. Participants with bipolar disorder were imaged in one or more mood states, yielding 27, 12, and 13 imaging sessions in euthymic, depressed, and manic mood states, respectively. Three‐dimensional, whole‐brain anatomical images and T1ρ maps were acquired for all participants, enabling voxel‐wise evaluation of T1ρ differences between bipolar mood state and healthy control groups.

Results

All three mood state groups had increased T1ρ relaxation times in the cerebellum compared to the healthy control group. Additionally, the depressed and manic groups had reduced T1ρ relaxation times in and around the basal ganglia compared to the control and euthymic groups.

Conclusions

The study implicated the cerebellum and basal ganglia in the pathophysiology of bipolar disorder and its mood states, the roles of which are relatively unexplored. These findings motivate further investigation of the underlying cause of the abnormalities, and the potential role of altered metabolic activity in these regions.     

Correspondence between patterns of cerebral blood flow and structure in adolescents with and without bipolar disorder

Adolescence is a period of rapid development of the brain’s inherent functional and structural networks; however, little is known about the region-to-region organization of adolescent cerebral blood flow (CBF) or its relationship to neuroanatomy. Here, we investigate both the regional covariation of CBF MRI and the covariation of structural MRI, in adolescents with and without bipolar disorder. Bipolar disorder is a disease with increased onset during adolescence, putative vascular underpinnings, and evidence of anomalous CBF and brain structure. In both groups, through hierarchical clustering, we found CBF covariance was principally described by clusters of regions circumscribed to the left hemisphere, right hemisphere, and the inferior brain; these clusters were spatially reminiscent of cerebral vascular territories. CBF covariance was associated with structural covariance in both the healthy group (n = 56; r = 0.20, p < 0.0001) and in the bipolar disorder group (n = 68; r = 0.36, p < 0.0001), and this CBF-structure correspondence was higher in bipolar disorder (p = 0.0028). There was lower CBF covariance in bipolar disorder compared to controls between the left angular gyrus and pre- and post-central gyri. Altogether, CBF covariance revealed distinct brain organization, had modest correspondence to structural covariance, and revealed evidence of differences in bipolar disorder.     

Verbal memory impairment in new onset bipolar disorder: Relationship with frontal and medial temporal morphology

Objectives. Verbal memory (VM) impairment is a trait feature of bipolar I disorder (BDI) that is present at illness onset and associated with functional outcome. However, little is known about the morphological abnormalities underlying this deficit early in the disease course. This study examined the neurobiological correlates of VM impairment in euthymic newly diagnosed patients, with attention to frontal and medial temporal (MT) structures known to contribute to VM. Methods. Euthymic patients with BDI recently recovered from their first episode of mania (n = 42) were compared with healthy subjects (n = 37) using measures of the California Verbal Learning Test (CVLT-II) associated with frontal and MT functioning. A subset of participants had 3T MRI scan (n = 31 patient group, n = 30 healthy subject group). Hippocampal and prefrontal volumes were analyzed using FreeSurfer 5.1 and correlated with their corresponding CVLT-II subscores. Results. Patients showed decreased performance in total learning as well as short and long delay verbal recall. Consistent with MT dysfunction, they also showed deficits in recognition discriminability and learning slope. In the patient group only, left hippocampal volumes were negatively correlated with these measures. Conclusions. These results suggest that anomalous MT functioning is involved with VM impairment early in the course of BDI.     

Substance abuse in bipolar disorder

Background: High rates of substance abuse have been reported in the general population, with males more often affected than females. Although high rates of substance abuse have also been reported in bipolar patients, the relationship between substance abuse and bipolar disorder has not been well characterized.

Methods: Substance abuse histories were obtained in 392 patients hospitalized for manic or mixed episodes of bipolar disorder and rates of current and lifetime abuse calculated. Analyses comparing sex, subtype (manic vs. mixed) and clinical history variables were conducted.

Results: Rates of lifetime substance abuse were high for both alcohol (48.5%) and drugs (43.9%). Nearly 60% of the cohort had a history of some lifetime substance abuse. Males had higher rates of abuse than females, but no differences in substance abuse were observed between subjects in manic and mixed bipolar states. Rates of active substance abuse were lower in older age cohorts. Subjects with a comorbid diagnosis of lifetime substance abuse had more psychiatric hospitalizations.

Conclusions: Substance abuse is a major comorbidity in bipolar patients. Although rates decrease in older age groups, substance abuse is still present at clinically important rates in the elderly. Bipolar patients with comorbid substance abuse may have a more severe course. These data underscore the significance of recognition and treatment of substance abuse in bipolar disorder patients.     

双相障碍与强迫症的共病

概述

在双相障碍患者中强迫症状是常见的。因为双相障碍和强迫症的共病状态会令这两种障碍的临床治疗复杂化，所以确定这些共病的患者是很重要的。我们讨论了强迫症和双相障碍的共病，介绍了可能导致这种常见共病状态的发病机制，也讨论了该领域最新的研究进展，并提出一些管理这些患者的临床原则。

中文全文

本文全文中文版从2015年10月26日起在http://dx.doi.org/10.11919/j.issn.1002-0829.215009可供免费阅览下载 Previous studies have documented high rates of comorbidity of other psychiatric conditions among individuals with bipolar disorders (BD).[1] One study estimated that obsessive-compulsive disorders (OCD) accounted for 21% of all comorbidities in BD.[2] There is continuing debate about whether (a) these are two independent conditions that can co-occur or (b) OCD is a specific subtype of BD. Regardless of the interrelationship of the two conditions, the comorbid occurrence of these two types of symptoms can cause a clinical dilemma because selective serotonin reuptake inhibitors (SSRIs)-which are quite commonly used to treat OCD-increases the risk of precipitating manic symptoms.[3,4,5,6] The OCD symptoms that occur in individuals with BD often occur during the depressive episodes or during the intervals between episodes of depressive or manic symptoms.[7,8] This timing of OCD symptoms during BD is consistent with the cyclic nature of BD and suggests shared biological mechanisms between the two disorders. In support of this hypothesis, a study using Positron Emission Tomography (PET) found that in untreated persons with BD the serotonin-transporter binding potential in the insular and dorsal cingulate cortex was higher among BD patients with pathological obsessions and compulsions than among BD patients without such symptoms.[9] Moreover, a linkage study found that compared to OCD patients without comorbid BD, patients with comorbid OCD and BD were more likely to have a family history of mood disorders but less likely to have a family history of OCD.[10] However, another study found no significant difference in the rates of a positive family history of OCD between patients with OCD alone and those with comorbid OCD and BD.[11] Further support for the hypothesized common etiology comes from a preliminary molecular genetic study which found that hyperpolarization activated cyclic nucleotide-gated channel 4 (HCN4) is a common susceptible locus for both mood disorders and OCD, but further studies with larger sample sizes are needed to replicate this finding.[12] The presence of OCD in BD complicates the clinical presentation. Compared to patients with BD without comorbid OCD, those that have comorbid BD and OCD often have a more severe form of BD, have more prolonged episodes, are less adherent to medication, and are less responsive to medication. Recent studies about comorbid BD and OCD have reported the following: (a) Temporal relationship. Some studies suggest that OCD is an antecedent of BD,[10] but others report concurrent onset of OCD and BD.[13,14] (b) Course of disease. In 44% of patients with comorbid BD and OCD the episodes are cyclic.[15] The course of disease is more chronic among BD patients with OCD compared to those without comorbid OCD.[16,17] OCD is more commonly observed in patients with Type II BD, among whom the prevalence of OCD has been reported to be as high as 75%.[18] (c) Compulsive behaviors. The most commonly reported compulsions among patients with comorbid OCD and BD are compulsive sorting,[14,19,20,21] controlling or checking, [20] repeating behaviors,[13,22] excessive washing,[20] and counting.[19] Obsessive reassurance-seeking is also commonly reported in these patients.[23] In children and adolescents with BD, compulsive hoarding, impulsiveness,[24] and sorting[25] are more common. (d) Substance and alcohol abuse. A study found a higher prevalence of sedative, nicotine, alcohol, and caffeine use among individuals with comorbid OCD and BD compared to those with BD without OCD.[14] Similarly, compared to OCD patients without comorbid mood disorders, those with a comorbid mood disorder were more likely to have a substance abuse diagnosis (OR=3.18, 95%CI=1.81-5.58) or alcohol abuse diagnosis (OR=2.21, 95%CI=1.34-3.65).[11,13,26,27,28] (e) Suicidal behaviors. Compared to BD patients without OCD, a greater proportion of patients with both disorders had a lifetime history of suicidal ideation and suicide attempts.[2,11,13,29,30] The clinical management of comorbid OCD and BD requires first focusing on stabilizing the patient’s mood, which requires the combined use of multiple medications such as the use of lithium with anticonvulsants or atypical antipsychotic medications such as quetiapine;[31,32,33] adjunctive treatment with aripiprazole may be effective for the comorbid OCD symptoms.[4] In the case of OCD comorbid with type II BD, after full treatment of the mood symptoms with mood stabilizers the clinician can, while monitoring for potential drug interactions, cautiously try adjunctive treatment with antidepressants that are effective for both depressive symptoms and OCD symptoms and that have a low risk of inducing a full manic episode, including the selective serotonin reuptake inhibitors (SSRIs): fluoxetine, fluvoxamine, paroxetine, and sertraline.[32,35] In summary, BD comorbid with OCD may be etiologically distinct from either of the disorders. Clinicians should pay attention to its complex clinical manifestations and carefully consider the treatment principles outlined above.     

Regional differences in Purkinje cell morphology in the cerebellar vermis of male mice

Regional differences in dendritic architecture can influence connectivity and dendritic signal integration, with possible consequences for neuronal computation. In the cerebellum, analyses of Purkinje cells (PCs), which are functionally critical as they provide the sole output of the cerebellar cortex, have suggested that the cerebellar cortex is not uniform in structure as traditionally assumed. However, the limitations of traditional staining methods and microscopy capabilities have presented difficulties in investigating possible local variations in PC morphology. To address this question, we used male mice expressing green fluorescent protein selectively in PCs. Using Neurolucida 360 with confocal image stacks, we reconstructed dendritic arbors of PCs residing in lobule V (anterior) and lobule IX (posterior) of the vermis. We then analyzed morphologies of individual arbors and the structure of the assembled “jungle,” comparing these features across anatomical locations and age groups. Strikingly, we found that in lobule IX, half of the reconstructed PCs had two primary dendrites emanating from their soma, whereas fewer than a quarter showed this characteristic in lobule V. Furthermore, PCs in lobule V showed more efficient spatial occupancy compared to lobule IX, as well as greater packing density and increased arbor overlap in the adult. When analyzing complete ensembles of PC arbors, we also observed “hot spots” of increased dendritic density in lobule V, whereas lobule IX showed a more homogeneous spread of dendrites. These differences suggest that input patterns and/or physiology of PCs could likewise differ along the vermis, with possible implications for cerebellar function.     

Life events and onset of a new phase in bipolar affective disorder

Background: There is an increasing focus on the impact of psychosocial factors and stressors on the course of bipolar affective disorder. The life event research has revealed many biases and the results are conflicting. In a prospective study we examined the relationship between life events and affective phases in a group of bipolar patients with a long duration of the disease. Methods: A group of patients with at least three admissions to hospital for bipolar disorder was followed every 3 months for up to 3 years. At each examination an evaluation of affective phase was made according to the Hamilton Depression Scale, the Newcastle Depression Rating Scale and the Bech‐Rafaelsen Mania Rating Scale. Moreover, the patients were rated according to the Paykel Life Events Scale. Their current medical treatment was noted. Results: Fifty‐six patients (19 men and 37 women) were included in the study. Women experienced a significantly higher number of life events than men. In 21% of the 353 examinations of women, a new phase was preceded by life events whereas this was the case only in 8% of the 152 examinations of men. In 13% of the male examinations the patients were in a manic phase and in 5% in a depressive phase. In 5% of the female examinations the patients were in a manic phase and in 15% in a depressive phase. Half of the women's depressive phases were preceded by life events, but none of the depressive phases of men. The categories of life events preceding the depressive phases presented a significant overweight of somatic ill health and conflicts in the family. Conclusion: We found a gender difference in the course of bipolar affective disorder, as women had a significantly higher number of depressive episodes than men and men had a higher number of manic episodes than women. In bipolar patients with long duration of disease a significant number of depressive episodes in women were preceded by negative life events. Somatic health problems and conflicts in the family were significant factors preceding new depressive phases.