Reduced white matter integrity is related to cognitive instability

Increased performance variability has been demonstrated in several groups and conditions, including aging and cognitive decline. Structural brain characteristics underlying this phenomenon have so far been elusive. However, there is reason to expect that disconnectivity in associative pathways, whether caused by immature or degraded white matter (WM) tracts, will increase performance variability by neural noise. The aim of this study was to test whether the quality of WM, measured by diffusion tensor imaging, is related to performance variability in healthy adults. Intraindividual standard deviation of the reaction time (sdRT) across trials and median reaction time (mRT) from 270 participants were obtained from a speeded continuous performance task (Eriksen flanker task) with two conditions (congruent, incongruent). Tract-based spatial statistics was used to test the relationship with diffusion characteristics [fractional anisotropy (FA), mean diffusion (MD), radial diffusion (RD), axial diffusion (AD)]. Robust relationships between sdRT and all diffusion measures were found in most WM areas, independently of mRT, age, and sex. The effects were anatomically more widespread in the congruent than the incongruent condition, covering almost 50% of the voxels for RD and MD, and >25% of the voxels for FA and AD. Partial betas were in the range 0.45-0.55, and the strength of the relationships increased significantly with age. For mRT, the effects were smaller and unstable across condition. We concluded that performance variability is a likely consequence of individual differences in WM integrity, and that it is a promising behavioral correlate of individual differences in WM microstructure.     

Frontal white matter biochemical abnormalities in late-life major depression detected with proton magnetic resonance spectroscopy

OBJECTIVE: Neuroanatomical abnormalities have been identified in patients with late-life mood disorders by using magnetic resonance imaging. This study examined the biochemical correlates of late-life major depression in the frontal gray and white matter by using single-voxel proton spectroscopy. METHOD: Twenty elderly patients with major depression and 18 comparison subjects similar in age and gender to the patients were scanned on a 1.5-T magnetic resonance scanner with head coil. Voxels were placed in the left dorsolateral white matter and bilaterally in the anterior cingulate gray matter. Absolute levels of N-acetylaspartate, choline, myo-inositol, and creatine were estimated with the LC-Model algorithm. Ratios of metabolite to creatine levels were computed from the absolute values. RESULTS: myo-Inositol/creatine and choline/creatine ratios were significantly higher in the frontal white matter in the major depression group than in the comparison group. The groups had no significant differences in the metabolite ratios in the gray matter. CONCLUSIONS: Biochemical changes in the white matter may provide some of the neurobiological substrates to late-life major depression.     

Frontal white matter integrity in borderline personality disorder with self-injurious behavior

Self-injurious behavior in borderline personality disorder is a frequent cause of morbidity and mortality, but neurobiological studies examining this behavior are few. Nine women with borderline personality disorder self-injurious behavior and seven comparison subjects underwent diffusion tensor imaging (DTI). Trace and fractional anisotropy (FA) were calculated for frontal and posterior regions. Borderline personality disorder-self-injurious behavior subjects also underwent a battery of neuropsychological tests that emphasized executive functions. They had significantly higher trace and lower FA in inferior frontal but not posterior regions. Correlational analyses between DTI and cognitive variables showed a pattern of results that was contrary to expectations with posterior white matter integrity correlating with isolated measures of executive function and anterior white matter integrity correlating with a component of verbal memory test performance. Women with borderline personality disorder-self-injurious behavior exhibit decreased white matter microstructural integrity in inferior frontal brain regions that may include components of orbito-frontal circuitry.     

Alterations of white matter integrity related to motor activity in schizophrenia

Altered structural connectivity is a key finding in schizophrenia, but the meaning of white matter alterations for behavior is rarely studied. In healthy subjects, motor activity correlated with white matter integrity in motor tracts. To explore the relation of motor activity and fractional anisotropy (FA) in schizophrenia, we investigated 19 schizophrenia patients and 24 healthy control subjects using Diffusion Tensor Imaging (DTI) and actigraphy on the same day. Schizophrenia patients had lower activity levels (AL). In both groups linear relations of AL and FA were detected in several brain regions. Schizophrenia patients had lower FA values in prefrontal and left temporal clusters. Furthermore, using a general linear model, we found linear negative associations of FA and AL underneath the right supplemental motor area (SMA), the right precentral gyrus and posterior cingulum in patients. This effect within the SMA was not seen in controls. This association in schizophrenia patients may contribute to the well known dysfunctions of motor control. Thus, structural disconnectivity could lead to disturbed motor behavior in schizophrenia.     

Relationships between psychomotor retardation and EEG power spectrum in major depression.

In 63 depressed patients, the associations between severity of depression, psychomotor retardation, assessed by the Bech-Rafaelsen Melancholia Scale, and EEG spectral analysis were examined. Slow EEG activity (theta 2/alpha 1 bands) was positively and fast activity (alpha 3/beta bands) negatively correlated with the observed retardation. Out of the four retardation subitems (motor, verbal, intellectual and emotional), motor retardation was closest correlated with slow EEG activity.     

Slow brain potentials and psychomotor retardation in depression

Event-related cortical potentials were recorded in 11 patients with primary depression and 11 healthy control subjects during a serial choice reaction task. Each new trial was voluntarily initiated when the subject pressed a microswitch; an acoustic go or no-go signal followed after a fixed interval. This elicited a Bereitschaftspotential (BP), a contingent negative variation (CNV), acoustically evoked potentials (N1, P2, P3), and a post-imperative negative variation (PINV) in direct succession. These were evaluated conventionally and by principal component analysis (PCA). Patients exhibited significantly longer reaction times and more negative PINVs. BP and CNV did not differ between groups. In conventional amplitude measurement small P3 amplitudes in depressives may be feigned by markedly negative PINVs.     

Frontal systems impairment in major depression

Recent studies point to the importance of frontal systems in the control of complex behavior. Because major depression affects the same systems the considerable overlap between some so-called "depressive symptoms" and the behavioral sequelae of frontal lobe brain damage can be explained. In other mental disorders, functional outcomes are closely related to frontal system impairment. Frontal deficits, rather than mood disturbance, may explain the disability of depressed patients. This should cause doctors to reconsider their approach to depression. Treatment for the cognitive aspects of depression may be needed to ensure improvement in functional domains.     

Visual white matter integrity in schizophrenia

OBJECTIVE: Patients with schizophrenia have visual-processing deficits. This study examines visual white matter integrity as a potential mechanism for these deficits. METHOD: Diffusion tensor imaging was used to examine white matter integrity at four levels of the visual system in 17 patients with schizophrenia and 21 comparison subjects. The levels examined were the optic radiations, the striate cortex, the inferior parietal lobule, and the fusiform gyrus. RESULTS: Schizophrenia patients showed a significant decrease in fractional anisotropy in the optic radiations but not in any other region. CONCLUSIONS: This finding indicates that white matter integrity is more impaired at initial input, rather than at higher levels of the visual system, and supports the hypothesis that visual-processing deficits occur at the early stages of processing.     

HF-rTMS treatment decreases psychomotor retardation in medication-resistant melancholic depression

Repetitive Transcranial Magnetic Stimulation (rTMS) applied to the left dorsolateral prefrontal cortex (DLPFC) might be a promising treatment strategy for depression. As one of the key features of melancholic depression is disturbances in psychomotor activity, we wanted to evaluate whether HF-rTMS treatment could influence psychomotor symptoms. Twenty antidepressant-free unipolar melancholic depressed patients, all at least stage III medication-resistant, were studied. All were treated with 10 sessions of High-Frequency (HF)-rTMS applied to the left dorsolateral prefrontal cortex (DLPFC) under MRI guidance. Forty percent of the patients showed a reduction of at least 50% on their initial 17-item Hamilton Depression Rating Score (HDRS) scale and were defined as clinical responders. Regardless of clinical outcome HF-rTMS treatment resulted in significant decreases on the Depressive Retardation Rating Scale (DRRS) scores. Although this was an open study in a relatively small sample, our results suggest that HF-rTMS might act on the ‘psychomotor’ level and these findings could add some further information as to why this kind of treatment can be beneficial for severely depressed patients of the melancholic subtype.     

Electroconvulsive therapy mediates neuroplasticity of white matter microstructure in major depression

Whether plasticity of white matter (WM) microstructure relates to therapeutic response in major depressive disorder (MDD) remains uncertain. We examined diffusion tensor imaging (DTI) correlates of WM structural connectivity in patients receiving electroconvulsive therapy (ECT), a rapidly acting treatment for severe MDD. Tract-Based Spatial Statistics (TBSS) applied to DTI data (61 directions, 2.5 mm³ voxel size) targeted voxel-level changes in fractional anisotropy (FA), and radial (RD), axial (AD) and mean diffusivity (MD) in major WM pathways in MDD patients (n=20, mean age: 41.15 years, 10.32 s.d.) scanned before ECT, after their second ECT and at transition to maintenance therapy. Comparisons made at baseline with demographically similar controls (n=28, mean age: 39.42 years, 12.20 s.d.) established effects of diagnosis. Controls were imaged twice to estimate scanning-related variance. Patients showed significant increases of FA in dorsal fronto-limbic circuits encompassing the anterior cingulum, forceps minor and left superior longitudinal fasciculus between baseline and transition to maintenance therapy (P<0.05, corrected). Decreases in RD and MD were observed in overlapping regions and the anterior thalamic radiation (P<0.05, corrected). Changes in DTI metrics associated with therapeutic response in tracts showing significant ECT effects differed between patients and controls. All measures remained stable across time in controls. Altered WM microstructure in pathways connecting frontal and limbic areas occur in MDD, are modulated by ECT and relate to therapeutic response. Increased FA together with decreased MD and RD, which trend towards normative values with treatment, suggest increased fiber integrity in dorsal fronto-limbic pathways involved in mood regulation.     

Action monitoring in major depressive disorder with psychomotor retardation

Major depressive disorder (MDD) is characterized by disturbances of mood and affect, but also by a distinct pattern of psychomotor and cognitive deficits such as motor retardation and impaired executive functioning. An important aspect of executive functioning is performance monitoring, i.e., a continuous checking whether intended action goals have been reached and whether correction of the applied strategy is necessary. A well-known marker for action monitoring is the error negativity (Ne) or error-related negativity (ERN), an event-related potential (ERP) component generated in the anterior cingulate cortex (ACC) following erroneous responses. To date, Ne/ERN amplitudes have been investigated in moderately depressed patients only. The present study is the first to investigate action monitoring in severely depressed patients (mean Hamilton score=28.4). In addition, the patients' psychomotor performance was assessed to see whether there is a relationship between action monitoring and psychomotor retardation. Behavioural and ERP measurements were obtained during performance on a speeded two-choice reaction task in 26 patients with MDD and 25 healthy, matched controls. Psychomotor performance measures were speed of simple movements in various psychomotor tasks and the score on the Salpêtrière retardation rating scale (SRRS). Relative to the controls, the patients' behavioural results revealed a similar, but slower performance pattern. Overall between-group differences were demonstrated for the error positivity (Pe) amplitudes, but not for the Ne/ERN amplitudes. However, correlations of the Ne/ERN amplitude with several psychomotor variables were strong. In the depressed patients taking benzodiazepines an additional attenuation of Ne/ERN amplitudes was observed. Only severely depressed patients manifesting retardation showed impeded action monitoring. The correlations between action monitoring and psychomotor performance indicate that in MDD these two processes are highly interdependent, both being deregulated. Moreover, the same network of brain regions is likely to be implicated in both processes.     

Frontal white matter microstructure and treatment response of late-life depression: a preliminary study

OBJECTIVE: This study tested the hypothesis that microstructural abnormalities in white matter areas of the brain containing frontostriatal tracts are associated with a low rate of remission of geriatric depression. METHOD: Thirteen older patients with major depression received open, but controlled, treatment with citalopram at a target daily dose of 40 mg for 12 weeks. Diffusion tensor imaging was used to determine fractional anisotropy in preselected white matter regions. RESULTS: Survival analysis with Cox's proportional hazards model revealed that lower fractional anisotropy of the right and the left frontal white matter regions 15 mm above the anterior commissure-posterior commissure plane was associated with a low remission rate after age was considered. Remission was not significantly associated with fractional anisotropy of lower frontal regions or a temporal region. CONCLUSIONS: Microstructural white matter abnormalities lateral to the anterior cingulate may be associated with a low rate of remission of geriatric depression.     

Clinical contributors to cerebral white matter integrity in HIV-infected individuals

HIV-infected people frequently exhibit brain dysfunction characterized by preferential damage to the cerebral white matter. Despite suppressed viral load and reconstituted immune function afforded by combination antiretroviral therapy (CART), brain dysfunction continues to be observed even in medically stable individuals. To provide insight into the etiology of HIV-associated brain dysfunction in the CART era, we examined the effects of HIV disease markers, antiretroviral treatment, hepatitis C (HCV) coinfection, and age on DTI measures of white matter integrity in a cohort of 85 individuals aged 23 to 65 years with chronic HIV infection. Fractional anisotropy and mean diffusivity were derived from 29 cerebral white matter regions, which were segmented on each individual brain using a high-resolution T1-weighted image and registered to diffusion images. Significant effects of clinical variables were found on white matter abnormalities in nearly all brain regions examined. Most notably, HCV coinfection and older age were associated with decreased anisotropy or increased diffusivity in the majority of brain regions. Individuals with higher current CD4 levels exhibited higher anisotropy in parietal lobe regions, while those undergoing antiretroviral treatment exhibited higher anisotropy in temporal lobe regions. The observed diffuse pattern of white matter injury suggests that future neuroimaging studies should employ methodologies that are not limited to circumscribed regions of interest. The current findings underline the multifactorial nature of HIV-associated brain dysfunction in the CART era, and the importance of examining the effects of HIV disease in the context of other comorbidities, in particular HCV coinfection and aging.     

Becoming consistent: developmental reductions in intraindividual variability in reaction time are related to white matter integrity

Cognitive development is known to involve improvements in accuracy, capacity, and processing speed. Less is known about the role of performance consistency, and there has been virtually no empirical examination of the neural underpinnings of within-person variability in development. In a sample of 92 healthy children and adolescents aged 8-19 years, we aimed to characterize age-related changes in trial-to-trial intraindividual variability (IIV) of reaction time (RT) and to test whether IIV is related to white matter (WM) integrity as indexed by diffusion tensor imaging. IIV was quantified as the SD of correct RTs in a speeded arrow flanker task, and Tract-Based Spatial Statistics was used to test relationships with diffusion characteristics. Large age-related reductions in IIV in both simple congruent trials and more complex incongruent trials were found. Independently of sex, age, and median RT (mRT), lower IIV was associated with higher fractional anisotropy and lower overall diffusivity. Effects were seen for IIV in one or both trial types in the corticospinal tract, the left superior longitudinal fasciculus, the uncinate fasciculus, the forceps minor, and in the genu and splenium of the corpus callosum. There were no significant associations between mRT and any of the diffusion indices. The findings support the proposition that developmental reductions in IIV reflect maturation of WM connectivity and highlight the importance of considering within-person variability in theories of cognitive development and its neurobiological foundation.     

重性抑郁症脑白质性别差异的初步研究

目的 利用磁共振弥散张量成像技术探讨重性抑郁症患者脑白质纤维是否存在性别差异.方法 24例重性抑郁症患者(男15例,女9例)及30名正常对照(男11名,女19名)均经常规核磁共振(MRI)和DTI扫描,基于像素的全脑分析技术对各组间DTI数据进行比较分析.结果 [1]男性患者左额中回、右颞叶回下、左梭状回、楔前叶及右顶叶回下等区域各向异性值(faraction anistropy, FA)低于男性正常对照(P<0.001);女性患者在右额上回、额叶回下、颞叶回下、左颞上回及右后扣带回等白质区域的FA值低于女性正常对照(P<0.001).[2]女性患者在右顶叶回下、左中央前回、右颞中回及右扣带回白质区域的FA值低于男性患者(P<0.001);女性正常对照仅在左边缘叶下回及左枕叶中回的区域的FA值低于男性正常对照(P<0.001).结论 男女抑郁症患者均存在脑白质异常区域,且两老少间存在差异.