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The default mode network (DMN) comprises brain structures maximally active at rest. Disturbance of network nodes or their connections occurs with some neuropsychiatric conditions and may underlie associated dysfunction. DMN connectivity has not been examined in alcoholism, which is marked by compromised DMN nodes and impaired spatial working memory. To test whether performance would be related to DMN integrity, we examined DMN functional connectivity using functional magnetic resonance imaging (fMRI) data and graph theory analysis. We assumed that disruption of short paths between network nodes would attenuate processing efficiency. Alcoholics and controls were scanned at rest and during a spatial working memory task. At rest, the spontaneous slow fluctuations of fMRI signals in the posterior cingulate and cerebellar regions in alcoholics were less synchronized than in controls, indicative of compromised functional connectivity. Graph theory analysis indicated that during rest, alcoholics had significantly lower efficiency indices than controls between the posterior cingulate seed and multiple cerebellar sites. Greater efficiency in several connections correlated with longer sobriety in alcoholics. During the task, on which alcoholics performed on par with controls, connectivity between the left posterior cingulate seed and left cerebellar regions was more robust in alcoholics than controls and suggests compensatory networking to achieve normal performance.

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Functional neuroimaging studies provide converging evidence for existence of intrinsic brain networks activated during resting states and deactivated with selective cognitive demands. Whether task-related deactivation of the default mode network signifies depressed activity relative to the remaining brain or simply lower activity relative to its resting state remains controversial. We employed 3D arterial spin labeling imaging to examine regional cerebral blood flow (CBF) during rest, a spatial working memory task, and a second rest. Change in regional CBF from rest to task showed significant normalized and absolute CBF reductions in posterior cingulate, posterior-inferior precuneus, and medial frontal lobes . A Statistical Parametric Mapping connectivity analysis, with an a priori seed in the posterior cingulate cortex, produced deactivation connectivity patterns consistent with the classic “default mode network” and activation connectivity anatomically consistent with engagement in visuospatial tasks. The large task-related CBF decrease in posterior-inferior precuneus relative to its anterior and middle portions adds evidence for the precuneus’ heterogeneity. The posterior cingulate and posterior-inferior precuneus were also regions of the highest CBF at rest and during task performance. The difference in regional CBF between intrinsic (resting) and evoked (task) activity levels may represent functional readiness or reserve vulnerable to diminution by conditions affecting perfusion.

▼  Objectives: 

Brain structures of a distributed ventral-limbic and dorsal brain network have been associated with altered mood states and emotion regulation in affective disorders. So far, diffusion tensor imaging studies in bipolar patients have focused on frontal/prefrontal brain regions and found alterations in white matter integrity in manic, depressed, and euthymic bipolar patients, observed as changes in fractional anisotropy and mean diffusivity. To extend previous findings, we investigated whole-brain modifications in white matter integrity in euthymic bipolar patients with minimal manic and depressive symptoms.

Methods: 

Twenty-two patients with a DSM-IV-TR diagnosis of bipolar I and II disorder in remission, with no lifetime or present comorbidities of substance abuse, and 21 sex- and age-matched healthy controls underwent diffusion tensor imaging with diffusion gradients applied along 41 directions. Fractional anisotropy and mean diffusivity group differences were explored using two voxel-based, whole-brain analyses that differ in their normalization approaches.

Results: 

Fractional anisotropy was significantly increased in bipolar patients relative to healthy controls in medial frontal, precentral, inferior parietal, and occipital white matter. No group differences in mean diffusivity were found.

Conclusions: 

The result of increased fractional anisotropy in euthymic bipolar patients in the present study suggests increased directional coherence of white matter fibers in bipolar patients during remission.

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The left superior temporal cortex, which supports linguistic functions, has consistently been reported to activate during auditory–verbal hallucinations in schizophrenia patients. It has been suggested that auditory hallucinations and the processing of normal external speech compete for common neurophysiological resources. We tested the hypothesis of a negative relationship between the clinical severity of hallucinations and local brain activity in posterior linguistic regions while patients were listening to external speech. Fifteen right-handed patients with schizophrenia and daily auditory hallucinations for at least 3 months were studied with event-related fMRI while listening to sentences in French or to silence. Severity of hallucinations, assessed using the auditory hallucination subscales of the Psychotic Symptom Rating Scales (PSYRATS) and of the Scale for the Assessment of Positive Symptoms (SAPS-AH), negatively correlated with activation in the left temporal superior region in the French minus silence condition. This finding supports the hypothesis that auditory hallucinations compete with normal external speech for processing sites within the temporal cortex in schizophrenia.

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As Norman Geschwind asserted in 1965, syndromes resulting from white matter lesions could produce deficits in higher-order functions and “disconnexion” or the interruption of connection between gray matter regions could be as disruptive as trauma to those regions per se. The advent of in vivo diffusion tensor imaging, which allows quantitative characterization of white matter fiber integrity in health and disease, has served to strengthen Geschwind’s proposal. Here we present an overview of the principles of diffusion tensor imaging (DTI) and its contribution to progress in our current understanding of normal and pathological brain function.

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Neuropathological, neuropsychological, and neuroimaging studies of human alcoholism provide evidence for degradation of frontal, pontine, thalamic, and cerebellar brain sites and disturbed associated functions. Current studies using neuroimaging combined with examination of executive functions, traditionally considered the sole purview of the frontal lobes, have identified a role for the cerebellum serving as a compensatory processing adjunct to enable normal performance on challenging tasks tapping executive functions. This overview proposes that disruption of an executive frontocerebellar network is a major contributor to characteristic behaviors of alcoholism that, on the one hand, enable alcohol use disorders, and on the other hand, lead to compensation for dysfunctions in alcoholism traditionally considered frontally-based.

▼ Background

Rab-GDI mutations are responsible for “pure” mental deficiency, without any specific clinical features or brain malformation. Therefore, screening for mutations in mentally retarded patients is not available on a routine basis. Moreover, neuronal networks involved in mental deficiency still remain largely unknown.

Methods

We performed a fine neuropsychological and imaging study in five patients from two unrelated families, affected with mental deficiency due to a mutation in the Rab-GDI gene. High resolution 3D brain MRI of the five mentally retarded adult males (mean age 33years) were compared to MRI of 14 healthy males (mean age 35years) using a Voxel-Based Morphometric analysis (VBM).

Results

All patients had isolated moderate mental retardation (WAIS-III IQ range, 41–50; mean 45) without specific morphological or behavioural features. No obvious brain abnormality was observed on visual inspection of individual scans. Using VBM analysis, Rab-GDI mutated patients' MRIs exhibited significant brain changes compared to normal subjects (p<0.05, corrected for multiple comparisons): increased grey matter density in left cerebellum and in left angular gyrus, decreased grey matter volume in thalami, decreased white matter density in prefrontal lobes, right fusiform occipito-temporal gyrus, and decreased white matter volume in cerebellar peduncles.

Conclusions

These morphological changes observed in Rab-GDI mutated patients, mainly localized in the cerebello-thalamo-prefrontal pathway, are consistent with the hypothesis that the cerebellum is one of the critical components of a global learning network. Our results open new avenues in the diagnosis of non-specific mental deficiency using gene-specific “brain maps” as endophenotypes.

▼  <title type="main">Background</title>

Associative learning is required for face–name association and is impaired in alcoholism, but the cognitive processes and brain structural components underlying this deficit remain unclear. It is also unknown whether prompting alcoholics to implement a deep level of processing during face–name encoding would enhance performance.

<title type="main">Methods</title>

Abstinent alcoholics and controls performed a levels-of-processing face–name learning task. Participants indicated whether the face was that of an honest person (deep encoding) or that of a man (shallow encoding). Retrieval was examined using an associative (face–name) recognition task and a single-item (face or name only) recognition task. Participants also underwent 3T structural MRI.

<title type="main">Results</title>

Compared with controls, alcoholics had poorer associative and single-item learning and performed at similar levels. Level of processing at encoding had little effect on recognition performance but affected reaction time (RT). Correlations with brain volumes were generally modest and based primarily on RT in alcoholics, where the deeper the processing at encoding, the more restricted the correlations with brain volumes. In alcoholics, longer control task RTs correlated modestly with smaller tissue volumes across several anterior to posterior brain regions; shallow encoding correlated with calcarine and striatal volumes; deep encoding correlated with precuneus and parietal volumes; and associative recognition RT correlated with cerebellar volumes. In controls, poorer associative recognition with deep encoding correlated significantly with smaller volumes of frontal and striatal structures.

<title type="main">Conclusions</title>

Despite prompting, alcoholics did not take advantage of encoding memoranda at a deep level to enhance face–name recognition accuracy. Nonetheless, conditions of deeper encoding resulted in faster RTs and more specific relations with regional brain volumes than did shallow encoding. The normal relation between associative recognition and corticostriatal volumes was not present in alcoholics. Rather, their speeded RTs occurred at the expense of accuracy and were related most robustly to cerebellar volumes.

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There is considerable evidence that neuroimaging findings can improve the early diagnosis of Wernicke’s encephalopathy (WE) in clinical settings. The most distinctive neuroimaging finding of acute WE are cytotoxic edema and vasogenic edema, which are represented by bilateral symmetric hyperintensity alterations on T2-weighted MR images in the periphery of the third ventricle, periaqueductal area, mammillary bodies and midbrain tectal plate. An initial bout of WE can result in Korsakoff’s syndrome (KS), but repeated bouts in conjunction with its typical comorbidity, chronic alcoholism, can result in signs of tissue degeneration in vulnerable brain regions. Chronic abnormalities identified with neuroimaging enable examination of brain damage in living patients with KS and have expanded the understanding of the neuropsychological deficits resulting from thiamine deficiency, alcohol neurotoxicity, and their comorbidity. Brain structure and functional studies indicate that the interactions involving the thalamus, mammillary bodies, hippocampus, frontal lobes, and cerebellum are crucial for memory formation and executive functions, and the interruption of these circuits by WE and chronic alcoholism can contribute substantially to the neuropsychological deficits in KS.

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Chronic alcoholism is known to disrupt functions served by distributed brain systems, including limbic and frontocerebellar circuits involved in resting-state and task-activated networks subserving component processes of memory often affected in alcoholics. Using an fMRI paradigm, we investigated whether memory performance by alcoholics on a face–name association test previously observed to be problematic for alcoholics could be explained by desynchronous activity between nodes of these specific networks. While in the scanner, 18 alcoholics and 15 controls performed a face–name associative learning task with different levels of processing at encoding. This task was designed to activate the hippocampus, cerebellum, and frontal cortex. Alcoholics and controls were also scanned at rest. Twelve alcoholics and 12 controls were selected to be matched on face–name recognition performance. Task-related fMRI analysis indicated that alcoholics had preserved limbic activation but lower cerebellar activation (Crus II) than the controls in the face–name learning task. Crus II was, therefore, chosen as a seed for functional connectivity MRI analysis. At rest, the left hippocampus and left Crus II had positively synchronized activity in controls, while hippocampal and cerebellar activities were negatively synchronized in alcoholics. Task engagement resulted in hippocampal-cerebellar desynchronization in both groups. We speculate that atypical cerebello-hippocampal activity synchronization during rest in alcoholics was reset to the normal pattern of asynchrony by task engagement. Aberrations from the normal pattern of resting-state default mode synchrony could be interpreted as enabling preserved face–name associative memory in alcoholism.

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Abnormal brain activity may reflect compensation when observed in patients who perform normally on tests requiring functions usually observed as impaired. Operational criteria defining compensation have been described and aid in distinguishing compensatory from chance events. Here, we tested whether previously published functional magnetic resonance imaging data acquired in 15 recovering alcoholics and 15 controls at rest and while performing a spatial working memory task would fulfill criteria defining functional compensation. Multivariate analysis tested how well abnormal activation in the affected group predicted normal performance, despite low or no activation in brain regions invoked by controls to accomplish the same task. By identifying networks that uniquely and positively correlated with good performance, we provide evidence for compensatory recruitment of cerebellar-based functional networks by alcoholics. Whereas controls recruited prefrontal-cerebellar regions VI/Crus I known to subserve working memory, alcoholics recruited 2 other parallel frontocerebellar loops: dorsolateral prefrontal cortex (DLPFC)-cerebellar VIII system during rest and DLPFC-cerebellar VI system while task engaged. Greater synchronous activity between cerebellar lobule VIII and DLPFC at rest and greater activation within cerebellar lobule VI and DLPFC during task predicted better working memory performance. Thus, higher intrinsic cerebellar activity in alcoholics was an adequate condition for triggering task-relevant activity in the frontal cortex required for normal working memory performance.

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Altered availability of the brain biochemical glutamate might contribute to the neural mechanisms underlying age-related changes in cognitive and motor functions. To investigate the contribution of regional glutamate levels to behavior in the aging brain, we used an in vivo magnetic resonance spectroscopy protocol optimized for glutamate detection in 3 brain regions targeted by cortical glutamatergic efferents—striatum, cerebellum, and pons. Data from 61 healthy men and women ranging in age from 20 to 86 years were used. Older age was associated with lower glutamate levels in the striatum, but not cerebellum or pons. Older age was also predictive of poorer performance on tests of visuomotor skills and balance. Low striatal glutamate levels were associated with high systolic blood pressure and worse performance on a complex visuomotor task, the Grooved Pegboard. These findings suggest that low brain glutamate levels are related to high blood pressure and that changes in brain glutamate levels might mediate the behavioral changes noted in normal aging.