The brain lipidomes of subcortical ischemic vascular dementia and mixed dementia

Despite its importance as the leading cause of vascular dementia, the primary pathogenic mechanisms in subcortical ischemic vascular dementia (SIVD) have remained elusive. Because of the lack of approved therapeutic agents for SIVD, there is a pressing need to identify novel therapeutic targets. Comparative lipidomic analyses of SIVD and mixed dementia (i.e., SIVD and Alzheimer's disease, MixD) may also confer new insights pertaining to the possible interaction between neurodegenerative and vascular mechanisms in the pathogenesis of dementia. Liquid chromatography coupled to mass spectrometry was used to comprehensively analyze the lipidomes of white and gray matter from the temporal cortex of nondemented controls, SIVD, and MixD subjects. Detailed molecular profiles highlighted the pathologic relevance of gray matter sphingolipid fatty acyl chain heterogeneity in dementia. In addition, the levels of sulfatides and lysobisphosphatidic acids were progressively increased in the temporal cortex gray matter from control to SIVD to MixD. White matter phospholipid profiles indicated possible adaptive mechanisms (i.e., increased unsaturation) to chronic ischemia in SIVD and elevated membrane degradation in MixD.     

The functional neuroanatomy of schizophrenic subsyndromes

BACKGROUND: There is considerable variability between patients in their expression of the diverse range of symptoms encompassed by the syndrome of schizophrenia, which may modulate functional activation to cognitive processing. METHOD: Here we investigate associations between schizophrenic subsyndrome scores, identified by factor analysis, and experimentally controlled brain activation. Five factors were defined by rotated principal components analysis of PANSS rating scale measurements in 100 patients with schizophrenia. A subsample of 30 patients and a group of 27 comparison subjects were studied using functional magnetic resonance imaging (fMRI) during the performance of two periodically designed cognitive activation experiments: verbal working memory and psychomotor sequencing. RESULTS: Factor analysis replicated the five dimensions consistently reported. Within the patient group. power of activation by working memory was negatively associated with global symptom severity in left lingual and temporo-parietal cortices; negatively associated with positive subsyndrome scores in left inferior frontal and superior temporal cortices and basal ganglia; and positively associated with negative subsyndrome scores in lateral and medial premotor cortex. No relationship was observed between subsyndrome scores and functional activation during the motor task. Between-group comparisons demonstrated reduced power of response to the working memory task by patients in bilateral dorsolateral prefrontal and left pre- and post-central cortices. CONCLUSIONS: In this study we observed task-specific modulation of functional response associated with symptom expression in schizophrenia. Our findings are compatible with previous empirical findings and theoretical conceptualization of human brain function, in terms of capacity constraints on activation in the face of competing demands from pathological and task-related cognitive activity.     

The functional human neuroanatomy of food pleasure cycles

Food ensures our survival and is a potential source of pleasure and general well-being. In order to survive, the human brain is required to optimize the resource allocation such that rewards are pursued when relevant. This means that food intake follows a similar cyclical time course to other rewards with phases related to expectation, consummation and satiety. Here we develop a multilevel model for the full cycle of eating behavior based on the evidence for the brain networks and mechanisms initiating, sustaining and terminating the various phases of eating. We concentrate on how the underlying reward mechanisms of wanting, liking and learning lead to how human food intake is governed by both hedonic and homeostatic principles. We describe five of the main processing principles controlling food intake: hunger and attentional signal processing; motivation-independent discriminative processing; reward representations; learning-dependent multimodal sensory representations and hedonic experience. Overall, the evidence shows that while human food intake is complex, we are making progress in understanding the underlying mechanisms and that the brain networks supporting the food pleasure cycle are remarkably similar to those underlying the processing of other rewards.     

The functional neuroanatomy of the human orbitofrontal cortex: evidence from neuroimaging and neuropsychology

The human orbitofrontal cortex is an important brain region for the processing of rewards and punishments, which is a prerequisite for the complex and flexible emotional and social behaviour which contributes to the evolutionary success of humans. Yet much remains to be discovered about the functions of this key brain region, and new evidence from functional neuroimaging and clinical neuropsychology is affording new insights into the different functions of the human orbitofrontal cortex. We review the neuroanatomical and neuropsychological literature on the human orbitofrontal cortex, and propose two distinct trends of neural activity based on a meta-analysis of neuroimaging studies. One is a mediolateral distinction, whereby medial orbitofrontal cortex activity is related to monitoring the reward value of many different reinforcers, whereas lateral orbitofrontal cortex activity is related to the evaluation of punishers which may lead to a change in ongoing behaviour. The second is a posterior-anterior distinction with more complex or abstract reinforcers (such as monetary gain and loss) represented more anteriorly in the orbitofrontal cortex than simpler reinforcers such as taste or pain. Finally, we propose new neuroimaging methods for obtaining further evidence on the localisation of function in the human orbitofrontal cortex.     

The functional neuroanatomy of spatial attention in autism spectrum disorder

This study investigated the functional neuroanatomical correlates of spatial attention impairments in autism spectrum disorders (ASD) using an event-related functional magnetic resonance imaging (FMRI) design. Eight ASD participants and 8 normal comparison (NC) participants were tested with a task that required stimulus discrimination following a spatial cue that preceded target presentation by 100 msec (short interstimulus interval [ISI]) or 800 msec (long ISI). The ASD group showed significant behavioral spatial attention impairment in the short ISI condition. The FMRI results showed a reduction in activity within frontal, parietal, and occipital regions in ASD relative to the NC group, most notably within the inferior parietal lobule. ASD behavioral performance improved in the long ISI condition but was still impaired relative to the NC group. ASD FMRI activity in the long ISI condition suggested that the rudimentary framework of normal attention networks were engaged in ASD including bilateral activation within the frontal, parietal, and occipital lobes. Notable activation increases were observed in the superior parietal lobule and extrastriate cortex. No reliable activation was observed in the posterior cerebellar vermis in ASD participants during either long or short ISI conditions. In addition, no frontal activation during short ISI and severely reduced frontal activation during long ISI was observed in the ASD group. Taken together, these findings suggest a dysfunctional cerebello-frontal spatial attention system in ASD. The pattern of findings suggests that ASD is associated with a profound deficit in automatic spatial attention abilities and abnormal voluntary spatial attention abilities. This article also describes a method for reducing the contribution of physical eye movements to the blood-oxygenation level dependent activity in studies of ASD.     

Sex differences in the functional and structural neuroanatomy of dental phobia

Although dental phobia is a common mental disorder, which afflicts both men and women, little is known about sex differences at the neural level. Patients suffering from dental phobia (20 men, 25 women) and healthy controls (18 men, 23 women) participated in a functional magnetic resonance imaging (fMRI) experiment. They were shown pictures depicting dental treatment, generally fear-eliciting, disgust-eliciting and neutral contents. After the fMRI experiment, the participants rated the affective value of the pictures. Additionally, grey matter volume (GMV) was compared between patients and controls, as well as between the sexes. Male and female patients responded differently to the phobogenic pictures. Women showed greater activation of the caudate nucleus, whereas men exhibited enhanced dorsolateral prefrontal cortex (DLPFC) involvement. Their DLPFC activation was negatively correlated with experienced arousal. Dentophobic females were characterized by a greater caudate volume relative to phobic males. The GMV of this structure was positively correlated with experienced arousal during exposure and symptom severity, only in female patients. This study provides first evidence of sex-specific brain activation and structure in patients suffering from dental phobia. The neural pattern during symptom provocation as well as the brain structural specificity might mirror different attention and self-control strategies of both sexes. The consideration of such differences could contribute to greater effectiveness in treating dental phobia.     

The functional neuroanatomy of working memory: contributions of human brain lesion studies

Studies of patients with focal brain lesions remain critical components of research programs attempting to understand human brain function. Whereas functional imaging typically reveals activity in distributed brain regions that are involved in a task, lesion studies can define which of these brain regions are necessary for a cognitive process. Further, lesion studies are less critical regarding the selection of baseline conditions needed in functional brain imaging research. Lesion studies suggest a functional subdivision of the visuospatial sketchpad of working memory with a ventral stream reaching from occipital to temporal cortex supporting object recognition and a dorsal stream connecting the occipital with parietal cortex enabling spatial operations. The phonological loop can be divided into a phonological short-term store in inferior parietal cortex and an articulatory subvocal rehearsal process relying on brain areas necessary for speech production, i.e. Broca's area, the supplementary motor association area and possibly the cerebellum. More uncertainty exists regarding the role of the prefrontal cortex in working memory. Whereas single cell studies in non-human primates and functional imaging studies in humans have suggested an extension of the ventral and dorsal path into different subregions of the prefrontal cortex, lesion studies together with recent single-cell and imaging studies point to a non-mnemonic role of the prefrontal cortex, including attentional control of sensory processing, integration of information from different domains, stimulus selection and monitoring of information held in memory. Our own data argue against a modulatory view of the prefrontal cortex and suggest that processes supporting working memory are distributed along ventral and dorsal lateral prefrontal cortex.     

Age-related changes in the functional neuroanatomy of overt speech production

Alterations of existing neural networks during healthy aging, resulting in behavioral deficits and changes in brain activity, have been described for cognitive, motor, and sensory functions. To investigate age-related changes in the neural circuitry underlying overt non-lexical speech production, functional MRI was performed in 14 healthy younger (21-32 years) and 14 healthy older individuals (62-84 years). The experimental task involved the acoustically cued overt production of the vowel /a/ and the polysyllabic utterance /pataka/. In younger and older individuals, overt speech production was associated with the activation of a widespread articulo-phonological network, including the primary motor cortex, the supplementary motor area, the cingulate motor areas, and the posterior superior temporal cortex, similar in the /a/ and /pataka/ condition. An analysis of variance with the factors age and condition revealed a significant main effect of age. Irrespective of the experimental condition, significantly greater activation was found in the bilateral posterior superior temporal cortex, the posterior temporal plane, and the transverse temporal gyri in younger compared to older individuals. Significantly greater activation was found in the bilateral middle temporal gyri, medial frontal gyri, middle frontal gyri, and inferior frontal gyri in older vs. younger individuals. The analysis of variance did not reveal a significant main effect of condition and no significant interaction of age and condition. These results suggest a complex reorganization of neural networks dedicated to the production of speech during healthy aging.     

阿尔茨海默病与血管性痴呆的相关性

阿尔茨海默病(AD)与血管性痴呆(VD)为两类独立的脑实质性疾病,但两者在临床工作中往往难以区分,且国际上尚未有统一标准鉴别这两种疾病。AD患者记忆力以及语言表达能力弱于VD患者,而VD患者的注意力受损程度重于AD患者。此外,AD与VD患者尚存在着血糖、血脂等血管因素,MRI以及脑电波方面的差异。本篇将着重探讨两种疾病的鉴别要点以及其在临床上的应用价值。     

The neuropsychological profile of vascular cognitive impairment--no dementia: comparisons to patients at risk for cerebrovascular disease and vascular dementia.

Hachinski and co-workers have used the term vascular cognitive impairment-no dementia (VaCIND) to represent the earliest stages of cognitive decline associated with vascular changes [Neurology 57 (4) (2001) 714]. However, the neuropsychological profile of vascular CIND remains unclear. Twenty-five healthy elders, 29 individuals at risk for cerebrovascular disease (R-CVD), 18 individuals with VaCIND, and 26 individuals with vascular dementia (VaD) were examined to determine whether patterns of neuropsychological assessment performance can assist in the differentiation of patients at varying levels of risk and severity for cerebrovascular disease and VaD. The R-CVD group performed within normal expectations on most cognitive measures as compared to the elderly control sample and published clinical norms. Relative to elderly controls, the VaCIND group demonstrated significant difficulties on measures of cognitive flexibility, verbal retrieval, and verbal recognition memory, but not on measures of confrontational naming or verbal fluency. The VaD group was impaired on all cognitive measures assessed. The current findings suggest that poor cognitive flexibility and verbal retrieval in the context of preserved function in other domains may characterize the prodromal stage of VaD.     

Toward a functional neuroanatomy of premenstrual dysphoric disorder

BACKGROUND: Premenstrual dysphoric disorder (PMDD) is a prevalent disorder in the spectrum of affective illness, and is associated with significant morbidity. The neurobiology of this underdiagnosed and undertreated illness is poorly understood. A functional magnetic resonance imaging (fMRI) probe of fronto-limbic function was used to advance understanding of PMDD pathophysiology. METHODS: We applied BOLD fMRI and Statistical Parametric Mapping to study neural response to emotional words in the context of an emotional Go/NoGo inhibitory control task. We examined alterations in this response across the menstrual cycle, in the premenstrual (late luteal) phase and the postmenstrual (late follicular) phase. RESULTS: In the premenstrual (vs. postmenstrual) phase, PMDD subjects, compared with asymptomatic subjects, showed an increased amygdala response to negative vs. neutral stimuli, and a decreased ventral striatum response to positive vs. neutral stimuli. PMDD subjects failed to show the asymptomatic subjects' patterns of increased medial and decreased lateral orbitofrontal cortex (OFC) response to negative vs. neutral stimuli in the premenstrual vs. postmenstrual phase. This decreased premenstrual medial OFC response to negative stimuli in PMDD subjects was further enhanced in the context of behavioral inhibition. LIMITATIONS: Further studies with larger numbers of subjects are needed. CONCLUSIONS: The results support a neurobiological model of enhanced negative emotional processing, diminished positive emotional processing, and diminished top-down control of limbic activity in PMDD during the premenstrual phase. These findings provide a basis for a neurocircuitry model of PMDD, and have implications for studies of mood/emotional regulation across the human menstrual cycle in health and disease.     

Mediators of cerebral hypoperfusion and blood‐brain barrier leakiness in Alzheimer’s disease,vascular dementia and mixed dementia

In vascular dementia (VaD) and Alzheimer’s disease (AD), cerebral hypoperfusion and blood‐brain barrier (BBB) leakiness contribute to brain damage. In this study, we have measured biochemical markers and mediators of cerebral hypoperfusion and BBB in the frontal (BA6) and parietal (BA7) cortex and underlying white matter, to investigate the pathophysiology of vascular dysfunction in AD, VaD and mixed dementia. The ratio of myelin‐associated glycoprotein to proteolipid protein‐1 (MAG:PLP1), a post‐mortem biochemical indicator of the adequacy of ante‐mortem cerebral perfusion; the concentration of fibrinogen adjusted for haemoglobin level, a marker of blood‐brain barrier (BBB) leakiness; the level of vascular endothelial growth factor‐A (VEGF), a marker of tissue hypoxia; and endothelin‐1 (EDN1), a potent vasoconstrictor, were measured by ELISA in the frontal and parietal cortex and underlying white matter in 94 AD, 20 VaD, 33 mixed dementia cases and 58 age‐matched controls. All cases were assessed neuropathologically for small vessel disease (SVD), cerebral amyloid angiopathy (CAA) severity, Aβ and phospho‐tau parenchymal load, and Braak tangle stage. Aβ40 and Aβ42 were measured by ELISA in guanidine‐HCl tissue extracts. We found biochemical evidence of cerebral hypoperfusion in AD, VaD and mixed dementia to be associated with SVD, Aβ level, plaque load, EDN1 level and Braak tangle stage, and to be most widespread in mixed dementia. There was evidence of BBB leakiness in AD—limited to the cerebral cortex and related to EDN1 level. In conclusion, abnormalities of cerebral perfusion and BBB function in common types of dementia can largely be explained by a combination of arteriolosclerosis, and Aβ‐, tau‐ and endothelin‐related vascular dysfunction. The relative contributions of these processes vary considerably both between and within the diseases.     

Adult age differences in the functional neuroanatomy of visual attention: a combined fMRI and DTI study

We combined measures from event-related functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), and cognitive performance (visual search response time) to test the hypotheses that differences between younger and older adults in top-down (goal-directed) attention would be related to cortical activation, and that white matter integrity as measured by DTI (fractional anisotropy, FA) would be a mediator of this age-related effect. Activation in frontal and parietal cortical regions was overall greater for older adults than for younger adults. The relation between activation and search performance supported the hypothesis of age differences in top-down attention. When the task involved top-down control (increased target predictability), performance was associated with frontoparietal activation for older adults, but with occipital (fusiform) activation for younger adults. White matter integrity (FA) exhibited an age-related decline that was more pronounced for anterior brain regions than for posterior regions, but white matter integrity did not specifically mediate the age-related increase in activation of the frontoparietal attentional network.     

The apolipoprotein E gene in Binswanger's disease and vascular dementia

We investigated the polymorphism of the apolipoprotein E (ApoE) gene using a PCR-RFLP method in patients with Binswanger's disease (BD), non-BD vascular dementia, or Alzheimer's disease (AD). The frequency of the e4 allele of the ApoE (ApoE4) in BD patients and non-BD vascular dementia patients did not differ from that observed in the non-demented elderly controls, but it was significantly lower than the frequency in AD patients. These results and other recent observations suggest that one or more factors other than the ApoE gene contribute to the pathogenesis of dementia in BD and non-BD vascular dementia.     

Object working memory and visuospatial processing: functional neuroanatomy analyzed by event-related fMRI

We report an event-related functional magnetic-resonance-imaging (fMRI) experiment that investigates the relationship of transient visual object memory, visuospatial orienting, and object recognition. Delayed object matching and visuospatial orienting involved a highly overlapping network of brain areas. Common areas were the frontal eye fields (FEF), the pre-supplementary motor area (pre-SMA)/SMA complex, the precentral gyri, and the horizontal and descending branches of the intraparietal sulcus (IPS). Selective delay activation was observed anterior to the FEF and in the ascending part of the IPS. Right dorsolateral prefrontal cortex was involved in goal-directed visual search, but showed no delay activity.     

The neuroanatomy of depression: A review

Depression is the most common psychiatric disorder, the number one cause of disability and affects up to 15% of the population. The aim of this review is to present a brief synopsis of the various biochemical imbalances thought to contribute to depression, aspects of anatomy possibly implicated in depression, and treatments related to targeting these specific locales. Multiple neurotransmitters and parts of the brain are involved with the disorder of depression. Although an exact etiology for depression has not been found in most cases, various treatments, medicinal, psychiatric and surgical, exist for this disabling disease. An improved knowledge of anatomical sites involved in patients with depression will help in future treatment modalities. Clin. Anat. 30:44–49, 2017. © 2016 Wiley Periodicals, Inc.     

Hypertension and vascular dementia.

Postmortem surveys on patients treated for chronic hypertension often fail to demonstrate significant vessel changes. Nevertheless, hypertensive alterations in the brain can include infarcts and hemorrhages. Autopsies in a primary care hospital have shown that hypertension can affect arteries, arterioles, and capillaries in various patterns and degrees in the brain. These vascular lesions may be associated with large and small infarcts and hemorrhages in isolated or diffuse patterns. Widespread cerebral edema can occur with rapidly progressive hypertension. Atherosclerosis, arterial and arteriolar fibrinoid necrosis, and micro-aneurysms may be observed. Chronic hypertensive encephalopathy causes vascular dementia and can be associated with subcortical arterial and arteriolar leukoencephalopathy, leukoaraiosis and/or Binswanger's disease. Epidemiologic evaluations based on complete autopsy studies need to be correlated with compliance of therapy, appropriate diagnosis of hypertension, and its long-term effects on the nervous system. Although persistent poorly controlled hypertension is known to damage the brain both acutely and chronically, the effects of intermittent hypertension remain to be defined.     

The functional neuroanatomy of classic delayed response tasks in humans and the limitations of cross-method convergence in prefrontal function

Three classic delay tasks: spatial delayed response, delayed spatial alternation and delayed object-alternation are prototypical experimental paradigms for mapping the functional neuroanatomy of prefrontal cortex in animals. These tasks have been applied in human lesion studies, yet there have been very few studies investigating their functional neuroanatomy in healthy human subjects. We used functional magnetic resonance imaging to investigate the functional neuroanatomy of these classic paradigms (and a fourth: object delayed response) in a single sample of healthy human participants. Consistent with previous animal, human lesion, and functional neuroimaging studies, activity was observed in prefrontal and posterior parietal cortices across all three delay tasks. Task-specific activations, however, were not entirely consistent with predictions drawn from animal lesion studies. For example, delayed object-alternation activated dorsolateral prefrontal cortex, a region not generally implicated in animal lesion reports. Spatial delayed response, classically associated with the dorsolateral prefrontal cortex, did not activate this region; it rather activated posterior premotor cortices involved in response preparation, as did spatial alternation. All three tasks activated the frontopolar cortex, a region not considered crucial in animal research but associated with manipulation of internally generated information in recent human research. While cross-method convergence may be attained for lower level perceptual or motor tasks, the results of this study caution against the assumption that lesion-specific effects in animals generalize to human prefrontal cortex function.