Human anterior cingulate function has been explained primarily within a cognitive framework. We used functional MRI experiments with simultaneous electrocardiography to examine regional brain activity associated with autonomic cardiovascular control during performance of cognitive and motor tasks. Using indices of heart rate variability, and high- and low-frequency power in the cardiac rhythm, we observed activity in the dorsal anterior cingulate cortex (ACC) related to sympathetic modulation of heart rate that was dissociable from cognitive and motor-related activity. The findings predict that during effortful cognitive and motor behaviour the dorsal ACC supports the generation of associated autonomic states of cardiovascular arousal. We subsequently tested this prediction by studying three patients with focal damage involving the ACC while they performed effortful cognitive and motor tests. Each showed abnormalities in autonomic cardiovascular responses with blunted autonomic arousal to mental stress when compared with 147 normal subjects tested in identical fashion. Thus, converging neuroimaging and clinical findings suggest that ACC function mediates context-driven modulation of bodily arousal states.

ABSTRACT:The hippocampus plays a crucial role within the neural systems for long-term memory, but little if any role in the short-term retention of some types of stimuli. Nonetheless, the hippocampus may be specialized for allocentric topographical processing, which impacts on short-term memory or even perception. To investigate this we developed performance-matched tests of perception (match-to-sample) and shortterm memory (2 s delayed-match-to-sample) for the topography and for the nonspatial aspects of visual scenes. Four patients with focal hippocampal damage and one with more extensive damage, including right parahippocampal gyrus, were tested. All five patients showed impaired topographical memory and spared nonspatial processing in both memory and perception. Topographical perception was profoundly impaired in the patient with parahippocampal damage, mildly impaired in two of the hippocampal cases, and clearly preserved in the other two hippocampal cases (including one with dense amnesia). Our results suggest that the hippocampus supports allocentric topographical processing that is indispensable when appropriately tested after even very short delays, while the presence of the sample scene can allow successful topographical perception without it, possibly via a less flexible parahippocampal representation. V V C 2006 Wiley-Liss, Inc.

Volumetric magnetic resonance imaging analyses of 30 subjects were undertaken to quantify the global and temporal lobe atrophy in semantic dementia and Alzheimer's disease. Three groups of 10 subjects were studied: semantic dementia patients, Alzheimer's disease patients, and control subjects. The temporal lobe structures measured were the amygdala, hippocampus, entorhinal cortex, parahippocampal gyrus, fusiform gyrus, and superior, middle, and inferior temporal gyri. Semantic dementia and Alzheimer's disease groups did not differ significantly on global atrophy measures. In semantic dementia, there was asymmetrical temporal lobe atrophy, with greater left-sided damage. There was an anteroposterior gradient in the distribution of temporal lobe atrophy, with more marked atrophy anteriorly. All left anterior temporal lobe structures were affected in semantic dementia, with the entorhinal cortex, amygdala, middle and inferior temporal gyri, and fusiform gyrus the most severely damaged. Asymmetrical, predominantly anterior hippocampal atrophy was also present. In Alzheimer's disease, there was symmetrical atrophy of the entorhinal cortex, hippocampus, and amygdala, with no evidence of an anteroposterior gradient in the distribution of temporal lobe or hippocampal atrophy. These data demonstrate that there is a marked difference in the distribution of temporal lobe atrophy in semantic dementia and Alzheimer's disease. In addition, the pattern of atrophy in semantic dementia suggests that semantic memory is subserved by anterior temporal lobe structures, within which the middle and inferior temporal gyri may play a key role.

Gradient echo T2*-weighted MRI has high sensitivity in detecting cerebral microbleeds, which appear as small dot-like hypointense lesions. Microbleeds are strongly associated with intracerebral haemorrhage, hypertension, lacunar stroke and ischaemic small vessel disease, and have generated interest as a marker of bleeding-prone microangiopathy. Microbleeds have generally been considered to be clinically silent; however, since they are located in widespread cortical and basal ganglia regions and are histologically characterized by tissue damage, we hypothesized that they would cause cognitive dysfunction. We therefore studied patients with microbleeds (n = 25) and a non-microbleed control group (n = 30) matched for age, gender and intelligence quotient. To avoid the confounding effects of coexisting cerebrovascular disease, the groups were also matched for the extent of MRI-visible white matter changes of presumed ischaemic origin, location of cortical strokes, and for the proportion of patients with different stroke subtypes (including lacunar stroke). A battery of neuropsychological tests was used to assess current intellectual function, verbal and visual memory, naming and perceptual skills, speed and attention and executive function. Microbleeds were most common in the basal ganglia but were also found in frontal, parieto-occipital, temporal and infratentorial regions. There was a striking difference between the groups in the prevalence of executive dysfunction, which was present in 60% of microbleed patients compared with 30% of non-microbleed patients (P = 0.03). Logistic regression confirmed that microbleeds (but not white matter changes) were an independent predictor of executive impairment (adjusted odds ratio = 1.32, 95% confidence interval 1.01-1.70, P = 0.04). Patients with executive dysfunction had more microbleeds in the frontal region (mean count 1.54 versus 0.03; P = 0.002) and in the basal ganglia (mean 1.17 versus 0.32; P = 0.048). There was a modest correlation between the number of microbleeds and the number of cognitive domains impaired (r = 0.44, P = 0.03). This study provides novel evidence that microbleeds are associated with cognitive dysfunction, independent of the extent of white matter changes of presumed ischaemic origin, or the presence of ischaemic stroke. The striking effect of microbleeds on executive dysfunction is likely to result from associated tissue damage in the frontal lobes and basal ganglia. These findings have implications for the diagnosis of stroke patients with cognitive impairment, and for the appropriate use of antihypertensive and antiplatelet treatments in these patients.

Fluency tasks have been widely used to tap the voluntary generation of responses. The anatomical correlates of fluency tasks and their sensitivity and specificity have been hotly debated. However, investigation of the cognitive processes involved in voluntary generation of responses and whether generation is supported by a common, general process (e.g. fluid intelligence) or specific cognitive processes underpinned by particular frontal regions has rarely been addressed. This study investigates a range of verbal and non-verbal fluency tasks in patients with unselected focal frontal (n=47) and posterior (n=20) lesions. Patients and controls (n=35) matched for education, age and sex were administered fluency tasks including word (phonemic/semantic), design, gesture and ideational fluency as well as background cognitive tests. Lesions were analysed by standard anterior/posterior and left/right frontal subdivisions as well as a finer-grained frontal localization method. Thus, patients with right and left lateral lesions were compared to patients with superior medial lesions. The results show that all eight fluency tasks are sensitive to frontal lobe damage although only the phonemic word and design fluency tasks were specific to the frontal region. Superior medial patients were the only group to be impaired on all eight fluency tasks, relative to controls, consistent with an energization deficit. The most marked fluency deficits for lateral patients were along material specific lines (i.e. left-phonemic and right-design). Phonemic word fluency that requires greater selection was most severely impaired following left inferior frontal damage. Overall, our results support the notion that frontal functions comprise a set of specialized cognitive processes, supported by distinct frontal regions.