Context-dependent, neural system-specific neurophysiological concomitants of ageing: mapping PET correlates during cognitive activation.
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We used PET to explore the neurophysiological changes that accompany cognitive disability in ageing, with a focus on the frontal lobe. Absolute regional cerebral blood flow (rCBF) was measured in 41 healthy volunteers, evenly distributed across an age range of 18-80 years, during two task paradigms: (i) the Wisconsin Card Sorting Test (WCST), which depends heavily on working memory and is particularly sensitive to dysfunction of the dorsolateral prefrontal cortex (DLPFC); and (ii) Raven's Progressive Matrices (RPM), which may also have a working memory component, but depends more on visuo-spatial processing and is most sensitive to dysfunction of postrolandic regions. We used voxel-wise correlational mapping to determine age-related changes in WCST and RPM activation and developed a method to quantitate and localize statistical differences between the correlation maps for the two task paradigms. Because both WCST and RPM performance declined with age, as expected, correlational analyses were performed with and without partialling out the effect of task performance. Task-specific reductions of rCBF activation with age were found in the DLPFC during the WCST and in portions of the inferolateral temporal cortex involved in visuo-spatial processing during the RPM. We also found reduced ability to suppress rCBF in the right hippocampal region during the WCST and in mesial and polar portions of the prefrontal cortex during both task conditions. Task-dependent alterations with age in the relationship between the DLPFC and the hippocampus were also documented; because the collective pattern of changes in the hippocampal-DLPFC relationship with ageing was opposite to that seen in a previous study using dextroamphetamine, we postulated a dopaminergic mechanism. These results indicate that, despite some cognitive overlap between the two tasks and the age-related cognitive decline in both, many of the changes in rCBF activation with age were task-specific, reflecting functional alteration of the different neural circuits normally engaged by young subjects during the WCST and RPM. Reduced activation of areas critical for task performance (i.e. the DLPFC during the WCST and posterior visual association areas of the inferolateral temporal cortex during the RPM), in conjunction with the inability to suppress areas normally not involved in task performance (i.e. the left hippocampal region during the WCST and mesial polar prefrontal cortex during both the WCST and RPM), suggest that, overall, reduced ability to focus neural activity may be impaired in older subjects. The context dependency of the age-related changes is most consistent with systems failure and disordered connectivity. (+info)
Common inhibitory mechanism in human inferior prefrontal cortex revealed by event-related functional MRI.
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Inhibition of an ongoing reaction tendency for adaptation to changing environments is a major function of the human prefrontal cortex. This function has been investigated frequently using the go/no-go task and set-shifting tasks such as the Wisconsin Card Sorting Test (WCST). Studies in humans and monkeys suggest the involvement of the dorsolateral prefrontal cortex in the two task paradigms. However, it remains unknown where in the dorsolateral prefrontal cortex this function is localized, whether a common inhibitory mechanism is used in these task paradigms and how this inhibitory function acts on two different targets, i.e. the go response in the go/no-go task and the cognitive set in the WCST. In the go/no-go task of this study, subjects were instructed to either respond (go trial) or not respond (no-go trial), depending on the cue stimulus presented. The signals of functional MRI (fMRI) related to the inhibitory function should be transient by nature. Thus, we used the temporal resolution of fMRI (event-related fMRI) by which transient signals in go and no-go trials can be analysed separately and compared with each other. We found a focus that showed transient no-go dominant activity in the posterior part of the inferior frontal sulcus in the right hemisphere. This was true irrespective of whether the subjects used their right or left hands. These results suggest that the transient activation in the right inferior prefrontal area is related to the neural mechanism underlying the response inhibition function. Furthermore, this area was found to be overlapped spatially with the area that was activated transiently during cognitive set shifting in the WCST. The transient signals in the go/no-go task peaked 5 s after the transient expression of the inhibitory function, and the transient signals in the WCST peaked 7s after the transient expression, reflecting different durations of neuronal activity in the two inhibitory task paradigms. These results imply that the right inferior prefrontal area is commonly involved in the inhibition of different targets, i.e. the go response during performance of the go/no-go task and the cognitive set during performance of the WCST. (+info)
From perception to action: temporal integrative functions of prefrontal and parietal neurons.
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The dorsolateral prefrontal cortex (DPFC) and the posterior parietal cortex (PPC) are anatomically and functionally interconnected, and have been implicated in working memory and the preparation for behavioral action. To substantiate those functions at the neuronal level, we designed a visuomotor task that dissociated the perceptual and executive aspects of the perception-action cycle in both space and time. In that task, the trial-initiating cue (a color) indicated with different degrees of certainty the direction of the correct manual response 12 s later. We recorded extracellular activity from 258 prefrontal and 223 parietal units in two monkeys performing the task. In the DPFC, some units (memory cells) were attuned to the color of the cue, independent of the response-direction it connoted. Their discharge tended to diminish in the course of the delay between cue and response. In contrast, few color-related units were found in PPC, and these did not show decreasing patterns of delay activity. Other units in both cortices (set cells) were attuned to response-direction and tended to accelerate their firing in anticipation of the response and in proportion to the predictability of its direction. A third group of units was related to the determinacy of the act; their firing was attuned to the certainty with which the animal could predict the correct response, whatever its direction. Cells of the three types were found closely intermingled histologically. These findings further support and define the role of DPFC in executive functions and in the temporal closure of the perception-action cycle. The findings also agree with the involvement of PPC in spatial aspects of visuomotor behavior, and add a temporal integrative dimension to that involvement. Together, the results provide physiological evidence for the role of a prefrontal-parietal network in the integration of perception with action across time. (+info)
Association of storage and processing functions in the dorsolateral prefrontal cortex of the nonhuman primate.
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The prominent role of the prefrontal cortex (PFC) in working memory (WM) is widely acknowledged both in nonhuman primates and in humans. However, less agreement exists on the issue of functional segregation within different subregions of the PFC with regard to the domains of spatial and nonspatial processing or involvement in simpler versus more complex aspects of WM, e.g., maintenance versus processing function. To address these issues, six monkeys were trained to perform four WM tasks that differed with respect to domain (spatial vs nonspatial) and level of WM demand (recall of one vs three items). The delayed response format was used to assess simple one-item memory, whereas self-ordering tasks were used to require the monkey to maintain and organize three items of information within WM. After training, the monkeys received bilateral PFC lesions in one of two different areas, Walker's areas 9 and 8B (dorsomedial convexity; n = 3) or areas 46 and 8A (dorsolateral cortex, n = 3) and then tested postoperatively on all tasks. Monkeys with lesions of the dorsomedial convexity were not impaired either on spatial or nonspatial WM tasks, whether the task required simple storage or sequential processing. By contrast, lesions of the dorsolateral cortex produced a significant and persistent impairment in both simple and complex spatial WM but no impairment in the two nonspatial WM tasks. These results support a functional segregation within the dorsolateral prefrontal cortex for WM: the dorsolateral prefrontal cortex (area 46/8A) is selectively involved in spatial WM, whereas the dorsomedial convexity (area 9/8B) is not critically engaged in either spatial or nonspatial working memory. Furthermore, the specific involvement of area 46/8A in spatial sequencing as well as in single-item storage WM tasks supports, in the nonhuman primate, an areal dissociation based on domain rather than on processing demand. (+info)
Role of the medial prefrontal cortex in 5-HT1A receptor-induced inhibition of 5-HT neuronal activity in the rat.
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1. We examined the involvement of the frontal cortex in the 5-HT2A receptor-induced inhibition of 5-HT neurones in the dorsal raphe nucleus (DRN) of the anaesthetized rat using single-unit recordings complemented by Fos-immunocytochemistry. 2. Both transection of the frontal cortex as well as ablation of the medial region of the prefrontal cortex (mPFC) significantly attenuated the inhibition of 5-HT neurones induced by systemic administration of the 5-HT1A receptor agonist, 8-OH-DPAT (0.5-16 microg kg(-1), i.v.). In comparison, the response to 8-OH-DPAT was not altered by ablation of the parietal cortex. The inhibitory effect of 8-OH-DPAT was reversed by the 5-HT1A receptor antagonist, WAY 100635 (0.1 mg kg(-1), i.v.) in all neurones tested. 3. In contrast, cortical transection did not alter the sensitivity of 5-HT neurones to iontophoretic application of 8-OH-DPAT into the DRN. Similarly, cortical transection did not alter the sensitivity of 5-HT neurones to systemic administration of the selective 5-HT reuptake inhibitor, paroxetine (0.1-0.8 mg kg(-1) , i.v.). 4. 8-OH-DPAT evoked excitation of mPFC neurones at doses (0.5-32 microg kg(-1), i.v.) in the range of those which inhibited 5-HT cell firing. At higher doses (32-512 microg kg(-1), i.v.) 8-OH-DPAT inhibited mPFC neurones. 8-OH-DPAT (0.1 mg kg(-1), s.c.) also induced Fos expression in the mPFC. The neuronal excitation and inhibition, as well as the Fos expression, were antagonized by WAY 100635. 5. These data add further support to the view that the inhibitory effect of 5-HT1A receptor agonists on the firing activity of DRN 5-HT neurones involves, in part, activation of a 5-HT1A receptor-mediated postsynaptic feedback loop centred on the mPFC. (+info)
Different contributions of the human amygdala and ventromedial prefrontal cortex to decision-making.
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The somatic marker hypothesis proposes that decision-making is a process that depends on emotion. Studies have shown that damage of the ventromedial prefrontal (VMF) cortex precludes the ability to use somatic (emotional) signals that are necessary for guiding decisions in the advantageous direction. However, given the role of the amygdala in emotional processing, we asked whether amygdala damage also would interfere with decision-making. Furthermore, we asked whether there might be a difference between the roles that the amygdala and VMF cortex play in decision-making. To address these two questions, we studied a group of patients with bilateral amygdala, but not VMF, damage and a group of patients with bilateral VMF, but not amygdala, damage. We used the "gambling task" to measure decision-making performance and electrodermal activity (skin conductance responses, SCR) as an index of somatic state activation. All patients, those with amygdala damage as well as those with VMF damage, were (1) impaired on the gambling task and (2) unable to develop anticipatory SCRs while they pondered risky choices. However, VMF patients were able to generate SCRs when they received a reward or a punishment (play money), whereas amygdala patients failed to do so. In a Pavlovian conditioning experiment the VMF patients acquired a conditioned SCR to visual stimuli paired with an aversive loud sound, whereas amygdala patients failed to do so. The results suggest that amygdala damage is associated with impairment in decision-making and that the roles played by the amygdala and VMF in decision-making are different. (+info)
Prospective coding for objects in primate prefrontal cortex.
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We examined neural activity in prefrontal (PF) cortex of monkeys performing a delayed paired associate task. Monkeys were cued with a sample object. Then, after a delay, a test object was presented. If the test object was the object associated with the sample during training (i.e., its target), they had to release a lever. Monkeys could bridge the delay by remembering the sample (a sensory-related code) and/or thinking ahead to the expected target (a prospective code). Examination of the monkeys' behavior suggested that they were relying on a prospective code. During and shortly after sample presentation, neural activity in the lateral PF cortex primarily reflected the sample. Toward the end of the delay, however, PF activity began to reflect the anticipated target, which indicated a prospective code. These results provide further confirmation that PF cortex does not simply buffer incoming visual inputs, but instead selectively processes information relevant to current behavioral demands, even when this information must be recalled from long-term memory. (+info)
Sensitization to the effects of tumor necrosis factor-alpha: neuroendocrine, central monoamine, and behavioral variations.
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Consistent with the proposition that cytokines act as immunotransmitters between the immune system and the brain, systemic administration of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha; 1.0-4.0 microg) induced mild illness in CD-1 mice, increased plasma corticosterone concentrations, and altered central norepinephrine, dopamine, and serotonin turnover. The actions of TNF-alpha were subject to a time-dependent sensitization effect. After reexposure to a subeffective dose of the cytokine (1.0 microgram) 14-28 d after initial treatment, marked illness was evident (reduced consumption of a palatable substance and diminished activity and social exploration), coupled with an elevation of plasma corticosterone levels. In contrast, cytokine reexposure 1-7 d after initial treatment did not elicit illness, and at the 1 d interval the corticosterone response to the cytokine was reduced. The increase of norepinephrine release within the paraventricular nucleus of the hypothalamus, as reflected by elevated accumulation of 3-methoxy-4-hydroxyphenylglycol, was augmented at the longer reexposure intervals. In contrast, within the central amygdala and the prefrontal cortex TNF-alpha reexposure at the 1 d interval was associated with a pronounced sensitization-like effect, which was not apparent at longer intervals. Evidently, systemic TNF-alpha proactively influences the response to subsequent treatment; however, the nature of the effects (i.e., the behavioral, neuroendocrine, and central transmitter alterations) vary over time after initial cytokine treatment. It is suggested that the sensitization may have important repercussions with respect to cognitive effects of TNF-alpha and may also be relevant to analyses of the neuroprotective or neurodestructive actions of cytokines. (+info)