Age effects on the neural correlates of episodic retrieval: increased cortical recruitment with matched performance

Functional neuroimaging investigations have revealed a range of age-related differences in the neural correlates of episodic memory retrieval. Typically, whereas activity is reduced in older compared with younger adults in some regions, other regions are engaged exclusively, or to a greater extent, in older adults. It is unclear whether such differences merely represent the neural correlates of the lower levels of memory performance and impaired recollection typical of older adults. This issue was addressed in the present event-related functional magnetic resonance imaging study. The level of recollection was matched between groups of healthy younger and older adults for a subset of picture items in a source memory task by manipulating the number of study presentations. Contrasts of the activity elicited by old items attracting correct source judgments and correctly identified new items revealed that the 2 groups recruited many of the same brain regions. However, a striking pattern of age-related differences was also observed. In older adults, retrieval-related increases in activity were more widespread and of greater magnitude than in the young. Moreover, regions demonstrating retrieval-related decreases in activity were almost absent in the older participants. These findings suggest an age-related decline in the efficiency with which neural populations support cognitive function.     

Diffusion tensor imaging reveals white matter reorganization in early blind humans

Multiple functional methods including functional magnetic resonance imaging, transcranial magnetic stimulation, and positron emission tomography have shown cortical reorganization in response to blindness. We investigated microanatomical correlates of this reorganization using diffusion tensor imaging and diffusion tensor tractography (DTT). Five early blind (EB) were compared with 7 normally sighted (NS) persons. DTT showed marked geniculocalcarine tract differences between EB and NS participants. All EB participants showed evidence of atrophy of the geniculocortical tracts. Connections between visual cortex and the orbital frontal and temporal cortices were relatively preserved in the EB group. Importantly, no additional tracts were found in any EB participant. Significant alterations of average diffusivity and relative anisotropy were found in the white matter (WM) of the occipital lobe in the EB group. These observations suggest that blindness leads to a reorganization of cerebral WM and plausibly support the hypothesis that visual cortex functionality in blindness is primarily mediated by corticocortical as opposed to thalamocortical connections.     

A direct comparison of anterior prefrontal cortex involvement in episodic retrieval and integration

Retrieval of information from episodic memory reliably engages regions within the anterior prefrontal cortex (aPFC). This observation has led researchers to suggest that these regions may subserve processes intimately tied to episodic retrieval. However, the aPFC is also recruited by other complex tasks not requiring episodic retrieval. One hypothesis concerning these results is that episodic retrieval recruits a general cognitive process that is subserved by the aPFC. The current study tested a specific version of this hypothesis--namely, that the integration of internally represented information is this process. Event-related fMRI was employed in a 2 (memory task: encoding versus retrieval) x 2 (level of integration: low versus high) factorial within-subjects design. A functional dissociation was observed, with one aPFC subregion uniquely sensitive to level of integration and another jointly sensitive to level of integration and memory task. Analysis of event-related activation latencies indicated that level of integration and memory task effects occurred with significantly different timing. The results provide the first direct evidence regarding the functional specialization within lateral aPFC and the nature of its recruitment during complex cognitive tasks. Moreover, the study highlights the benefits of activation latency analysis for understanding functional contributions and dissociations between closely linked brain regions.     

Hippocampal activation for autobiographical memories over the entire lifetime in healthy aged subjects: an fMRI study

We used functional magnetic resonance imaging to determine the cerebral structures required during the recollection of episodic autobiographical memories according to 5 time periods covering the whole lifespan to test the 2 concurring models of memory consolidation, which propose either a temporary (standard model) or a permanent (multiple-trace model) role of the hippocampus in episodic memory retrieval. The experimental paradigm was specially designed to engage subjects (67.17 +/- 5.22 years old) in the retrieval of episodic autobiographical memories, whatever the time period, from personally relevant cues selected by questioning a family member. Moreover, the nature of the memories was checked at debriefing by means of behavioral measures to control the degree of episodicity. Behavioral data showed that recollected memories were characterized by specificity and details whatever their remoteness. Main neuroimaging data (Statistical Parametric Mapping 99) revealed the activation of a network including the left superior frontal gyri, bilateral precuneus/posterior cingulate and lingual gyri, left angular gyrus, and left hippocampus, although the subtraction analyses detected subtle differences between certain time periods. Small volume correction centered on the hippocampus detected left hippocampal activation for all time periods and additional right hippocampal activation for the intermediate periods. Further confirmation was provided by using a 3-way analysis of variance on blood oxygen level-dependent values, which revealed hippocampal activation whatever the time interval. The present data challenge the standard model of memory consolidation and support the multiple-trace model, instead. The comparison with previous literature stresses the idea that a bilateral involvement of the hippocampus characterizes rich episodic autobiographical memory recollection.     

Functional cerebral reorganization for auditory spatial processing and auditory substitution of vision in early blind subjects

Early blind (EB) individuals can recognize bidimensional shapes using a prosthesis substituting vision with audition (PSVA) and activate right dorsal extrastriate visual cortex during the execution of this task. The present study used repetitive transcranial magnetic stimulation (rTMS) to further examine the functional role of this structure in the successful use of the PSVA. Moreover, we investigated which auditory parameter used in the prosthesis (pitch, intensity, or spatial location) might contribute to this occipital activation. Results revealed that rTMS applied to right dorsal extrastriate cortex in EB subjects interferes with both the PSVA use and the auditory spatial location task but not with pitch and intensity discriminations. By contrast, rTMS targeting the same cortical areas in sighted subjects did not affect performance on any auditory tasks. Early visual deprivation thus leads to functional cerebral cross-modal reorganization in the processing of auditory information and auditory-to-visual sensory substitution. The findings also point to the specific involvement of the dorsal visual stream for auditory spatial processing in blind subjects. Moreover, this suggests that sensory substitution prostheses can be developed using these additional neural resources to perform tasks that partially compensate for the loss of vision.     

Human functional neuroimaging of brain changes associated with practice

The discovery that experience-driven changes in the human brain can occur from a neural to a cortical level throughout the lifespan has stimulated a proliferation of research into how neural function changes in response to experience, enabled by neuroimaging methods such as positron emission tomography and functional magnetic resonance imaging. Studies attempt to characterize these changes by examining how practice on a task affects the functional anatomy underlying performance. Results are incongruous, including patterns of increases, decreases and functional reorganization of regional activations. Following an extensive review of the practice-effects literature, we distinguish a number of factors affecting the pattern of practice effects observed, including the effects of task domain, changes at the level of behavioural and cognitive processes, the time-window of imaging and practice, and of a number of other influences and miscellaneous confounding factors. We make a novel distinction between patterns of reorganization and redistribution as effects of task practice on brain activation, and emphasize the need for careful attention to practice-related changes occurring on the behavioural, cognitive and neural levels of analysis. Finally, we suggest that functional and effective connectivity analyses may make important contributions to our understanding of changes in functional anatomy occurring as a result of practice on tasks.     

Increased neural efficiency with repeated performance of a working memory task is information-type dependent

Unlike tasks in which practice leads to an automatic stimulus-response association, it is thought working memory (WM) tasks continue to require cognitive control processes after repeated performance. Previous studies investigating WM task repetition are in accord with this. However, it is unclear whether changes in neural activity after repetition imply alterations in general control processes common to all WM tasks or are specific to the selection, encoding and maintenance of the relevant information. In the present study, functional magnetic resonance imaging (fMRI) was used to examine changes during sample, delay and test periods during repetition of both object and spatial delayed recognition tasks. We found decreases in fMRI activation in both spatial and object-selective areas after spatial WM task repetition, independent of behavioral performance. Few areas showed changed activity after object WM task repetition. These results indicate that spatial task repetition leads to increased efficiency of maintaining task-relevant information and improved ability to filter out task-irrelevant information. The specificity of this repetition effect to the spatial task suggests a difference exists in the nature of the representation of object and spatial information and that their maintenance in WM is likely subserved by different neural systems.     

Degradation of signal timing in cortical areas V1 and V2 of senescent monkeys

Senescence in monkeys results in a degradation of the functional properties of cortical cells as well as prolonged hyperactivity. We have now compared the spontaneous and visually evoked activity levels, as well as the visual response latencies of cells in cortical areas V1 and V2 of young and very old monkeys. We found that V1 cells within layer 4 exhibit normal latencies. In contrast, in other parts of V1 and throughout V2 hyperactivity in old monkeys is accompanied by dramatic delays in both the intracortical and intercortical transfer of information. Extrastriate cortex (area V2) is affected more severely than striate cortex (V1). Delayed information processing in cerebral cortex should contribute to the declines in cortical function that accompany old age.     

Mental visual synthesis is originated in the fronto-temporal network of the left hemisphere

Mental visual synthesis is the capacity for experiencing, constructing, or manipulating 'mental imagery'. To investigate brain networks involved in mental visual synthesis, brain activity was measured in right-handed healthy volunteers during mental imagery tasks, in which the subjects were instructed to imagine a novel object, that does not exist in the real world, by composing it from two visually presented words associated with a real object or two achromatic line drawings of a real object, using functional magnetic resonance imaging (fMRI). Both tasks activated the same areas in the inferior frontal and inferior temporal cortices of the left hemisphere. Our results indicate that the source of mental visual synthesis may be formed by activity of a brain network consisting of these areas, which are also involved in semantic operations and visual imagery.     

Enhanced temporal non-linearities in human object-related occipito-temporal cortex

To what extent does neural activation in human visual cortex follow the temporal dynamics of the optical retinal stimulus? Specifically, to what extent does stimulus evoked neural activation persist after stimulus termination? In the present study, we used functional magnetic resonance imaging (fMRI) to explore the resulting temporal non-linearities across the entire constellation of human visual areas. Gray-scale images of animals, houses and faces were presented at two different presentation rates - 1 and 4 Hz - and the fMRI signal was analyzed in retinotopic and in high order occipito-temporal visual areas. In early visual areas and the motion sensitive area MT/V5, a fourfold increase in stimulus presentation rate evoked a twofold increase in signal amplitude. However, in high order visual areas, signal amplitude increased only by 25%. A control experiment ruled out the possibility that this difference was due to signal saturation ('ceiling') effects. A likely explanation for the stronger non-linearities in occipito-temporal cortex is a persistent neuronal activation that continues well after stimulus termination in the 1 Hz condition. These persistent activations might serve as a short term (iconic) memory mechanism for preserving a trace of the stimulus even in its absence and for future integration with temporally correlated stimuli. Two alternative models of persistence (inhibitory and excitatory) are proposed to explain the data.     

Neurons in V1 patch columns project to V2 thin stripes

In the primate, connections between primary visual cortex (V1) and the second visual area (V2) are segregated according to the characteristic pattern of cytochrome oxidase (CO) activity in each of these cortical areas. Patches supply thin stripes, whereas interpatches supply pale stripes and thick stripes. Previously, the projection from patches to thin stripes was reported to arise exclusively from layer 2/3. In this present report, we made injections of a retrograde tracer, cholera toxin-B (CTB-Au), into macaque V2 thin stripes to re-examine the laminar origin of their input from V1. While the great majority of cells indeed resided in layer 2/3, small populations were also present in layers 4A, 4B, and 5/6. The location of CTB-filled cells in each layer was analyzed to determine the relationship with CO patches. Cells in layers 2/3, 4A, and 4B were aggregated into patches, forming columns that project to thin stripes. Surprisingly, cells in layer 5/6 were scattered, seemingly at random. These findings confirm that the main V1 projection to V2 stripes emanates from patches in layer 2/3. However, multiple V1 layers innervate V2 thin stripes, and the projection from layer 5/6 does not respect the patch/interpatch dichotomy.     

Functional specializations in lateral prefrontal cortex associated with the integration and segregation of information in working memory

Control processes are thought to play an important role in working memory (WM), by enabling the coordination, transformation, and integration of stored information. Yet little is known about the neural mechanisms that subserve such control processes. This study examined whether integration operations within WM involve the activation of distinct neural mechanisms within lateral prefrontal cortex (PFC). Event-related functional magnetic resonance imaging was used to monitor brain activity while participants performed a mental arithmetic task. In the integration (IN) condition, a WM preload item had to be mentally inserted into the last step of the math problem. This contrasted with the segregation (SG) condition, which also required maintenance of the WM preload while performing mental arithmetic but had no integration requirement. Two additional control conditions involved either ignoring the preload (math only condition) or ignoring the math problem (recall only condition). Left anterior PFC (Brodmann's Area [BA] 46/10) was selectively engaged by integration demands, with activation increasing prior to, as well as during the integration period. A homologous right anterior PFC region showed selectively increased activity in the SG condition during the period in which the math problem and preload digit were reported. Left middorsolateral PFC regions (BA 9/46) showed increased, but equivalent, activity in both the SG and IN conditions relative to both control conditions. These results provide support for the selective role of lateral PFC in cognitive control over WM and suggest more specific hypotheses regarding dissociable PFC mechanisms involved during the integration and segregation of stored WM items.     

Prefrontal cortical activation associated with working memory in adults and preschool children: an event-related optical topography study

It is well known that lateral areas of the prefrontal cortex (LPFC) play a central role in working memory (a critical basis of various cognitive functions), but it remains unknown whether the LPFC of children of preschool age is responsible for working memory. To address this issue, we adopted a recently developed non-invasive imaging technique, optical topography (OT), which can potentially be applied to functional mapping in childhood. We firstly examined changes of activity in the LPFC using OT while adult subjects performed an item-recognition task, which requires working memory, under different memory-load conditions. We observed activation in the bilateral LPFC during performance of this task, the magnitude of which differed depending on memory-load. Then, we applied the same technique on 5- and 6-year-old children and observed the activation associated with working memory in the LPFC. Areas and properties of such activity were similar in adults and preschool children. Thus, for the first time, we demonstrate that the LPFC of preschoolers is active during working memory processes, indicating that in 5- and 6-year-old children, the LPFC has already developed processing of this important cognitive function.     

Decreased input-specific plasticity of the auditory cortex in mice lacking M1 muscarinic acetylcholine receptors

Muscarinic acetylcholine receptors are extensively involvedin cortical cognition and learning-induced or experience-dependentcortical plasticity. The most abundant muscarinic receptor subtypein the cerebral cortex is the M₁ receptor, but little is knownabout its contribution to experience-dependent plasticity ofthe adult auditory cortex. We have examined the role of theM₁ receptor in experience-dependent plasticity of the auditorycortex in mice lacking the M₁ (chrm1) gene. We show here thatelectrical stimulation of the basal forebrain, a major sourceof cortical cholinergic inputs, facilitated the auditory responsesof cortical neurons in both wild types and M₁ mutants. The basalforebrain stimulation alone caused change in the best frequenciesof cortical neurons that were significantly greater in M₁ mutants.When animals received the paired stimuli of electrical stimulationof the basal forebrain and tone, the frequency tuning of corticalneurons systematically shifted toward the frequency of the pairedtone in both wild types and M₁ mutants. However, the shift rangein M₁ mutants was much smaller than that in wild-type mice.Our data suggest that the M₁ receptor is important for the experience-dependentplasticity of the auditory cortex.     

Changes in fMRI activation following rehabilitation of reading and visual processing deficits in subjects with traumatic brain injury

In this case series fMRI was used to examine activation patterns during presentation of a reading comprehension (RC) task in three adult subjects with a history of severe traumatic brain injury (TBI). These subjects received cognitive rehabilitation therapy (CRT) for visual processing and acquired reading deficits. fMRI and neuropsychological testing occurred pre- and post-rehabilitation. The study's objective was to evaluate the neurobiological changes using fMRI occurring with CRT and to compare these results to repeat fMRI in matched control subjects. While improvements in neuropsychological testing occurred post-CRT, diffuse and variable activation patterns in the subjects with TBI were still demonstrated when compared to the control subjects repeat imaging. Multiple networks exist to accomplish the complex task of sentence reading and rehabilitation of the cognitive components of reading, such as visual processing; in subjects with TBI, can alter the activation pattern demonstrated during reading comprehension in subjects many years post-injury. This is the first demonstration of changes in network activation patterns post-CRT in patients with severe, chronic TBI on an fMRI task shown to have imaging stability in a normal control sample.     

Insulin resistance is associated with subclinical vascular disease in humans

Insulin resistance is associated with subclinical vascular disease that is not justified by conventional cardiovascular risk factors, such as smoking or hypercholesterolemia. Vascular injury associated to insulin resistance involves functional and structural damage to the arterial wall that includes impaired vasodilation in response to chemical mediators, reduced distensibility of the arterial wall(arterial stiffness), vascular calcification, and increased thickness of the arterial wall. Vascular dysfunction associated to insulin resistance is present in asymptomatic subjects and predisposes to cardiovascular diseases, such as heart failure, ischemic heart disease, stroke, and peripheral vascular disease.Structural and functional vascular disease associated to insulin resistance is highly predictive of cardiovascular morbidity and mortality. Its pathogenic mechanisms remain undefined. Prospective studies have demonstrated that animal protein consumption increases the risk of developing cardiovascular disease and predisposes to type 2 diabetes(T2 D) whereas vegetable protein intake has the opposite effect. Vascular disease linked to insulin resistance begins to occur early in life. Children and adolescents with insulin resistance show an injured arterial system compared with youth free of insulin resistance, suggesting that insulin resistance plays a crucial role in the development of initial vascular damage. Prevention of the vascular dysfunction related to insulin resistance should begin early in life. Before the clinical onset of T2 D, asymptomatic subjects endure a long period of time characterized by insulin resistance. Latent vascular dysfunction begins to develop during this phase, so that patients with T2 D are at increased cardiovascular risk long before the diagnosis of the disease.     

High response reliability of neurons in primary visual cortex (V1) of alert, trained monkeys

The reliability of neuronal responses determines the resources needed to represent the external world and constrains the nature of the neural code. Studies of anesthetized animals have indicated that neuronal responses become progressively more variable as information travels from the retina to the cortex. These results have been interpreted to indicate that perception must be based on pooling across relatively large numbers of cells. However, we find that in alert monkeys, responses in primary visual cortex (V1) are as reliable as the inputs from the retina and the thalamus. Moreover, when the effects of fixational eye movements were minimized, response variability (variance/mean - Fano factor, FF) in all V1 layers was low. When presenting optimal stimuli, the median FF was 0.3. High variability, FF approximately 1, was found only near threshold. Our results suggest that in natural vision, suprathreshold perception can be based on small numbers of optimally stimulated cells.     

Simple radiographic assessment of bone quality is associated with loss of surgical fixation in patients with proximal humeral fractures

AimThis study aimed to determine if the ratio of cortical thickness to shaft diameter of the humerus, as measured on a simple anterior-posterior shoulder radiograph, is associated with surgical fixation failure.Patients and Methods64 consecutive fractures in 63 patients (mean age 66.1years, range 35–90) operated with surgical fixation between March 2011 and July 2014 using PERI-LOC locking plate and screws (Smith and Nephew, UK) were identified. Predictors of bone quality were measured from preoperative radiographs, including ratio of the medial cortex to shaft diameter (medial cortical ratio, MCR). Loss of fixation (displacement, screw cut out, or change in neck-shaft angle >4 degrees) was determined on follow-up radiographs.ResultsLoss of fixation occurred in 14 patients (21.9%) during the follow up. Patients were older in the failure group 72.8 vs. 64.2 years (p = 0.007). The MCR was significantly lower in patients with failed fixation 0.170 vs 0.202, p = 0.019. Loss of fixation is three times more likely in patients with a MCR <0.16 (41% vs. 14%, p = 0.015). Increased fracture parts led to increased failure rate (p = 0.0005).ConclusionMedial cortex ratio is significantly associated with loss of surgical fixation and may prove to be a useful adjunct for clinical decision making in patients with proximal humeral fractures.     

Teriparatide for acceleration of fracture repair in humans: A prospective,randomized, double‐blind study of 102 postmenopausal women with distal radial fractures

Animal experiments show a dramatic improvement in skeletal repair by teriparatide. We tested the hypothesis that recombinant teriparatide, at the 20 µg dose normally used for osteoporosis treatment or higher, would accelerate fracture repair in humans. Postmenopausal women (45 to 85 years of age) who had sustained a dorsally angulated distal radial fracture in need of closed reduction but no surgery were randomly assigned to 8 weeks of once‐daily injections of placebo (n = 34) or teriparatide 20 µg (n = 34) or teriparatide 40 µg (n = 34) within 10 days of fracture. Hypotheses were tested sequentially, beginning with the teriparatide 40 µg versus placebo comparison, using a gatekeeping strategy. The estimated median time from fracture to first radiographic evidence of complete cortical bridging in three of four cortices was 9.1, 7.4, and 8.8 weeks for placebo and teriparatide 20 µg and 40 µg, respectively (overall p = .015). There was no significant difference between the teriparatide 40 µg versus placebo groups (p = .523). In post hoc analyses, there was no significant difference between teriparatide 40 µg versus 20 µg (p = .053); however, the time to healing was shorter in teriparatide 20 µg than placebo (p = .006). The primary hypothesis that teriparatide 40 µg would shorten the time to cortical bridging was not supported. The shortened time to healing for teriparatide 20 µg compared with placebo still may suggest that fracture repair can be accelerated by teriparatide, but this result should be interpreted with caution and warrants further study. © 2010 American Society for Bone and Mineral Research