Behavioral phenotype of individuals with Down syndrome

Evidence is reviewed for a developmentally-emerging behavioral phenotype in individuals with Down syndrome that includes significant delay in nonverbal cognitive development accompanied by additional, specific deficits in speech, language production, and auditory short-term memory in infancy and childhood, but fewer adaptive behavior problems than individuals with other cognitive disabilities. Evidence of dementia emerges for up to half the individuals studied after age 50. Research issues affecting control group selection in establishing phenotypic characteristics are discussed, as well as the possible genetic mechanisms underlying variation in general cognitive delay, specific language impairment, and adult dementia. MRDD Research Reviews 2000;6:84-95. Wiley-Liss, Inc.     

成瘾人群跨期选择的神经机制及干预方法

成瘾可分为物质成瘾和行为成瘾, 两类成瘾人群在跨期选择上都表现出高时间折扣率的缺陷, 但也有各自的特异性特征。成瘾人群跨期选择缺陷的神经基础主要集中在评估网络(腹内侧前额叶、纹状体、后扣带皮层等)、认知控制网络(前额叶皮层、前扣带皮层等)和预期想象网络(海马、杏仁核等); 可利用心理训练来改善成瘾人群跨期选择缺陷, 其干预方法包括工作记忆训练、预期想象训练、金钱管理指导等。未来研究应该从成瘾者跨期选择缺陷的认知机制、3个神经网络系统的交互作用机理、行为遗传学以及开发有效的干预方法等方面展开大量研究。     

Differential effects of assisted cycling therapy on short-term and working memory of adolescents with Down syndrome

Persons with Down syndrome (DS) suffer from prefrontal cortex dysfunction and deficits in executive functions. The current study examined the effects assisted cycling therapy (ACT) on short-term (STM) and working memory (WM) in adolescents with DS. During ACT, the cadence of participants on a stationary bicycle was augmented with an electrical motor to 180% of the voluntary cadence. Participants completed eight weeks of ACT (n?=?17), eight weeks of voluntary cycling (VC) at their own preferred cadence (n?=?16), or eight weeks of no cycling (np?≥?.149) and working memory improved only in the ACT group (Hedge’s g?=?1.66; p?=?.003). The results indicate that assisted high-cadence cycling (i.e. ACT) produces superior neural benefits in the dorsolateral prefrontal cortex compared to VC.     

Dissociable spatial memory systems revealed by typical and atypical human development

Rodent lesion studies have revealed the existence of two causally dissociable spatial memory systems, localized to the hippocampus and striatum that are preferentially sensitive to environmental boundaries and landmark objects, respectively. Here we test whether these two memory systems are causally dissociable in humans by examining boundary‐ and landmark‐based memory in typical and atypical development. Adults with Williams syndrome (WS)—a developmental disorder with known hippocampal abnormalities—and typical children and adults, performed a navigation task that involved learning locations relative to a boundary or a landmark object. We found that boundary‐based memory was severely impaired in WS compared to typically‐developing mental‐age matched (MA) children and chronological‐age matched (CA) adults, whereas landmark‐based memory was similar in all groups. Furthermore, landmark‐based memory matured earlier in typical development than boundary‐based memory, consistent with the idea that the WS cognitive phenotype arises from developmental arrest of late maturing cognitive systems. Together, these findings provide causal and developmental evidence for dissociable spatial memory systems in humans.     

Developmental differences in prefrontal activation during working memory maintenance and manipulation for different memory loads

The ability to keep information active in working memory is one of the cornerstones of cognitive development. Prior studies have demonstrated that regions which are important for working memory performance in adults, such as dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex (VLPFC), and superior parietal cortex, become increasingly engaged across school-aged development. The primary goal of the present functional MRI study was to investigate the involvement of these regions in the development of working memory manipulation relative to maintenance functions under different loads. We measured activation in DLPFC, VLPFC, and superior parietal cortex during the delay period of a verbal working memory task in 11-13-year-old children and young adults. We found evidence for age-related behavioral improvements in working memory and functional changes within DLPFC and VLPFC activation patterns. Although activation profiles of DLPFC and VLPFC were similar, group differences were most pronounced for right DLPFC. Consistent with prior studies, right DLPFC showed an interaction between age and condition (i.e. manipulation versus maintenance), specifically at the lower loads. This interaction was characterized by increased activation for manipulation relative to maintenance trials in adults compared to children. In contrast, we did not observe a significant age-dependent load sensitivity. These results suggest that age-related differences in the right DLPFC are specific to working memory manipulation and are not related to task difficulty and/or differences in short-term memory capacity.     

Functional connectivity differences in autism during face and car recognition: underconnectivity and atypical age‐related changes

Face recognition abilities improve between adolescence and adulthood over typical development (TD), but plateau in autism, leading to increasing face recognition deficits in autism later in life. Developmental differences between autism and TD may reflect changes between neural systems involved in the development of face encoding and recognition. Here, we focused on whole‐brain connectivity with the fusiform face area (FFA), a well‐established face‐preferential brain region. Older children, adolescents, and adults with and without autism completed the Cambridge Face Memory Test, and a matched car memory test, during fMRI scanning. We then examined task‐based functional connectivity between the FFA and the rest of the brain, comparing autism and TD groups during encoding and recognition of face and car stimuli. The autism group exhibited underconnectivity, relative to the TD group, between the FFA and frontal and primary visual cortices, independent of age. Underconnectivity with the medial and rostral lateral prefrontal cortex was face‐specific during encoding and recognition, respectively. Conversely, underconnectivity with the L orbitofrontal cortex was evident for both face and car encoding. Atypical age‐related changes in connectivity emerged between the FFA and the R temporoparietal junction, and R dorsal striatum for face stimuli only. Similar differences in age‐related changes in autism emerged for FFA connectivity with the amygdala across both face and car recognition. Thus, underconnectivity and atypical development of functional connectivity may lead to a less optimal face‐processing network in the context of increasing general and social cognitive deficits in autism.     

A System for Relational Reasoning in Human Prefrontal Cortex

The integration of multiple relations between mental representations is critical for higher level cognition. For both deductive- and inductive-reasoning tasks, patients with prefrontal damage exhibited a selective and catastrophic deficit in the integration of relations, whereas patients with anterior temporal lobe damage, matched for overall IQ but with intact prefrontal cortex, exhibited normal relational integration. In contrast, prefrontal patients performed more accurately than temporal patients on tests of both episodic memory and semantic knowledge. These double dissociations suggest that integration of relations is a specific source of cognitive complexity for which intact prefrontal cortex is essential. The integration of relations may be the fundamental common factor linking the diverse abilities that depend on prefrontal function, such as planning, problem solving, and fluid intelligence.     

Alterations in working memory networks in amnestic mild cognitive impairment

Patients with amnestic mild cognitive impairment (aMCI) show preserved or mildly impaired working memory, despite their deficits in episodic memory. We aimed to identify performance and/or neural differences between aMCI patients and matched controls on a standard working memory fMRI task. Neuropsychological assessment demonstrated aMCI impairments in verbal and visual episodic long-term memory, with intact IQ and executive function. Participants completed a standard three-level N-back task where patients were unimpaired. Functional activations in the control group were found in expected areas, including the inferior parietal lobule and dorsolateral prefrontal cortex. Group differences were found in the insula and lingual gyrus and, in a region of interest analysis, in the hippocampus. In all cases, these were caused by an absence of task-related deactivations in the aMCI group. The results are consistent with reports of failure in task-related deacivations in aMCI and could be early indications of pathology.     

Medial prefrontal cortex supports source memory for self-referenced materials in young and older adults

Behavioral evidence suggests that young and older adults show a benefit in source memory accuracy when processing materials in reference to the self. In the young, activity within the medial prefrontal cortex supports this source memory benefit at study. In this investigation, we examined whether the same neural regions support this memory benefit in both age groups. Using fMRI, we scanned participants while they studied and retrieved pictures of objects paired with one of three scenes (source) under self-reference and other-reference conditions. At the time of study, half of the items were presented once and half twice, allowing us to match behavioral performance between the groups. Both groups showed equivalent source accuracy benefits for objects encoded self-referentially. Activity in the left dorsal medial prefrontal cortex supported subsequent source memory in both age groups for the self-referenced relative to the other-referenced items. At the time of test, source accuracy for both the self- and other-referenced items was supported by a network of regions including the precuneus in both age groups. At both study and test, little in the way of age differences emerged, suggesting that when they are matched on behavioral performance, young and older adults engage similar regions in support of source memory when processing materials in reference to the self; however, when we did not match performance, age differences in functional recruitment were prevalent. These results suggest that by capitalizing on preserved processes (self-referential encoding), older adults can show improvement in memory for source details that they would typically not remember well, relative to the young.     

Differential brain shrinkage over 6 months shows limited association with cognitive practice

The brain shrinks with age, but the timing of this process and the extent of its malleability are unclear. We measured changes in regional brain volumes in younger (age 20–31) and older (age 65–80) adults twice over a 6 months period, and examined the association between changes in volume, history of hypertension, and cognitive training. Between two MRI scans, 49 participants underwent intensive practice in three cognitive domains for 100 consecutive days, whereas 23 control group members performed no laboratory cognitive tasks. Regional volumes of seven brain structures were measured manually and adjusted for intracranial volume. We observed significant mean shrinkage in the lateral prefrontal cortex, the hippocampus, the caudate nucleus, and the cerebellum, but no reliable mean change of the prefrontal white matter, orbital-frontal cortex, and the primary visual cortex. Individual differences in change were reliable in all regions. History of hypertension was associated with greater cerebellar shrinkage. The cerebellum was the only region in which significantly reduced shrinkage was apparent in the experimental group after completion of cognitive training. Thus, in healthy adults, differential brain shrinkage can be observed in a narrow time window, vascular risk may aggravate it, and intensive cognitive activity may have a limited effect on it.     

Constitutive activation of the G-protein subunit Galphas within forebrain neurons causes PKA-dependent alterations in fear conditioning and cortical Arc mRNA expression

Memory formation requires cAMP signaling; thus, this cascade has been of great interest in the search for cognitive enhancers. Given that medications are administered long-term, we determined the effects of chronically increasing cAMP synthesis in the brain by expressing a constitutively active isoform of the G-protein subunit Galphas (Galphas*) in postnatal forebrain neurons of mice. Previously, we showed that Galphas* mice exhibit increased adenylyl cyclase activity but decreased cAMP levels in cortex and hippocampus due to a PKA-dependent increase in total cAMP phosphodiesterase (PDE) activity. Here, we extend previous findings by determining if Galphas* mice show increased activity of specific PDE families that are regulated by PKA, if Galphas* mice show PKA-dependent deficits in fear memory, and if these memory deficits are associated with PKA-dependent alterations in neuronal activity as mapped by Arc mRNA expression. Consistent with previous findings, we show here that Galphas* mice exhibit a significant compensatory increase in cAMP PDE1 activity and a trend toward increased cAMP PDE4 activity. Further, inhibiting the presumably elevated PKA activity in Galphas* mice fully rescues short- and long-term memory deficits in a fear-conditioning task, while extending the training session from one to four CS-US pairings partially rescues these deficits. Mapping of Arc mRNA levels suggests these PKA-dependent memory deficits may be related to decreased neuronal activity specifically within the cortex. Galphas* mice show decreased Arc mRNA expression in CA1, orbital cortex, and cortical regions surrounding the hippocampus; however, only the deficits in cortical regions surrounding the hippocampus are PKA dependent. Our results imply that chronically stimulating targets upstream of cAMP may detrimentally affect cognition.     

Identifying the nature of impairments in executive functioning and working memory of children with severe difficulties in arithmetic

An age-matched achievement-matched design was used to examine whether the executive functioning and working memory impairments exhibited by children with severe difficulties in arithmetic (SDA) are better viewed as developmental lags or as cognitive deficits. Three groups of children were included: 20 SDA children, 20 typically achieving children (CM) matched in chronological age with the SDA children, and 20 younger typically achieving children (AM) matched in achievement with the SDA group. While children with SDA did not exhibit impairments in color-word inhibition and verbal working memory, they did demonstrate impairments in shifting, quantity-digits inhibition, and visuospatial working memory. As children with SDA did not perform more poorly than their AM counterparts on any of these tasks, impairments in specific areas of executive functioning and working memory appear to reflect developmental lags rather than cognitive deficits.     

Executive Cognitive Functioning and Risk for Substance Abuse

Individuals with a substance use disorder (SUD) exhibit deficits in executive cognitive functioning (ECF). ECF is involved in the regulation of goal-directed behavior and includes abilities such as attentional control, strategic goal planning, organization, and cognitive flexibility. The prefrontal cortex is believed to be the primary cortical substrate that subserves ECF. Children deemed at high risk for drug abuse because they have parents with SUD similarly demonstrate cognitive limitations suggesting an ECF deficit. High-risk children, as a group, also exhibit deviations in temperament, an attenuated amplitude of the P300 event-related potential, and heightened aggressivity compared with control groups. These latter characteristics are associated with low ECF capacity and are believed to reflect dysfunction within the prefrontal cortex. It is hypothesized that deviations on these traits form a core disorder of affective, cognitive, and behavioral dysregulation that serves as a general vulnerability factor for SUD.     

Working Memory and Cognitive Skills in Individuals with Down Syndrome

This work is aimed at analyzing working memory (WM) components and their relationships with other cognitive processes in individuals with Down syndrome (DS). Particular attention is given to examine whether a verbal WM deficit is due to difficulties in verbal abilities often showed by individuals with DS, or whether it is a deficit per se. A group of 20 individuals with DS was compared to a group of 20 typically developing (TD) children matched on vocabulary comprehension and to a group of 20 TD children matched on general verbal intelligence. The groups received a battery of 3 verbal and 3 visuospatial WM tasks requiring different degrees of control, and tests assessing verbal abilities (WPPSI verbal scale, PPVT), nonverbal skills (WPPSI performance scale), and logical thinking (LO). The results revealed that individuals with DS have deficits in both central executive (control) and verbal components of the WM system, and the latter one is independent of the general verbal abilities deficit. The data suggest that the development of central executive proceeds at a slower rate in individuals with DS and differently from TD children with comparable verbal abilities. The performance of individuals with DS on high-control WM tasks requires additional general resources that are strictly linked to intelligence.     

情景变换诱发已消退恐惧记忆重现的神经环路

暴露疗法是治疗创伤后应激障碍的主要行为疗法。当被试反复暴露于可引起恐惧反应的条件刺激(如白噪音), 但却不伴有非条件刺激(如足底电击)时, 恐惧记忆将被消退, 形成消退记忆。但恐惧记忆并未从根本上被擦除, 当被试在消退训练以外的情景暴露于条件刺激时, 已消退的恐惧记忆将会重现。海马、内侧前额叶皮层、杏仁核等脑区及其相互连接的神经环路是情景诱发恐惧记忆重现的生理基础。情景变化诱发恐惧记忆重现过程中, 海马可能是通过直接投射至杏仁核基底核、杏仁核外侧核或通过边缘前皮质间接调控杏仁核基底核、杏仁核外侧核的功能, 产生恐惧反应。     

Effects of aging on the neural correlates of successful item and source memory encoding

To investigate the neural basis of age-related source memory (SM) deficits, young and older adults were scanned with fMRI while encoding faces, scenes, and face-scene pairs. Successful encoding activity was identified by comparing encoding activity for subsequently remembered versus forgotten items or pairs. Age deficits in successful encoding activity in hippocampal and prefrontal regions were more pronounced for SM (pairs) as compared with item memory (faces and scenes). Age-related reductions were also found in regions specialized in processing faces (fusiform face area) and scenes (parahippocampal place area), but these reductions were similar for item and SM. Functional connectivity between the hippocampus and the rest of the brain was also affected by aging; whereas connections with posterior cortices were weaker in older adults, connections with anterior cortices, including prefrontal regions, were stronger in older adults. Taken together, the results provide a link between SM deficits in older adults and reduced recruitment of hippocampal and prefrontal regions during encoding. The functional connectivity findings are consistent with a posterior-anterior shift with aging previously reported in several cognitive domains and linked to functional compensation.     

Linguistic profile of individuals with Down syndrome: comparing the linguistic performance of three developmental disorders.

An increasing number of studies, addressing the linguistic abilities of individuals with Down syndrome (DS) suggest that they exhibit strengths and weaknesses within the linguistic domain. This article critically reviews the literature on the linguistic profile of individuals with DS, with particular emphasis on the expression and reception of vocabulary and grammar, including nonverbal linguistic expression during infant development. In doing so, attention is given to recent comparative studies of the linguistic abilities of individuals with DS, Specific Language Impairment (SLI), and Williams syndrome (WS). The possibility that deficits in one cognitive system may have consequences in another cognitive system, and that these consequences may define the nature of the impairment in each clinical syndrome is further discussed with suggestions for future research.     

Prehension in young children with Down syndrome

Prehension was examined in 3-year old children with Down syndrome (DS, n = 3) and in typically-developing children matched in chronological age (3-year olds; n = 3) or mental age and motor experience (2-year olds; n = 3). The task required reaching to grasp dowels. Video-based movement analysis yielded temporal and kinematic measures. Children with DS were hypothesized to have deficits in feedback-dependent components of prehension (anticipatory grip-closure and deceleration of reach), whereas feedforward components (reach's acceleration phase; grasp's preshaping) were assumed to be unimpaired [Latash, 1993, Control of human movement, pp. 283-292; Latash, 1994, What is clumsiness? In: Motor Control and Down Syndrome II Proceedings of the second international conference, pp. 68-71]. The findings supported these hypotheses. In comparison to control groups, children with DS had significantly: (a) less time in deceleration of reaching, (b) fewer anticipatory grip-closures, and (c) longer movement times for dowel-lift. Young children with DS appeared to use dowel-contact to decelerate the limb and initiate grip-closure. In contrast, reach-acceleration time and grasp-preshaping did not differ across groups. These findings suggest that children with DS display qualitative differences in motor capabilities rather than simply a delayed rate of typical developmental progression.     

An experimental approach to detecting dementia in Down syndrome: a paradigm for Alzheimer's disease

Measures developed from animal models of aging may detect dementia of the Alzheimer's type in a population at-risk for Alzheimer's disease (AD). Although, by middle age, individuals with Down syndrome (DS) show an extraordinarily high prevalence of AD-type pathology, their severe idiopathic cognitive deficits tend to confound the clinical diagnosis of AD. The current study was designed to improve detection of AD in DS by using measures of learning and memory derived from animal models of aging. Adults with DS (N=34) were assessed and reassessed (n=19) approximately one year later using stimulus-response (S-R) test methods derived from experimental literature, as well as standardized informant-based tests. Results demonstrated high validity and reliability of select tests. The implication of early symptom detection in a population at-risk for AD-type dementia was discussed in terms of potential brain regions of interest.