Attention and executive function deficits in chronic low-dose MPTP-treated non-human primates

Parkinson's disease (PD) is a complex disorder consisting of motor deficits coupled with dysfunction in cognitive domains that are dependent upon the integrity of the frontal lobes and/or the fronto-striatal axis. Although it is increasingly acknowledged that PD patients have attentional and executive function deficits, it has been difficult to model these in nonhuman primates because of the nature of the cognitive tasks that have been used previously. The present studies were conducted to further define the nature of the cognitive impairment in a nonhuman primate model of early parkinsonism consequent to chronic low dose MPTP exposure and to further validate this model in monkeys trained to perform a battery of attentional and executive function tasks. Following chronic low dose MPTP exposure, monkeys developed deficits in maintenance of a response set as well problems in shifting attentional sets, suggesting decreased mental flexibility. On other tasks inattentiveness, an impaired ability to sustain spatial attention or to focus attention, a deficit in motor readiness and planning, and impaired time estimation were also observed. These results provide direct evidence of attention and executive function deficits in a nonhuman primate model of early parkinsonism. Based on these findings, we suggest that in addition to being useful for studying the cognitive deficits related to early PD and for developing new therapeutics for these problems, this model and these testing procedures may also provide a useful large animal model for studying attention deficit disorder and for developing new therapeutics for that condition as well.     

Differences in alpha7 nicotinic acetylcholine receptor binding in motor symptomatic and asymptomatic MPTP-treated monkeys

We studied [(125)I]alpha-bungarotoxin (btx) binding to alpha7 nicotinic acetylcholine receptors in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposed macaque monkeys. [(125)I]alpha-Btx binds throughout the normal monkey brain, with the greatest density in the thalamic nuclei and with moderate to low binding in the hippocampus, prefrontal cortex, caudate, putamen, and substantia nigra. Chronic administration of low doses of MPTP resulted in animals with stable cognitive deficits without overt parkinsonian motor symptoms. [(125)I]alpha-Btx binding in the brains of these animals was significantly increased in the outermost layers of the supplementary motor cortex (area 6M, approximately 50%), primary motor cortex (area 4, approximately 112%) and throughout the putamen (approximately 50-72%). In contrast, there was no change in [(125)I]alpha-btx binding in the brain regions thought to be involved in mediating the cognitive functions impaired in these monkeys (e.g., the hippocampus, areas 9/46D and 46D of the principal sulcus, and area 24c of the cingulate sulcus). Animals with cognitive dysfunction that received escalating doses of MPTP for >6 months developed motor signs of parkinsonism which were indistinguishable from those seen in animals rendered acutely parkinsonian with short term administration of large doses of MPTP. These two "motor symptomatic" groups had significantly increased [(125)I]alpha-btx binding only in the dorsolateral putamen. Immunohistochemical studies showed that the increased [(125)I]alpha-btx binding, when observed, was associated with enhanced immunohistochemical staining localized to neurons and was not a result of an astrocytic response to MPTP. These results suggest that the increase in alpha7 nicotinic acetylcholine receptor expression in the chronic low-dose MPTP treated, motor asymptomatic monkeys may be a part of compensatory processes contributing to the maintained motor functioning in these animals.     

Enhancement of executive functioning skills: an additional tier in the treatment of schizophrenia

Schizophrenia is viewed by most as having a neuropsychological component, with deficits primarily occurring in the areas of attention/concentration, memory, and executive functioning. These deficits often contribute to difficulties in everyday living and social functioning. The purpose of this study is to examine the efficacy of cognitive rehabilitation methods, typically utilized by brain-injured patients, to improve the executive functioning skills of patients with schizophrenia spectrum disorders. While this pilot study is limited in terms of sample size, results suggest that the addition of cognitive rehabilitation to the comprehensive treatment of schizophrenia could be beneficial in enhancing daily living skills.     

Exploring the differential associations between components of executive functioning and reactive and proactive aggression

Objective: A large body of literature confirms the importance of executive functioning (EF) in the explanation of aggressive and antisocial behaviors. However, the common and specific associations between subtypes of aggression, such as reactive (RA), proactive aggression (PA), and EF are unclear. The current study explored the nuanced associations between components of EF and subtypes of aggression, using a latent variable approach. Method: Participants were 384 racially diverse undergraduate students (ages 18–52 years) who completed a self-report measure of RA and PA, and traditional neuropsychological tasks of EF. The appropriateness of using a nested bifactor model of EF was confirmed, and this bifactor model of EF was then used to examine the specific associations between components of EF and RA and PA. Results: Results revealed that components of EF are differentially associated with RA and PA. Specifically, impulsive, provoked aggression (i.e., RA) was associated with lower levels of goal-oriented inhibition and higher levels of flexibility, whereas planned, goal-oriented aggression (i.e., PA) was associated with higher levels of working memory. Conclusions: Findings from the current study underscore the importance of considering the multidimensional nature of EF, as well as the heterogeneity within aggression, rather than considering either construct as a single monolithic construct. The current study suggests that potentially unique brain-based pathways from aspects of EF to subtypes of aggression may exist, and points toward potential avenues through which to intervene.     

儿童Tourette综合征患者执行功能的研究

目的 探讨儿童Tourette综合征患者执行功能的特征.方法 采用视觉记忆测验、流畅性测验、字色干扰测验、威斯康星卡片分类测验,分别测试53例Tourette综合征患儿和51名正常儿童的工作记忆、注意抑制、认知灵活性、计划性和定势转移能力等多项执行功能,并进行比较.结果 Tourette综合征患儿在即时和延迟图形记忆、3项流畅性测验、字色干扰测验、威斯康星卡片分类测验中的成绩均明显低于正常儿童(均P＜0.01).结论 Tourette综合征患儿的工作记忆能力下降,在持续性注意和反应抑制、认知灵活性、思维组织性、计划性和定势转移等能力方面存在障碍.     

Effects of the partial glycine agonist D-cycloserine on cognitive functioning in chronic low dose MPTP-treated monkeys

D-Cycloserine, a partial agonist at the glycine recognition site of the N-methyl-D-aspartate (NMDA) receptor complex, has been shown to facilitate certain forms of memory formation and to improve visual recognition memory in normal monkeys. In the present study, the effects of D-cycloserine on spatial short-term memory deficits in monkeys induced by chronic low-dose 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) administration were examined. Chronic low-dose MPTP administration resulted in deficits in the performance of a variable delayed-response task (VDR). Single administration of D-cycloserine (320 or 1000 microgram/kg) significantly improved the performance on this task. High-dose D-cycloserine (8000 microgram/kg) or MK-801 (10-32 microgram/kg) administration had no effects on delayed-response performance but impaired performance on a visual discrimination (VD) task that was not adversely affected by MPTP administration. These results show that at low doses, D-cycloserine has cognition-enhancing properties in this model of early Parkinsonism.     

HIV-associated executive dysfunction in the era of modern antiretroviral therapy: A systematic review and meta-analysis

Objective: While some reports suggest that HIV+ individuals continue to display executive function (EF) impairment in the era of cART, findings have been contradictory and appear to differ based on the aspect of EF being measured. To improve the understanding of how discrete executive abilities may be differentially affected or spared in the context of HIV infection, we conducted a systematic review and meta-analysis to (a) determine whether and to what extent HIV+ adults experience deficits in EFs, and (b) understand how demographic and clinical characteristics may modify the associations between HIV infection and executive abilities.

Method: Studies comparing HIV+ and HIV-uninfected groups on measures of working memory, set-shifting, inhibition, decision-making, and apathy between 2000 and 2017 were identified from three databases. Effect sizes (Cohen’s d) were calculated using inverse variance weighted random effects models. Meta-regression was used to examine the moderating effect of demographic and clinical variables.

Results: Thirty-seven studies (n = 3935 HIV+; n = 2483 HIV-uninfected) were included in the meta-analysis. Pooled effect sizes for deficits associated with HIV infection were small for domains of set-shifting (d = ?0.34, 95% CI [?0.47, ?0.20]) and inhibition (d = ?0.31, 95% CI [?0.40, ?0.21]), somewhat larger for measures of decision-making (d = ?0.41, 95% CI [?0.53, ?0.28]) and working memory (d = ?0.42, 95% CI [?0.59, ?0.29]), and largest for apathy (d = ?0.87, 95% CI [?1.09, ?0.66]). Meta-regression demonstrated that age, sex, education, current CD4 count, and substance dependence differentially moderated the effects of HIV infection on specific EFs. However, lower nadir CD4 count was the only variable associated with greater deficits in nearly all EF domains.

Conclusions: Our results suggest that discrete domains of EF may be differentially affected by HIV infection and moderating demographic and clinical variables. These findings have implications for the development of targeted cognitive remediation strategies.     

Structural brain indices and executive functioning in multiple sclerosis: A review

Multiple sclerosis (MS) is a neurological disease characterized by lesion-induced white matter deterioration. Brain atrophy and damage to normal appearing white matter (NAWM) and normal appearing gray matter (NAGM) have also been identified as consequences of MS. Neuroimaging has played an integral role in investigating the effects of white and gray matter damage across the three primary clinical phenotypes of the disease—primary progressive (PPMS), relapsing remitting (RRMS), and secondary progressive (SPMS) MS. Both conventional (e.g., T1-weighted imaged) and nonconventional (e.g., diffusion tensor imaging) neuroimaging methods have yielded important information regarding the structural integrity of the brain during the course of the disease. Moreover, it has provided the opportunity to explore the relationship between structural brain indices and cognitive functioning, such as executive functioning, in MS. In this paper, we provide a brief overview of executive functioning in MS, a general review of how structural damage presents in MS by way of sclerotic lesions, atrophy, and microstructural white matter damage, and, finally, how structural brain damage relates to executive dysfunction.     

Mild traumatic brain injury and executive functions in school-aged children

Objective: This study sought to examine the effects of mild traumatic brain injury (TBI) on executive functions in school-aged children.

Participants and method: The prospective, longitudinal study involved 8–15 year old children, 186 with mild TBI and 99 with mild orthopaedic injuries (OI). They were administered the Stockings of Cambridge and Spatial Working Memory sub-tests from the Cambridge Neuropsychological Testing Automated Battery (CANTAB) ～10 days, 3 months and 12 months post-injury. Parents completed the Behavior Rating Inventory of Executive Functions (BRIEF) on each occasion, with ratings at the initial assessment intended to assess pre-morbid functioning retrospectively.

Results: On the CANTAB, the groups did not differ on the Stockings of Cambridge and the mild TBI group unexpectedly performed better than the OI group on Spatial Working Memory. On the BRIEF, children with mild TBI showed a marginally significant trend toward more problems than the OI group on the Metacognition Index composite. The only BRIEF sub-scale on which they demonstrated significantly more problems was Organization of Materials. The presence of intracranial abnormalities on MRI was associated with more problems on the BRIEF Organization of Materials sub-scale at 3 months, but other findings were not consistent with hypothesized effects of TBI severity. The CANTAB sub-tests were significant predictors of later ratings on the BRIEF, but accounted for modest variance.

Discussion: Children with mild TBI show limited evidence of deficits in executive functions, either cognitively or behaviourally, irrespective of injury characteristics. Cognitive tests of executive functions are modest predictors of ratings of executive functions in everyday life, for children both with and without mild TBI.     

A review of executive functions in obstructive sleep apnea syndrome

OBJECTIVES: To provide an update on recent research concerning obstructive sleep apnea syndrome (OSAS) and executive functions. METHODS: A systematic review was carried out on reports drawn from MEDLINE and PSYCHLIT (January 1990-December 2005) and identified from lists of references in these reports. The selection criteria were met by 40 articles. RESULTS: The sample sizes in the reviewed studies varied widely and consisted mostly of selected groups. Most patient samples were heterogeneous in terms of the severity of OSAS. Executive functions were generally assessed with standardized test methods. Half of the studies assessed executive functions using only one or two tests. The most defected domains of executive functions were working memory, phonological fluency, cognitive flexibility, and planning. Continuous positive airway pressure (CPAP) treatment improved performance times, cognitive flexibility, and planning. Deficits in working memory and phonological fluency persisted. CONCLUSIONS: Executive functions are the most defected cognitive domain in OSAS. Previous studies are affected by the heterogeneity of patient samples and the definitions of the domains of executive functions. Executive functions in OSAS should be assessed with a standardized neuropsychological test battery including assessments of different domains of executive functions. More research is needed on the efficiency of CPAP treatment on executive dysfunctions.     

Motor dysfunction influence on executive functioning in manifest and premanifest Huntington's disease

Motor disturbances can be present in both manifest and premanifest Huntington's disease (HD). We aimed to investigate the role of motor functioning on executive functioning to better understand the progression of cognitive dysfunction in HD. Forty patients with manifest HD, 21 patients with premanifest HD, and a group of 28 controls were tested twice with a 1‐year interval. For the Symbol Digit Modalities Test and the Figure Fluency Test, extra conditions were designed to measure motor involvement. Subtraction of this motor score from the original test score resulted in isolation of the cognitive component. Groups were compared on motor, cognitive, and original test scores using multilevel regression analysis. Manifest patients had lower baseline scores of 0.53 standard deviations (SD) on the original Symbol Digit Modalities Test (P = 0.03) and 0.71 SD on the motor isolation part (P = 0.006), and they showed a deterioration of 0.47 SD over 1 year of follow‐up on the original Symbol Digit Modalities Test (P = 0.001) compared with controls. Premanifest patients had lower baseline scores of 0.67 SD on the Symbol Digit Modalities motor part (P = 0.008) and deterioration of 0.48 SD on the original (P = 0.001) and cognitive isolation (P = 0.02) parts. Secondary analyses revealed that the premanifest deterioration resulted from the close‐to‐predicted‐onset group. Motor disturbances have a negative influence on performance on the Symbol Digit Modalities Test. Isolation of the cognitive component of this test revealed cognitive deterioration in the premanifest group only, caused by deteriorating scores for patients who were close to their predicted clinical disease onset. The Figure Fluency Test did not prove sensitive to cognitive change. © 2014 International Parkinson and Movement Disorder Society     

Effects of amygdala lesions on sleep in rhesus monkeys

The amygdala is important in processing emotion and in the acquisition and expression of fear and anxiety. It also appears to be involved in the regulation of sleep and wakefulness. The purpose of this study was to assess the effects of, fiber-sparing lesions of the amygdala on sleep in rhesus monkeys (Macaca mulatta). We recorded sleep from 18 age-matched male rhesus monkeys, 11 of which had previously received ibotenic acid lesions of the amygdala and seven of which were normal controls. Surface electrodes for sleep recording were attached and the subjects were seated in a restraint chair (to which they had been adapted) for the nocturnal sleep period. Despite adaptation, control animals had sleep patterns characterized by frequent arousals. Sleep was least disrupted in animals with large bilateral lesions of the amygdala. They had more sleep and a higher proportion of rapid-eye-movement (REM) sleep than did either animals with smaller lesions or control animals. Based on these results, it seems likely that, in the primate, the amygdala plays a role in sleep regulation and may be important in mediating the effects of emotions/stress on sleep. These findings may also be relevant to understanding sleep disturbances associated with psychopathology.     

The role of executive function and attention in gait

Until recently, gait was generally viewed as a largely automated motor task, requiring minimal higher‐level cognitive input. Increasing evidence, however, links alterations in executive function and attention to gait disturbances. This review discusses the role of executive function and attention in healthy walking and gait disorders while summarizing the relevant, recent literature. We describe the variety of gait disorders that may be associated with different aspects of executive function, and discuss the changes occurring in executive function as a result of aging and disease as well the potential impact of these changes on gait. The attentional demands of gait are often tested using dual tasking methodologies. Relevant studies in healthy adults and patients are presented, as are the possible mechanisms responsible for the deterioration of gait during dual tasking. Lastly, we suggest how assessments of executive function and attention could be applied in the clinical setting as part of the process of identifying and understanding gait disorders and fall risk. © 2007 Movement Disorder Society