Attentional effects of lesions to the anterior cingulate cortex: how prior reinforcement influences distractibility

Morphological changes in the anterior cingulate cortex are found in subjects with schizophrenia, attention deficit hyperactivity disorder, and obsessive-compulsive disorder. These changes are hypothesized to underlie the impairments these individuals show on tasks that require cognitive control. The anterior cingulate cortex has previously been shown to be active in situations involving high conflict, presentation of salient, distracting stimuli, and error processing, that is, situations that occur when a shift in attention or responding is required. However, there is some uncertainty as to what specific role the anterior cingulate cortex plays in these situations. The current study used converging evidence from two behavioral paradigms to determine the effects of excitotoxic lesions in the anterior cingulate cortex on executive control. The first assay tests reversal learning, attentional set formation and shifting. The second assesses sustained attention with and without distractors. Animals with anterior cingulate cortex lesions were impaired during reinforcement reversals, discriminations that required subjects to disregard previously relevant stimulus attributes and showed a more rapid decline in attentional ability than Sham-Lesioned subjects when maintaining sustained attention for extended periods of time. These results are consistent with the hypothesis that the anterior cingulate cortex is involved in attending to stimulus attributes that currently predict reinforcement in the presence of previously relevant, salient distractors and maintaining sustained attention over prolonged time on task.     

Noradrenergic, but not cholinergic, deafferentation of prefrontal cortex impairs attentional set-shifting

Both norepinephrine and acetylcholine have been shown to be critically involved in mediating attention but there remains debate about whether they serve similar or unique functions. Much of what is known about the role of these neurochemicals in cognition is based on manipulations done at the level of the cell body but these findings are difficult to reconcile with data regarding the unique contribution of cortical subregions, e.g. the dorsolateral prefrontal cortex, to attention. In the current study, we directly compared the effects of noradrenergic and cholinergic deafferentation of the rat medial prefrontal cortex, the homologue of primate dorsolateral prefrontal cortex, using an intradimensional/extradimensional attentional set shifting task, a task previously shown to be able to dissociate the function of the primate dorsolateral prefrontal cortex from orbitofrontal cortex. We found that noradrenergic, but not cholinergic, deafferentation produces specific impairments in the ability to shift attentional set. We also clarified the nature of the attentional deficits by assessing the ability of rats to disregard irrelevant stimuli. Noradrenergic lesions did not alter the ability of rats to ignore irrelevant stimuli, suggesting that the attentional deficit results from an overly focused attentional state that retards learning that a new stimulus dimension predicts reward.     

Atomoxetine reverses attentional deficits produced by noradrenergic deafferentation of medial prefrontal cortex

BACKGROUND: The majority of studies assessing executive function in attention deficit disorder (ADD) have shown deficits in attentional set shifting using either the Wisconsin card sorting task or the intra-dimensional/extra-dimensional set-shifting task (ID/ED). Damage to the prefrontal cortex in humans, primates, and rodents impairs extra-dimensional (ED) shifts. Noradrenergic depletion of the medial prefrontal cortex in rats is sufficient to impair attentional set shifting. Atomoxetine, a selective norepinephrine (NE) re-uptake inhibitor, is hypothesized to produce beneficial effects in patient with ADD by augmenting NE release in prefrontal cortex. MATERIALS AND METHODS: We assessed the effects of systemic administration of atomoxetine (0.0, 0.1, 0.3, and 0.9 mg/kg/ml) in normal and noradrenergically lesioned (NE-LX) rats on attentional-set shifts. We replicated findings showing NE-LX rats are selectively impaired on the ED shifts but not reversals or other discriminations. RESULTS: Atomoxetine remediated the attentional set-shifting impairments in NE-LX rats but impaired ED performance of non-lesioned rats. DISCUSSION: Though atomoxetine is neurochemically selective, it is not wholly specific at doses >0.3 mg/kg. All doses of the drug were similar in their efficacy in reversing the ED deficit, but the effectiveness of the 0.1 mg/kg dose supports the hypothesis that increases in prefrontal NE alone are sufficient to improve attention in NE-LX rats. Moreover, the detrimental effects of the drug in non-lesioned rats support the hypothesis that optimal levels of NE in prefrontal cortex are critical to attentional set shifting with both supra- and sub-optimal levels producing attentional impairments.     

Comparative analysis of lesion development and intraspinal inflammation in four strains of mice following spinal contusion injury

Susceptibility to neuroinflammatory disease is influenced in part by genetics. Recent data indicate that survival of traumatized neurons is strain dependent and influenced by polygenic loci that control resistance/susceptibility to experimental autoimmune encephalomyelitis (EAE), a model of CNS autoimmune disease. Here, we describe patterns of neurodegeneration and intraparenchymal inflammation after traumatic spinal cord injury (SCI) in mice known to exhibit varying degrees of EAE susceptibility [EAE-resistant (r) or EAE-susceptible (s) mice]. Spinal cords from C57BL/6 (EAE-s), C57BL/10 (EAE-r), BALB/c (EAE-r), and B10.PL (EAE-s) mice were prepared for stereological and immunohistochemical analysis at 6 hours or 3, 7, 14, 28, or 42 days following midthoracic (T9) spinal contusion injury. In general, genetic predisposition to EAE predicted the magnitude of intraparenchymal inflammation but not lesion size/length or locomotor recovery. Specifically, microglia/macrophage activation, recruitment of neutrophils and lymphocytes, and de novo synthesis of MHC class II were greatest in C57BL/6 mice and least in BALB/c mice at all times examined. However, lesion volume and axial spread of neurodegeneration were similar in C57BL/6 and BALB/c mice and were significantly greater than in C57BL/10 or B10.PL mice. Strains with marked intraspinal inflammation also developed the most intense lesion fibrosis. Thus, strain-dependent neuroinflammation was observed after SCI, but without a consistent relationship to EAE susceptibility or lesion progression. Only in C57BL/6 mice was the magnitude of intraspinal inflammation predictive of secondary neurodegeneration, functional recovery, or fibrosis.     

Crossmodal divided attention in rats: effects of chlordiazepoxide and scopolamine

Divided attention is a psychological construct that hinges on assumptions about a fixed finite capacity of subjects to simultaneously process multiple sets of information. A model of a crossmodal divided attention task was developed in rats. Initially, rats were trained consecutively in operant auditory and visual conditional discrimination tasks. The final task consisted of two successive blocks of 20 trials per modality (modality certainty), followed by 60 trials comprising a semi-randomized sequence of stimuli of both modalities (auditory or visual) and qualities (flashing/pulsing or constantly turned on; modality uncertainty). In comparison to unimodal blocks of trials, performance in the mixed condition was assumed to reflect the demands on the parallel processing of two sets of stimulus-response rules. While response accuracy remained unchanged, response latencies were generally longer in the bimodal condition. Administration of scopolamine (0.03, 0.06, 0.1 mg/kg) or chlordiazepoxide (1, 3, 5, 8 mg/kg) dose-dependently increased response latencies. The scopolamine-induced increase in response latencies was greater in the mixed condition. Cost-benefit analyses demonstrated that the absolute divided attention costs (in ms) were generally higher for visual than for auditory stimuli. Both drugs produced qualitatively similar effects; however, scopolamine was more potent in increasing the absolute divided attention costs than chlordiazepoxide. These data are discussed in terms of the validity of this animal paradigm, and of hypotheses about the effects of benzodiazepine receptor agonists and muscarinic antagonists on brain information processing capacity.     

Hematogenous macrophages express CD8 and distribute to regions of lesion cavitation after spinal cord injury

Historically, CD4 and CD8 antigens have been used to designate functionally distinct T-lymphocyte subsets. However, these antigens also have been described on macrophages in the normal and pathologic central nervous system (CNS). Signaling through CD4 or CD8 may impart unique functions in macrophage subsets that express these antigens. In the current study, the distribution and temporal patterns of expression of CD4 and CD8 were evaluated on various cell types within the traumatically injured spinal cord. The data reveal divergent patterns of CD4 and CD8 expression on unique macrophage populations. Specifically, we show sustained elevations of CD4 expression on microglia and macrophages throughout the lesion site and spared white matter. In contrast, CD8 is predominantly associated with hematogenous macrophages that are recruited from the blood during the first week postinjury. The distribution of CD8-positive cells is restricted to areas of necrotic cavitation. Differential signaling of resident and recruited macrophages through CD4 or CD8 may explain the apparent dichotomy of CNS-macrophage-mediated injury and repair.     

The role of cortical cholinergic afferent projections in cognition: impact of new selective immunotoxins

Previous investigations aimed at determining the role of corticopetal cholinergic afferents in cognition have relied upon human psychopharmacological studies, neuropsychological analyses of Alzheimer's patients, or psychopharmacological manipulations and excitotoxic lesions in animals. Unfortunately, each approach has its limitations. The interpretation of neuropsychological data relies upon correlations of post-mortem assessments of cholinergic degeneration that may be quite temporally distant from the time of cognitive assessment. In contrast, the use of animals allows direct manipulations of the cholinergic system and the establishment of causal relationships between acetylcholine and cognitive function but is limited by the selectivity of the toxins and drugs available to manipulate the system. The recent introduction of immunotoxins to lesion cortical cholinergic pathways with greater selectivity has allowed the effective testing of these hypotheses of cholinergic functions in cognition. Previous neuropsychological, psychopharmacological and excitotoxic lesion data are reviewed and compared to results produced using the more selective immunotoxins to provide an update to the current hypotheses of the role of corticopetal cholinergic afferents in cognitive function. Additionally, the conceptual and methodological cost and benefits of the methods of infusion used to produce lesions with these immunotoxins is assessed.     

Interaction of age,cognitive function,and gait performance in 50–80-year-olds

The variability of walking gait timing increases with age and is strongly related to fall risk. The purpose of the study was to examine the interaction of age, cognitive function, and gait performance during dual-task walking. Forty-two, healthy men and women, 50–80 years old, completed the Mini-Mental State Exam (MMSE) and Trail Making Test (TMT) to assess cognitive performance and were separated into groups by decade of life. They then performed dual-task walking, at a self-selected pace, on an instrumented treadmill during three cognitive loading conditions: (1) no cognitive load, (2) subtraction from 100 by 1s, and (3) subtraction from 100 by 3s. The treadmill recorded spatiotemporal gait parameters that were used to calculate the mean and coefficient of variation for each variable over ten strides. Time to complete the TMT was positively correlated with age, stride time, double-limb support time, and mediolateral instability and was inversely correlated with single-limb support time. Subjects in their 70s increased their stride time and double-limb support time during the most challenging dual-task condition (subtraction by 3s), whereas subjects in their 50s and 60s did not. Across conditions, the variability of stride length, stride time, and single-limb support time was greatest in the 70s. Mediolateral instability increased only for subjects in their 70s in the subtraction by 3s condition. Reduced cognitive function with age makes it difficult for older adults to maintain a normal, rhythmical gait pattern while performing a cognitive task, which may place them at greater risk for falling.     

Experimental sleep fragmentation impairs attentional set-shifting in rats

STUDY OBJECTIVE: To evaluate the effect of experimental sleep fragmentation (sleep interruption; SI) on complex learning in an intradimensional-extradimensional (ID/ED) set-shifting task in rats. DESIGN: A sleep fragmentation paradigm of intermittent forced locomotion was validated in adult rats by examining electrographic effects. Discrimination task performances were assessed in rats following sleep fragmentation or 2 control conditions. PARTICIPANTS: 41 young adult male Fischer-Norway rats. INTERVENTION: A treadmill was used to produce 30 awakenings/h for the 24-h period prior to testing. Exercise control rats received an equivalent amount of treadmill-induced locomotion that permitted 30-minute pauses to allow consolidated sleep. MEASUREMENT AND RESULTS: SI rats were selectively impaired on the extradimensional-shift phase of the task, taking significantly more trials to achieve criterion performance (15.4 +/- 2.0) than either control group (cage control = 10.4 +/- 0.9; exercise control = 6.3 +/- 0.2). The SI schedule reduced the average duration of nonREM sleep (NREMS) episodes to 56 s (baseline = 182 s), while the exercise control group increased average NREMS episode duration to 223 s. Total (24-h) NREMS time declined from 50% during baseline to 33% during SI, whereas rapid eye movement sleep (REMS) was absent in SI animals (7% during baseline and 0% during SI), and time spent awake increased proportionally (from 43% during baseline to 67% during SI). CONCLUSION: 24-hour SI produced impairment in an attentional set-shifting that is comparable to the executive function and cognitive deficits observed in humans with sleep apnea or after a night of experimental sleep fragmentation.