Adult rat cortical thickness changes across age and following adolescent intermittent ethanol treatment.

Human studies have established that adolescence is a period of brain maturation that parallels the development of adult behaviors. However, little is known regarding cortical development in the adult rat brain. We used magnetic resonance imaging (MRI) and histology to assess the impact of age on adult Wistar rat cortical thickness on postnatal day (P)80 and P220 as well as the effect of adolescent binge ethanol exposure on adult (P80) cortical thickness. MRI revealed changes in cortical thickness between P80 and P220 that differ across cortical region. The adult P220 rat prefrontal cortex increased in thickness whereas cortical thinning occurred in both the cingulate and parietal cortices relative to young adult P80 rats. Histological analysis confirmed the age-related cortical thinning. In the second series of experiments, an animal model of adolescent intermittent ethanol (AIE; 5.0 g/kg, intragastrically, 20 percent ethanol w/v, 2 days on/2 days off from P25 to P55) was used to assess the effects of alcohol on cortical thickness in young adult (P80) rats. MRI revealed that AIE resulted in region-specific cortical changes. A small region within the prefrontal cortex was significantly thinner whereas medial cortical regions were significantly thicker in young adult (P80) AIE-treated rats. The observed increase in cortical thickness was confirmed by histology. Thus, the rat cerebral cortex continues to undergo cortical thickness changes into adulthood, and adolescent alcohol exposure alters the young adult cortex that could contribute to brain dysfunction in adulthood.

Diffusion tensor imaging reveals adolescent binge ethanol-induced brain structural integrity alterations in adult rats that correlate with behavioral dysfunction.

Adolescence is characterized by considerable brain maturation that coincides with the development of adult behavior. Binge drinking is common during adolescence and can have deleterious effects on brain maturation because of the heightened neuroplasticity of the adolescent brain. Using an animal model of adolescent intermittent ethanol [AIE; 5.0 g/kg, intragastric, 20 percent EtOH w/v; 2 days on/2 days off from postnatal day (P)25 to P55], we assessed the adult brain structural volumes and integrity on P80 and P220 using diffusion tensor imaging (DTI). While we did not observe a long-term effect of AIE on structural volumes, AIE did reduce axial diffusivity (AD) in the cerebellum, hippocampus and neocortex. Radial diffusivity (RD) was reduced in the hippocampus and neocortex of AIE-treated animals. Prior AIE treatment did not affect fractional anisotropy (FA), but did lead to long-term reductions of mean diffusivity (MD) in both the cerebellum and corpus callosum. AIE resulted in increased anxiety-like behavior and diminished object recognition memory, the latter of which was positively correlated with DTI measures. Across aging, whole brain volumes increased, as did volumes of the corpus callosum and neocortex. This was accompanied by age-associated AD reductions in the cerebellum and neocortex as well as RD and MD reductions in the cerebellum. Further, we found that FA increased in both the cerebellum and corpus callosum as rats aged from P80 to P220. Thus, both age and AIE treatment caused long-term changes to brain structural integrity that could contribute to cognitive dysfunction.

Adolescent alcohol exposure reduces behavioral flexibility, promotes disinhibition, and increases resistance to extinction of ethanol self-administration in adulthood.

The prefrontal cortex (PFC) is a brain region that is critically involved in cognitive function and inhibitory control of behavior, and adolescence represents an important period of continued PFC development that parallels the maturation of these functions. Evidence suggests that this period of continued development of the PFC may render it especially vulnerable to environmental insults that impact PFC function in adulthood. Experimentation with alcohol typically begins during adolescence when binge-like consumption of large quantities is common. In the present study, we investigated the effects of repeated cycles of adolescent intermittent ethanol (AIE) exposure (postnatal days 28-42) by vapor inhalation on different aspects of executive functioning in the adult rat. In an operant set-shifting task, AIE-exposed rats exhibited deficits in their ability to shift their response strategy when the rules of the task changed, indicating reduced behavioral flexibility. There were no differences in progressive ratio response for the reinforcer suggesting that AIE did not alter reinforcer motivation. Examination of performance on the elevated plus maze under conditions designed to minimize stress revealed that AIE exposure enhanced the number of entries into the open arms, which may reflect either reduced anxiety and/or disinhibition of exploratory-like behavior. In rats that trained to self-administer ethanol in an operant paradigm, AIE increased resistance to extinction of ethanol-seeking behavior. This resistance to extinction was reversed by positive allosteric modulation of mGluR5 during extinction training, an effect that is thought to reflect promotion of extinction learning mechanisms within the medial PFC. Consistent with this, CDPPB was also observed to reverse the deficits in behavioral flexibility. Finally, diffusion tensor imaging with multivariate analysis of 32 brain areas revealed that while there were no differences in the total brain volume, the volume of a subgroup of regions (hippocampus, thalamus, dorsal striatum, neocortex, and hypothalamus) were significantly different in AIE-exposed adults compared with litter-matched Control rats. Taken together, these findings demonstrate that binge-like exposure to alcohol during early to middle adolescence results in deficits in PFC-mediated behavioral control in adulthood.

Comparison of magnetic resonance imaging in live vs. post mortem rat brains.

Magnetic Resonance Imaging (MRI) is an increasingly popular technique for examining neurobiology in rodents because it is both noninvasive and nondestructive. MRI scans can be acquired from either live or post mortem specimens. In vivo scans have a key advantage in that subjects can be scanned at multiple time-points in longitudinal studies. However, repeated exposure to anesthesia and stress may confound studies. In contrast, post mortem scans offer improved image quality and increased signal-to-noise ratio (SNR) due to several key advantages: First, the images are not disrupted by motion and pulsation artifacts. Second, they allow the brain tissue to be perfused with contrast agents, enhancing tissue contrast. Third, they allow longer image acquisition times, yielding higher resolution and/or improved SNR. Fourth, they allow assessment of groups of animals at the same age without scheduling complications. Despite these advantages, researchers are often skeptical of post mortem MRI scans because of uncertainty about whether the fixation process alters the MRI measurements. To address these concerns, we present a thorough comparative study of in vivo and post mortem MRI scans in healthy male Wistar rats at three age points throughout adolescence (postnatal days 28 through 80). For each subject, an in vivo scan was acquired, followed by perfusion and two post mortem scans at two different MRI facilities. The goal was to assess robustness of measurements, to detect any changes in volumetric measurements after fixation, and to investigate any differential bias that may exist between image acquisition techniques. We present this volumetric analysis for comparison of 22 anatomical structures between in vivo and post mortem scans. No significant changes in volumetric measurements were detected; however, as hypothesized, the image quality is dramatically improved in post mortem scans. These findings illustrate the validity and utility of using post mortem scans in volumetric neurobiological studies.

Neural mechanisms of risky decision-making and reward response in adolescent onset cannabis use disorder.

BACKGROUND: Neural mechanisms of decision-making and reward response in adolescent cannabis use disorder (CUD) are underexplored. METHODS: Three groups of male adolescents were studied: CUD in full remission (n=15); controls with psychopathology without substance use disorder history (n=23); and healthy controls (n=18). We investigated neural processing of decision-making and reward under conditions of varying risk and uncertainty with the Decision-Reward Uncertainty Task while participants were scanned using functional magnetic resonance imaging. RESULTS: Abstinent adolescents with CUD compared to controls with psychopathology showed hyperactivation in one cluster that spanned left superior parietal lobule/left lateral occipital cortex/precuneus while making risky decisions that involved uncertainty, and hypoactivation in left orbitofrontal cortex to rewarded outcomes compared to no-reward after making risky decisions. Post hoc region of interest analyses revealed that both control groups significantly differed from the CUD group (but not from each other) during both the decision-making and reward outcome phase of the Decision-Reward Uncertainty Task. In the CUD group, orbitofrontal activations to reward significantly and negatively correlated with total number of individual drug classes the CUD patients experimented with prior to treatment. CUD duration significantly and negatively correlated with orbitofrontal activations to no-reward. CONCLUSIONS: The adolescent CUD group demonstrated distinctly different activation patterns during risky decision-making and reward processing (after risky decision-making) compared to both the controls with psychopathology and healthy control groups. These findings suggest that neural differences in risky decision-making and reward processes are present in adolescent addiction, persist after remission from first CUD treatment, and may contribute to vulnerability for adolescent addiction.

Behavioral risk elicits selective activation of the executive system in adolescents: clinical implications.

We investigated adolescent brain processing of decisions under conditions of varying risk, reward, and uncertainty. Adolescents (n = 31) preformed a Decision-Reward Uncertainty task that separates decision uncertainty into behavioral and reward risk, while they were scanned using functional magnetic resonance imaging. Behavioral risk trials involved uncertainty about which action to perform to earn a fixed monetary reward. In contrast, during reward risk the decision that might lead to a reward was known, but the likelihood of earning a reward was probabilistically determined. Behavioral risk trials evoked greater activation than the reward risk and no risk conditions in the anterior cingulate, medial frontal gyrus, bilateral frontal poles, bilateral inferior parietal lobe, precuneus, bilateral superior-middle frontal gyrus, inferior frontal gyrus, and insula. Our results were similar to those of young adults using the same task (Huettel, 2006) except that adolescents did not show significant activation in the posterior supramarginal gyrus during behavioral risk. During the behavioral risk condition regardless of reward outcome, overall mean frontal pole activity showed a positive correlation with age during the behavioral and reward risk conditions suggesting a developmental difference of this region of interest. Additionally, reward response to the Decision-Reward Uncertainty task in adolescents was similar to that seen in young adults (Huettel, 2006). Our data did not show a correlation between age and mean ventral striatum activity during the three conditions. While our results came from a healthy high functioning non-maltreated sample of adolescents, this method can be used to address types of risks and reward processing in children and adolescents with predisposing vulnerabilities and add to the paucity of imaging studies of risk and reward processing during adolescence.

The role of color diagnosticity in object recognition and representation.

The role of color diagnosticity in object recognition and representation was assessed in three Experiments. In Experiment 1a, participants named pictured objects that were strongly associated with a particular color (e.g., pumpkin and orange). Stimuli were presented in a congruent color, incongruent color, or grayscale. Results indicated that congruent color facilitated naming time, incongruent color impeded naming time, and naming times for grayscale items were situated between the congruent and incongruent conditions. Experiment 1b replicated Experiment 1a using a verification task. Experiment 2 employed a picture rebus paradigm in which participants read sentences one word at a time that included pictures of color diagnostic objects (i.e., pictures were substituted for critical nouns). Results indicated that the "reading" times of these pictures mirrored the pattern found in Experiment 1. In Experiment 3, an attempt was made to override color diagnosticity using linguistic context (e.g., a pumpkin was described as painted green). Linguistic context did not override color diagnosticity. Collectively, the results demonstrate that color information is regularly utilized in object recognition and representation for highly color diagnostic items.

Experiential simulations of negated text information.

We investigated the question of whether comprehenders mentally simulate a described situation even when this situation is explicitly negated in the sentence. In two experiments, participants read negative sentences such as There was no eagle in the sky, and subsequently responded to pictures of mentioned entities in the context of a recognition task. Participants' responses following negative sentences were faster when the depicted entity matched rather than mismatched the negated situation. These results suggest that comprehenders simulate the negated situation when processing a negated sentence. The results thereby provide further support for the experiential-simulations view of language comprehension.

Simulating visibility during language comprehension.

In this study, participants performed a sentence-picture verification task in which they read sentences about an agent viewing an object (e.g., moose) through a differentially occlusive medium (e.g., clean vs. fogged goggles), and then verified whether a subsequently pictured object was mentioned in the previous sentence. Picture verification latencies were shorter when the resolution of the pictured object and the resolution implied by the sentence matched than when they did not. These results suggest that the degree of visibility implied in linguistic context can influence immediate object interpretation. These data suggest that readers mentally simulate the visibility of objects during language comprehension. Thus, the simulation of linguistic descriptions is not limited to the activation of intrinsic object properties (e.g., object shape), but also invokes the perceptibility of referential objects given implied environmental context.

Perception of auditory motion affects language processing.

Previous reports have demonstrated that the comprehension of sentences describing motion in a particular direction (toward, away, up, or down) is affected by concurrently viewing a stimulus that depicts motion in the same or opposite direction. We report 3 experiments that extend our understanding of the relation between perception and language processing in 2 ways. First, whereas most previous studies of the relation between perception and language processing have focused on visual perception, our data show that sentence processing can be affected by the concurrent processing of auditory stimuli. Second, it is shown that the relation between the processing of auditory stimuli and the processing of sentences depends on whether the sentences are presented in the auditory or visual modality.

Attentional bias affects change detection.

Thirty smokers and 30 nonsmokers participated in a flicker study in which the role of attentional bias in change detection was examined. The participants observed picture pairs of everyday objects flicker on a computer screen until they detected the one object that had changed. In half of the pictures, a smoking-related object (e.g., a lighter) was included among smoking-unrelated objects (e.g., a spoon). Half of the smokers and half of the nonsmokers were aware of the experiment's focus, and the other half were not. The smokers exhibited shorter detection latencies than did the nonsmokers when a smoking object changed and longer detection latencies when a nonsmoking object changed while a smoking object was present, and they exhibited detection latencies similar to those of the nonsmokers when smoking objects were not present. Interestingly, the nonsmokers displayed the same attentional bias as the smokers when they were aware of the experiment's smoking focus, but they did not display any attentional bias when they were unaware. Thus, these findings provide evidence for long-term context-independent, as well as for short-term context-dependent, attentional bias.

Perception of motion affects language processing.

Recently developed accounts of language comprehension propose that sentences are understood by constructing a perceptual simulation of the events being described. These simulations involve the re-activation of patterns of brain activation that were formed during the comprehender's interaction with the world. In two experiments we explored the specificity of the processing mechanisms required to construct simulations during language comprehension. Participants listened to (and made judgments on) sentences that described motion in a particular direction (e.g. "The car approached you"). They simultaneously viewed dynamic black-and-white stimuli that produced the perception of movement in the same direction as the action specified in the sentence (i.e. towards you) or in the opposite direction as the action specified in the sentence (i.e. away from you). Responses were faster to sentences presented concurrently with a visual stimulus depicting motion in the opposite direction as the action described in the sentence. This suggests that the processing mechanisms recruited to construct simulations during language comprehension are also used during visual perception, and that these mechanisms can be quite specific.

Lateralization of object-shape information in semantic processing.

An experiment was conducted to examine whether perceptual information, specifically the shape of objects, is activated during semantic processing. Subjects judged whether a target word was related to a prime word. Prime-target pairs that were not associated, but whose referents had similar shapes (e.g. LADDER-RAILROAD) yielded longer "no" responses than unassociated prime-target pairs, suggesting that shape information had been activated. A visual-field manipulation showed that, in right-handed subjects, this effect was localized in the left hemisphere. This finding is consistent with behavioral, brain imaging, and lesion data, which suggest that object shape at the category level is represented in the left hemisphere.

The role of age and perceptual symbols in language comprehension.

Older and younger participants read sentences about objects and were then shown a picture of an object that either matched or mismatched the implied shape of the object in the sentence. Participants' response times were recorded when they judged whether the object had been mentioned in the sentence. Responses were faster in the shape-matching condition for all participants, but the mismatch effect was stronger for older than for younger adults, even when the larger variability of the older group's response times was controlled for. These results suggest that older adults may construct stronger situation models than younger adults.

Hemispheric differences in semantic-relatedness judgments.

Subjects judged the semantic relatedness of word pairs presented to the left or right visual field. The word pairs were presented one below the other. On critical trials, the words' referents had a typical spatial relation, with one referent oriented above the other (e.g. ATTIC/BASEMENT). The spatial relation of the words either matched or mismatched the spatial relation of their referents. When presented to the left hemisphere, the match or mismatch did not have an effect. However, there was a reliable mismatch effect for pairs presented to the right hemisphere. The results are interpreted in the context of perceptual theories of mental representation.

Spatial iconicity affects semantic relatedness judgments.

Three experiments were conducted to examine whether spatial iconicity affects semantic-relatedness judgments. Subjects made speeded decisions with regard to whether members of a simultaneously presented word pair were semantically related. In Experiment 1, the words were presented one above the other. In the experimental pair, the words denoted parts of larger objects (e.g., ATTIC-BASEMENT). The words were either in an iconic relation with their referents (e.g., ATTIC presented above BASEMENT) or in a reverse-iconic relation (BASEMENT above ATTIC). The reverse-iconic condition yielded significantly slower semantic-relatedness judgments than did the iconic condition. Experiments 2 and 3 showed that this effect did not occur when the words were presented horizontally, thus ruling out that the iconicity effect is due to the order in which the words are read. Two alternative explanations for this finding are discussed.

Language comprehenders mentally represent the shapes of objects.

We examined the prediction that people activate perceptual symbols during language comprehension. Subjects read sentences describing an animal or object in a certain location. The shape of the object or animal changed as a function of its location (e.g., eagle in the sky, eagle in a nest). However, this change was only implied by the sentences. After reading a sentence, subjects were presented with a line drawing of the object in question. They judged whether the object had been mentioned in the sentence (Experiment 1) or simply named the object (Experiment 2). In both cases, responses were faster when the pictured object's shape matched the shape implied by the sentence than when there was a mismatch. These results support the hypothesis that perceptual symbols are routinely activated in language comprehension.