Neural correlates of chocolate brand preference: A functional MRI study.

BACKGROUND AND PURPOSE: Preferences can be developed for, or against, specific brands and services. Using two functional magnetic resonance imaging (fMRI) experiments, this study investigated two dissociable aspects of reward processing, craving and liking, in chocolate lovers. The goal was to further delineate the neural basis supporting branding effects using familiar chocolate (FC) and unfamiliar chocolate (UC) brand images. METHODS: In the first experiment, subjects rated their subjective craving and liking on a scale of 1-5 (weak-strong) for each FC and UC image. In the second experiment, they performed a choice task between FC and UC images. RESULTS: Both the craving and liking ratings were significantly greater for FC and were differentially correlated with choice behavior. Craving ratings predicted greater preference for UC, and liking ratings predicted greater preference for FC. A contrast of neural activity for UC versus FC choice trials revealed significantly greater activation for UC choices in the bilateral inferior frontal gyrus and right caudate head. Response times for the FC images were faster than UC images; fMRI activity in the ventromedial prefrontal cortex was significantly correlated with response times during FC trials, but not UC trials. These correlations were significantly different from each other at the group level. CONCLUSIONS: The choices for branded chocolate products are driven by higher subjective reward ratings and lower neural processing demands.

Risky decision-making strategies mediate the relationship between amygdala activity and real-world financial savings among individuals from lower income households: A pilot study.

Lower financial savings among individuals experiencing adverse social determinants of health (SDoH) increases vulnerabilities during times of crisis. SDoH including low socioeconomic status (low-SES) influence cognitive abilities as well as health and life outcomes that may perpetuate poverty and disparities. Despite evidence suggesting a role for financial growth in minimizing SDoH-related disparities and vulnerabilities, neurobiological mechanisms linked with financial behavior remain to be elucidated. As such, we examined the relationships between brain activity during decision-making (DM), laboratory-based task performance, and money savings behavior. Participants (N = 24, 14 females) from low-SES households (income<$20,000/year) underwent fMRI scanning while performing the Balloon Analogue Risk Task (BART), a DM paradigm probing risky- and strategic-DM processes. Participants also completed self-report instruments characterizing relevant personality characteristics and then engaged in a community outreach financial program where amount of money saved was tracked over a 6-month period. Regarding BART-related brain activity, we observed expected activity in regions implicated in reward and emotional processing including the amygdala. Regarding brain-behavior relationships, we found that laboratory-based BART performance mediated the impact of amygdala activity on real-world behavior. That is, elevated amygdala activity was linked with BART strategic-DM which, in turn, was linked with more money saved after 6 months. In exploratory analyses, this mediation was moderated by emotion-related personality characteristics such that, only individuals reporting lower alexithymia demonstrated a relationship between amygdala activity and savings. These outcomes suggest that DM-related amygdala activity and/or emotion-related personality characteristics may provide utility as an endophenotypic marker of individual's financial savings behavior.

Reward Processing in Children With Disruptive Behavior Disorders and Callous-Unemotional Traits in the ABCD Study.

OBJECTIVE: Disrupted reward processing is implicated in the etiology of disruptive behavior disorders (DBDs) and callous-unemotional traits. However, neuroimaging investigations of reward processing underlying these phenotypes remain sparse. The authors examined neural sensitivity in response to reward anticipation and receipt among youths with DBDs, with and without callous-unemotional traits. METHODS: Data were obtained from the Adolescent Brain and Cognitive Development Study (mean age=9.51 years [SD=0.50]; 49% female). Reward-related activation during the monetary incentive delay task was examined across 16 brain regions, including the amygdala, anterior cingulate cortex (ACC), nucleus accumbens (NAcc), and orbitofrontal cortex (OFC). Latent variable modeling was used to examine network-level coactivation. The following diagnostic groups were compared: typically developing youths (N=693) and youths with DBDs (N=995), subdivided into those with callous-unemotional traits (DBD+CU, N=198) and without callous-unemotional traits (DBD only, N=276). RESULTS: During reward anticipation, youths in the overall DBD group (with and without callous-unemotional traits) showed decreased dorsal ACC activation compared with typically developing youths. The DBD-only group exhibited reduced ventral and dorsal striatal activity compared with the DBD+CU and typically developing groups. During reward receipt, youths with DBDs showed increased cortical (e.g., OFC) and subcortical (e.g., NAcc) regional activation compared with typically developing youths. The DBD+CU group demonstrated greater activation in several regions compared with those in the typically developing (e.g., amygdala) and DBD-only (e.g., dorsal ACC) groups. At the network level, the DBD-only group showed reduced anticipatory reward activation compared with the typically developing and DBD+CU groups, whereas youths in the DBD+CU group showed increased activation during reward receipt compared with those in the typically developing group. CONCLUSIONS: These findings advance our understanding of unique neuroetiologic pathways to DBDs and callous-unemotional traits.

Disruptive Behavior Problems, Callous-Unemotional Traits, and Regional Gray Matter Volume in the Adolescent Brain and Cognitive Development Study.

BACKGROUND: Neurobiological differences linked to socioemotional and cognitive processing are well documented in youths with disruptive behavior disorders (DBDs), especially youths with callous-unemotional (CU) traits. The current study expanded this literature by examining gray matter volume (GMV) differences among youths with DBD with CU traits (DBDCU+), youths with DBD without CU traits (DBD-only), and youths that were typically developing (TD). METHODS: Data were from the first full sample release of the Adolescent Brain and Cognitive Development Study (mean age = 9.49 years; 49% female). We tested whether the GMVs of 11 regions of interest selected a priori differentiated between our 3 groups: DBDCU+ (n = 288), DBD-only (n = 362), and TD (n = 915). Models accounted for demographic confounders, attention-deficit/hyperactivity disorder, and intracranial volume. We examined two potential moderators of the relationship between GMVs and group membership: sex and clinically significant anxiety (i.e., primary vs. secondary CU traits subtype). RESULTS: Youths in the DBDCU+ group had lower right amygdala GMV, and youths in the DBD-only group had lower bilateral amygdala GMV relative to TD youths. Youths in the DBDCU+ group had lower bilateral hippocampal GMV, and youths in the DBD-only group had lower left hippocampal GMV relative to TD youths. Youths in the DBDCU+ group evidenced lower left insula GMV relative to TD youths. Finally, youths in the DBD-only group had lower left superior frontal gyrus and lower right caudal anterior cingulate cortex GMVs relative to TD youths. There was no moderation of associations between GMV and group membership by sex. CONCLUSIONS: Our findings implicate structural aberrations in both the amygdala and hippocampus in the etiology of DBDs, with minimal evidence for differences based on the presence or absence of CU traits.

Different patterns of age-related central olfactory decline in men and women as quantified by olfactory fMRI.

Age-related olfactory decline, or presbyosmia, is a prevalent condition with potentially devastating consequences on both quality of life and safety. Despite clear evidence for this decline, it is unknown whether presbyosmia is sex-dependent and also whether it is due to central or peripheral olfactory system deterioration. Therefore, the goals of this study were to investigate the neurofunctional substrate of olfactory decline and examine its relationship to age and sex in thirty-seven (18 women, 19 men) healthy older participants using olfactory functional MRI (fMRI). The olfactory fMRI paradigm utilized unique odor+visual and visual-only conditions to contrast peripheral-to-central and central-to-central olfactory processing, respectively. Age was negatively correlated with fMRI activation in olfactory-related regions. Significant aging effects were identifiable in male participants in all target regions. Female participants, however, showed a different pattern of functional decline. Extended unified structural equation modeling (euSEM) analysis revealed that the effective functional connectivity profile was drastically different between male and female participants, with females manifesting a top-down mechanism to offset age-related olfactory activation decline. Our results support the hypotheses that the central olfactory system is involved in age-related olfactory decline, and that resilience to age-related olfactory decline in women may be due to their profuse olfactory network effective connectivity.

Dynamic functional connectivity and individual differences in emotions during social stress.

Exposure to acute stress induces multiple emotional responses, each with their own unique temporal dynamics. Dynamic functional connectivity (dFC) measures the temporal variability of network synchrony and captures individual differences in network neurodynamics. This study investigated the relationship between dFC and individual differences in emotions induced by an acute psychosocial stressor. Sixteen healthy adult women underwent fMRI scanning during a social evaluative threat (SET) task, and retrospectively completed questionnaires that assessed individual differences in subjectively experienced positive and negative emotions about stress and stress relief during the task. Group dFC was decomposed with parallel factor analysis (PARAFAC) into 10 components, each with a temporal signature, spatial network of functionally connected regions, and vector of participant loadings that captures individual differences in dFC. Participant loadings of two networks were positively correlated with stress-related emotions, indicating the existence of networks for positive and negative emotions. The emotion-related networks involved the ventromedial prefrontal cortex, cingulate cortex, anterior insula, and amygdala, among other distributed brain regions, and time signatures for these emotion-related networks were uncorrelated. These findings demonstrate that individual differences in stress-induced positive and negative emotions are each uniquely associated with large-scale brain networks, and suggest that dFC is a mechanism that generates individual differences in the emotional components of the stress response. Hum Brain Mapp 38:6185-6205, 2017. © 2017 Wiley Periodicals, Inc.

Age-related resting-state functional connectivity in the olfactory and trigeminal networks.

Brain networks for intranasal chemosensation have been shown to be intrinsically organized in humans . However, little is known about how changes in the intrinsic functional connectivity (FC) in chemosensory networks are related to aging. We, therefore, investigated the impact of age on resting-state FC in the olfactory and trigeminal networks (ON and TN) by combining two freely available resting-state fMRI data sets (obtained from the NITRC.org; Atlanta and New York) with data collected in our lab to generate a large sample size (N=103; 51 women) spanning the age range of 20-61 years. Seed regions were defined using Montreal Neurological Institute's coordinates that anchor ON and TN in activation studies and meta-analyses. The ON included the piriform cortex and the oribtofrontal cortex. The TN included the anterior insula and the cingulate cortex. Scanner site, sex, and age were used as covariates in group-level analyses. The FC between the ON and the parahippocampal gyrus was correlated negatively with age. The FC between the TN and the parahippocampal gyrus, however, was positively correlated. Similarly, age was correlated positively with the ON FC to the ventral striatum and the TN FC to the default mode network. These results reflect divergent age-related alterations in the intrinsic FC of the human chemosensory system.

Tool selection and the ventral-dorsal organization of tool-related knowledge.

Tool selection is a cognitive process necessary for tool use, and may rely on distinct knowledge under different conditions. This fMRI experiment was designed to identify neural substrates mediating tool selection under different conditions. Participants performed a picture-matching task that presented a recipient object and an action-goal, and required the selection of the best tool object from among four candidates. Some trials allowed selection of the prototypical tool, whereas others forced selection of either a functionally substitutable or impossible tool. Statistical contrasts revealed significantly different activation between Proto and Sub conditions in frontal, parietal, and temporal lobes. The middle temporal gyrus (MTG) bilaterally, and the right posterior cingulate were more strongly activated by prototypical tool selection, and left inferior parietal lobule (IPL), intraparietal sulcus (IPS), middle frontal gyrus, and precuneus were more strongly activated when selecting substitutable objects. These findings are concordant with previous neuroimaging studies of tool use knowledge in demonstrating that activation of the MTG represents functional knowledge for conventional tool usage, and activation of the IPL/IPS supports action (i.e., praxic) knowledge representations. These results contribute to the literature that dissociates the roles of ventral and dorsal streams in tool-related knowledge and behavior, and emphasize the role of the left hemisphere for processing goal-directed object interactions.

Default mode network deactivation during odor-visual association.

Default mode network (DMN) deactivation has been shown to be functionally relevant for goal-directed cognition. In this study, the DMN's role during olfactory processing was investigated using two complementary functional magnetic resonance imaging (fMRI) paradigms with identical timing, visual-cue stimulation, and response monitoring protocols. Twenty-nine healthy, non-smoking, right-handed adults (mean age = 26 ± 4 years, 16 females) completed an odor-visual association fMRI paradigm that had two alternating odor + visual and visual-only trial conditions. During odor + visual trials, a visual cue was presented simultaneously with an odor, while during visual-only trial conditions the same visual cue was presented alone. Eighteen of the twenty-nine participants (mean age = 27.0 ± 6.0 years, 11 females) also took part in a control no-odor fMRI paradigm that consisted of a visual-only trial condition which was identical to the visual-only trials in the odor-visual association paradigm. Independent Component Analysis (ICA), extended unified structural equation modeling (euSEM), and psychophysiological interaction (PPI) were used to investigate the interplay between the DMN and olfactory network. In the odor-visual association paradigm, DMN deactivation was evoked by both the odor + visual and visual-only trial conditions. In contrast, the visual-only trials in the no-odor paradigm did not evoke consistent DMN deactivation. In the odor-visual association paradigm, the euSEM and PPI analyses identified a directed connectivity between the DMN and olfactory network which was significantly different between odor + visual and visual-only trial conditions. The results support a strong interaction between the DMN and olfactory network and highlights the DMN's role in task-evoked brain activity and behavioral responses during olfactory processing. Hum Brain Mapp 38:1125-1139, 2017. © 2016 Wiley Periodicals, Inc.

Context-specific behavioral surprise is differentially correlated with activity in anterior and posterior brain systems.

This experiment investigated whether behavioral surprise, an information-theoretic measure of the amount of memory and information integration associated with a response, is correlated with neural activity during decision making. A total of 30 participants (age 18-30) were scanned with functional MRI while completing 240 trials of a sequential decision-making task in which they selected an amount to wager from four possible values on each trial. Behavioral surprise was computed trial by trial using both context-free and context-specific formulations, and was used as a parametric modulator in functional MRI analyses. Whereas context-free surprise was not significantly correlated, two sets of clusters (P<0.005; cluster size>156 voxels) were differentially modulated by context-specific behavioral surprise. An anterior system comprised of the inferior frontal gyrus and anterior cingulate (each bilaterally), and left caudate, was positively modulated. A posterior system comprised of the posterior cingulate, parahippocampal gyrus and posterior hippocampus (each bilaterally), and left angular gyrus, was negatively modulated. These anticorrelated systems indicate that more surprising (resource demanding) actions recruit greater activity from the anterior system and less activity from the posterior system and less surprising actions (memory-guided) recruit greater activity from the posterior system and less activity from the anterior system. These results show that context-specific behavioral surprise is a unique neural signal and may be related to mechanisms for both cognitive control and memory-guided behavior, and support contemporary theories that the brain is a statistical observer of external and internal events.

Intrinsic intranasal chemosensory brain networks shown by resting-state functional MRI.

The human brain is organized into functional networks for sensory-motor and cognitive processing. Intrinsic networks are detectable in the absence of stimulation or task demands, whereas extrinsic networks are detectable when stimulated by sensory or cognitive demands. Intranasal chemosensory processing relies on two dissociable networks for processing incoming trigeminal and olfactory stimulation, but it is not known whether these networks are intrinsically organized. The aim of this study was to identify whether brain networks for intranasal chemosensory processing are detectable in functional connectivity resting-state functional MRI (fMRI). Sixteen healthy adults participated in a 5-min resting-state fMRI study. Functional connectivity seeds were defined from coordinates that anchor olfactory (i.e. bilateral piriform and orbitofrontal cortex) and trigeminal (bilateral anterior insula and cingulate cortex) networks in published task activation studies, and the resulting networks were thresholded at P less than 0.001. The olfactory network showed extended functional connectivity to the thalamus, medial prefrontal cortex, caudate, nucleus accumbens, parahippocampal gyrus, and hippocampus. The trigeminal network showed extended functional connectivity to the precuneus, thalamus, caudate, brainstem, and cerebellum. Both networks overlapped in the thalamus, caudate, medial prefrontal cortex, and insula. These results show that brain networks for intranasal chemosensory processing are intrinsically organized, not just extrinsically instantiated in response to task demands, and resemble networks for processing olfactory and trigeminal stimulation. As such, it may be possible to study the functional organization and dynamics of the olfactory network in resting-state fMRI as well as its implications for aging and disease.

Altered behavioral and neural responsiveness to counterfactual gains in the elderly.

Counterfactual information processing refers to the consideration of events that did not occur in comparison to those actually experienced, in order to determine optimal actions, and can be formulated as computational learning signals, referred to as fictive prediction errors. Decision making and the neural circuitry for counterfactual processing are altered in healthy elderly adults. This experiment investigated age differences in neural systems for decision making with knowledge of counterfactual outcomes. Two groups of healthy adult participants, young (N = 30; ages 19-30 years) and elderly (N = 19; ages 65-80 years), were scanned with fMRI during 240 trials of a strategic sequential investment task in which a particular strategy of differentially weighting counterfactual gains and losses during valuation is associated with more optimal performance. Elderly participants earned significantly less than young adults, differently weighted counterfactual consequences and exploited task knowledge, and exhibited altered activity in a fronto-striatal circuit while making choices, compared to young adults. The degree to which task knowledge was exploited was positively correlated with modulation of neural activity by expected value in the vmPFC for young adults, but not in the elderly. These findings demonstrate that elderly participants' poor task performance may be related to different counterfactual processing.

Rapidly acquired multisensory association in the olfactory cortex.

BACKGROUND: The formation of an odor percept in humans is strongly associated with visual information. However, much less is known about the roles of learning and memory in shaping the multisensory nature of odor representations in the brain. METHOD: The dynamics of odor and visual association in olfaction was investigated using three functional magnetic resonance imaging (fMRI) paradigms. In two paradigms, a visual cue was paired with an odor. In the third, the same visual cue was never paired with an odor. In this experimental design, if the visual cue was not influenced by odor-visual pairing, then the blood-oxygen-level-dependent (BOLD) signal elicited by subsequent visual cues should be similar across all three paradigms. Additionally, intensity, a major dimension of odor perception, was used as a modulator of associative learning which was characterized in terms of the spatiotemporal behavior of the BOLD signal in olfactory structures. RESULTS: A single odor-visual pairing cue could subsequently induce primary olfactory cortex activity when only the visual cue was presented. This activity was intensity dependent and was also detected in secondary olfactory structures and hippocampus. CONCLUSION: This study provides evidence for a rapid learning response in the olfactory system by a visual cue following odor and visual cue pairing. The novel data and paradigms suggest new avenues to explore the dynamics of odor learning and multisensory representations that contribute to the construction of a unified odor percept in the human brain.

The effect of estrogen synthesis inhibition on hippocampal memory.

17-Beta-estradiol (E2) facilitates long term-potentiation (LTP) and increases spine synapse density in hippocampal neurons of ovariectomized rodents. Consistent with these beneficial effects on the cellular level, E2 improves hippocampus-dependent memory. A prominent approach to study E2 effects in rodents is the inhibition of its synthesis by letrozole, which reduces LTPs and spine synapse density. In the current longitudinal functional magnetic resonance imaging (fMRI) study, we translated this approach to humans and compared the impact of E2 synthesis inhibition on memory performance and hippocampal activity in post-menopausal women taking letrozole (n = 21) to controls (n = 24). In particular, we employed various behavioral memory paradigms that allow the disentanglement of hippocampus-dependent and -independent memory. Consistent with the literature on rodents, E2 synthesis inhibition specifically impaired hippocampus-dependent memory, however, this did not apply to the same degree to all of the employed paradigms. On the neuronal level, E2 depletion tended to decrease hippocampal activity during encoding, whereas it increased activity in the anterior cingulate and the dorsolateral prefrontal cortex. We thus infer that the inhibition of E2 synthesis specifically impairs hippocampal functioning in humans, whereas the increased prefrontal activity presumably reflects a compensatory mechanism, which is already known from studies on cognitive aging and Alzheimer's disease.

Differential lateralization of hippocampal connectivity reflects features of recent context and ongoing demands: an examination of immediate post-task activity.

Neuroimaging studies have shown that task demands affect connectivity patterns in the human brain not only during task performance but also during subsequent rest periods. Our goal was to determine whether ongoing connectivity patterns during rest contain information about both the current rest state, as well as the recently terminated task. Our experimental design consisted of two types of active tasks that were followed by two types of low-demand rest states. Using this design, we examined whether hippocampal functional connectivity during wakeful rest reflects both features of a recently terminated task and those of the current resting-state condition. We identified four types of networks: (i) one whose connectivity with the hippocampus was determined only by features of a recently terminated task, (ii) one whose connectivity was determined only by features of the current resting-state, (iii) one whose connectivity reflected aspects of both the recently terminated task and ongoing resting-state features, and (iv) one whose connectivity with the hippocampus was strong, but not affected by any external factor. The left and right hippocampi played distinct roles in these networks. These findings suggest that ongoing hippocampal connectivity networks mediate information integration across multiple temporal scales, with hippocampal laterality moderating these connectivity patterns.

Risk-sensitive reinforcement learning.

We derive a family of risk-sensitive reinforcement learning methods for agents, who face sequential decision-making tasks in uncertain environments. By applying a utility function to the temporal difference (TD) error, nonlinear transformations are effectively applied not only to the received rewards but also to the true transition probabilities of the underlying Markov decision process. When appropriate utility functions are chosen, the agents' behaviors express key features of human behavior as predicted by prospect theory (Kahneman & Tversky, 1979 ), for example, different risk preferences for gains and losses, as well as the shape of subjective probability curves. We derive a risk-sensitive Q-learning algorithm, which is necessary for modeling human behavior when transition probabilities are unknown, and prove its convergence. As a proof of principle for the applicability of the new framework, we apply it to quantify human behavior in a sequential investment task. We find that the risk-sensitive variant provides a significantly better fit to the behavioral data and that it leads to an interpretation of the subject's responses that is indeed consistent with prospect theory. The analysis of simultaneously measured fMRI signals shows a significant correlation of the risk-sensitive TD error with BOLD signal change in the ventral striatum. In addition we find a significant correlation of the risk-sensitive Q-values with neural activity in the striatum, cingulate cortex, and insula that is not present if standard Q-values are used.

Neural systems mediating recognition of changes in statistical regularities.

Neuroimaging research has identified several brain systems sensitive to statistical regularities within environmental input. However, the continuous input impinging on sensory organs is rarely stationary and its degree of regularity may itself change over time. The goals of the current fMRI study were to identify systems sensitive to changes in statistical regularities within an ongoing stimulus, and determine to what extent sensitivity to such changes depends on intentional monitoring of order. We predicted that changes in regularity would be coded for in systems previously associated with statistical coding (hippocampus and middle frontal regions) or event segmentation (posterior medial regions). Participants listened to a rapid train of four different tones whose order levels fluctuated over time. In an active task, participants monitored the tones and indicated when they perceived a change in regularity; in a passive task, they performed a concurrent visuo-motor task and could ignore the auditory input. Behavioral responses in the active task were used to define points of consensus between participants regarding changes in regularity. Activity in 7.5s epochs that preceded these order-change points was contrasted with activity during matched-length epochs where no participant indicated a change in order. We found that brain regions differentiating these two types of epochs matched those identified in prior research as mediating event segmentation in narratives and movies. These consisted mainly of medial posterior parietal and occipital regions, with limited involvement of temporal and lateral frontal cortices and no hippocampal involvement. In both tasks, order-change epochs were associated with a higher BOLD response than stable-order epochs, but the specific regions showing this pattern varied across tasks. We suggest that partitioning an input stream on the basis of statistical shifts constitutes a basic neural function underlying the ability to segment both semantic and non-semantic inputs. We further discuss the implications of these findings for neurobiological theories of statistical coding and event segmentation.

Multiple sensitivity profiles to diversity and transition structure in non-stationary input.

Recent formalizations suggest that the human brain codes for the degree of order in the environment and utilizes this knowledge to optimize perception and performance in the immediate future. However, the neural bases of how the brain spontaneously codes for order are poorly understood. It has been shown that activity in lateral temporal cortex and the hippocampus is linearly correlated with the order of short visual series under tasks requiring attention to the input and when series order is invariant over time. Here, we examined if sensitivity to order is manifested in both linear and non-linear BOLD response profiles, quantified the degree to which order-sensitive regions operate as a functional network, and evaluated these questions using a paradigm in which performance of the ongoing task could be completed without any attention to the stimulus whose order was manipulated. Participants listened to a 10-minute sequence of tones characterized by non-stationary order, and fMRI identified cortical regions sensitive to time-varying statistical features of this input. Activity in perisylvian regions was negatively correlated with input diversity, quantified via Shannon's Entropy. Activity in ventral premotor, lateral temporal, and insular regions was correlated linearly, parabolically, or via a step-function with the strength of transition constraints in the series, quantified via Markov Entropy. Granger-causality analysis revealed that order-sensitive regions form a functional network, with regions showing non-linear responses to order associated with more afferent connectivity than those showing linear responses. These findings identify networks that spontaneously code and respond to diverse aspects of order via multiple response profiles, and that play a central role in generating and gating predictive neural activity.

Delay eyeblink classical conditioning is impaired in Fragile X syndrome.

The authors examined 400 ms delay eyeblink classical conditioning in 20 participants with Fragile X syndrome ages 17 to 77 years, and 20 age-matched, healthy control participants. The participants in the Fragile X group demonstrated impaired learning and abnormal conditioned response timing. Adults with Fragile X (n=16) were also tested at two successive 12-month follow-up sessions to examine reacquisition and long-term retention. Participants in groups who were older and younger than 45 years demonstrated significant learning during each reacquisition session. Younger participants demonstrated greater retention of the conditioned stimulus/unconditioned stimulus association at each follow-up session than older participants. Fragile X impairs the acquisition and timing of conditioned eyeblink responses, but with repeated training adults with Fragile X syndrome show significant plasticity.

Preclinical investigation of the functional effects of memantine and memantine combined with galantamine or donepezil.

Combinations of drugs approved to treat Alzheimer's disease (AD) were tested in older rabbits with delay eyeblink classical conditioning, a form of associative learning severely impaired in AD. In Experiment 1 (n=49 rabbits), low doses (0.1, 0.5, 1.0, and 0.0 (vehicle) mg/kg) of memantine (Namenda) were tested. These three doses neither improved nor impaired acquisition at a statistically significant level. The 0.5 mg/kg dose had the greatest effect numerically and did not cause sensitization or habituation in explicitly unpaired controls. In Experiment 2 (n=56), doses of galantamine (Razadyne; 3.0 mg/kg) and donepezil (Aricept; 0.75 mg/kg) that had comparable magnitudes of cholinesterase inhibition were tested alone and in combination with 0.5 mg/kg memantine. Older rabbits treated with galantamine and with galantamine+memantine learned significantly better than vehicle-treated rabbits, but adding memantine did not improve learning over galantamine alone. Older rabbits treated with donepezil or a combination of memantine and donepezil did not learn significantly better than rabbits treated with vehicle. Galantamine has two mechanisms of action: mild cholinesterase inhibition and allosteric modulation of nicotinic acetylcholine receptors (nAChRs). When equated for cholinesterase inhibition, galantamine had significant efficacy in the eyeblink conditioning model system, but donepezil did not, indicating that modulation of nAChRs may be the mechanism that significantly ameliorates learning deficits in this model. In the absence of AD neuropathology in older rabbits, memantine had no efficacy alone or in combination with the other drugs.