Nicotine Facilitation of Conditioned Place Preference to Food Reward in Humans.

BACKGROUND: Nicotine has recently been shown to enhance the motivational value of non-nicotine stimuli in nonhumans. To investigate whether nicotine also enhances reward in humans, we used a virtual translation of the conditioned place preference (CPP) paradigm to examine nicotine's reward-enhancing effects using a low-dose 2 mg nicotine lozenge targeted to a mild use population. Methods: Sixty-eight nicotine-using undergraduates were randomly assigned to receive either a 2 mg nicotine or placebo lozenge prior to conditioning. During each of six, three-minute conditioning sessions, participants were confined to one of two VR rooms. In one room, they received real chocolate M&Ms, whereas no M&Ms were administered in the other room. Following conditioning, a three-minute free-access test session occurred during which participants had unrestricted access to both rooms without reward. Results: Individuals who received nicotine demonstrated a CPP by spending significantly more time in the room previously paired with M&Ms compared to the unrewarded room (p = 0.04). Those who received placebo did not demonstrate a CPP (p > 0.05). Moreover, we observed no significant differences between treatment groups in terms of the amount of time spent in each virtual room. Conclusion: While nicotine seems to facilitate CPP expression for a virtual environment previously paired with chocolate food rewards, further characterization of the mechanism by which this occurs is needed.

Avoidance biases for vaping stimuli among college students with electronic-cigarette use.

Previous research has suggested that individuals who smoke demonstrate a behavioral tendency to approach rather than avoid smoking-related stimuli (i.e., approach bias). This study assessed whether 149 undergraduates with varying levels of e-cigarette use demonstrated an approach bias for vaping-related stimuli on an Approach-Avoidance Task (AAT). In contrast to our hypotheses, participants with e-cigarette use demonstrated a significant avoidance bias to vaping-related stimuli, and this effect appeared to be primarily driven by female e-cigarette users. Further, we found that more severe e-cigarette use was associated with numerous adverse outcomes, including reduced quality of life and increased vaping cravings, depressive symptoms, perceived stress, and cannabis use severity. Overall, our findings elucidate various negative impacts of e-cigarette use and suggest a potential role for sex differences in approach-avoidance tendencies toward vaping-related stimuli among young adults.

Conditioned place preferences for virtual alcohol cues.

This study examined whether a conditioned place preference (CPP) could be established for a virtual reality (VR) room that previously contained virtual alcohol stimuli. 298 undergraduates with varying levels of alcohol use completed six, three-minute conditioning sessions in which they were confined to one of two visually-distinct VR rooms: one of the VR rooms contained virtual alcohol cues (CS+) while the other VR room was neutral (CS-). Following conditioning, participants completed a three-minute test session during which they had unrestricted access to both VR rooms and neither room contained any alcohol-related cues. Although no virtual alcohol cues were present, participants with alcohol use (n = 248) spent significantly longer in CS+ relative to CS- compared to participants with alcohol non-use (n = 50) during the test session. This is the first study to show that a CPP can be established using virtual alcohol cues, in the absence of any actual alcohol administration. However, participants with alcohol use did not subjectively report enjoying CS+ more than CS- and explicitly chose CS- as their preferred room. Interestingly, these findings suggest that implicit and explicit measures of CPP may tap into distinct, separable processes and should be investigated further.

The effect of acute nicotine administration on human delay cued and context fear conditioning.

Nicotine has been shown to facilitate hippocampal-dependent context fear conditioning (FC), but not hippocampal-independent delay cued fear conditioning. Studies examining the effects of nicotine on learned fear have been exclusively limited to nonhumans. The present study aimed to translate nonhuman findings by investigating the effects of nicotine on cued and context fear in humans using a virtual reality (VR) analog of the fear conditioning task. Sixty-seven nicotine-using undergraduates were randomly assigned to receive either a 2 mg nicotine or placebo lozenge prior to conditioning. During conditioning, participants were confined to a virtual room and were conditioned to green floodlight presentations (conditioned stimulus [CS +]) paired with a wrist shock (unconditioned stimulus [US]). A red floodlight served as the CS- during which no shock occurred. Delay cued and context fear testing immediately followed conditioning. Physiological skin conductance responses (SCRs) were recorded continuously throughout all sessions. Nicotine enhanced context fear conditioning such that SCRs to the shock-paired context were significantly greater for the nicotine group than the placebo group. Nicotine did not enhance delay cued fear. Exploratory analyses examining the relationship between fear conditioning and self-reported anxiety revealed that relative to those with lower levels of trait anxiety, nicotine-treated individuals with higher trait anxiety levels were less likely to demonstrate differential conditioning to the shock-paired cue. These findings support abundant nonhuman literature indicating that nicotine facilitates hippocampus-dependent versions of fear conditioning in humans. Results also suggest a role for dysregulated safety learning in pathological anxiety, which may be exacerbated by nicotine use. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Avoidance tendencies toward cannabis stimuli in a college sample.

Individuals with addictions often exhibit approach bias, or the relatively automatic action tendency to approach rather than avoid addiction-related stimuli. The current study used a cannabis-Approach-Avoidance Task (AAT) to assess approach-avoidance tendencies toward cannabis stimuli among 211 undergraduate college students with varying levels of cannabis use. Frequency and severity of cannabis use was assessed using the Cannabis Use Disorder Identification Test - Short Form (CUDIT-R). The sample did not demonstrate a significant approach or avoidance bias toward cannabis stimuli; instead, participants were significantly slower to approach and avoid cannabis stimuli relative to neutral stimuli. Individuals with problematic cannabis use who met criteria for a possible cannabis use disorder (CUD) based on CUDIT-R criteria were significantly slower to avoid but not to approach cannabis stimuli compared to individuals with nonuse and non-problematic use. Moreover, increased frequency and severity of cannabis use was significantly associated with increased reaction times to avoid cannabis stimuli. Findings appear to differ from some previous studies examining approach-avoidance tendencies toward cannabis, suggesting that the role of cognitive biases in cannabis use is complex and should be further investigated.

Estradiol effects on spatial memory in women.

To examine the role of estradiol in hippocampal-dependent spatial memory in women, 86 female undergraduates were tested in a virtual Morris water task (VMWT), a virtual radial arm maze (VRAM), and a mental rotation task (MRT) within a single daily session. The VMWT and RAM were also administered 24 h later to examine the effects of estradiol on memory consolidation. Women on oral contraceptives (OCs) or those who were naturally cycling and exhibited low estradiol (LE) or high estradiol (HE), as determined by salivary assays, were included. At the start of day two, the HE group showed superior spatial reference memory on the VMWT relative to the LE group, as evidenced by significantly shorter distances navigating to the hidden platform. The LE group also had the poorest probe trial performance at the start of day two compared to both other groups. There were no group differences in performance on the RAM or MRT. These results provide support for estradiol's role in the consolidation of spatial reference memory in women, and emphasize the differential sensitivities of various virtual memory tasks in assessing spatial memory function in women.

Disruptions in functional network connectivity during alcohol intoxicated driving.

BACKGROUND: Driving while under the influence of alcohol is a major public health problem whose neural basis is not well understood. In a recently published functional magnetic resonance imaging (fMRI) study (Meda et al., 2009), our group identified 5, independent critical driving-associated brain circuits whose inter-regional connectivity was disrupted by alcohol intoxication. However, the functional connectivity between these circuits has not yet been explored in order to determine how these networks communicate with each other during sober and alcohol-intoxicated states. METHODS: In the current study, we explored such differences in connections between the above brain circuits and driving behavior, under the influence of alcohol versus placebo. Forty social drinkers who drove regularly underwent fMRI scans during virtual reality driving simulations following 2 alcohol doses, placebo and an individualized dose producing blood alcohol concentrations (BACs) of 0.10%. RESULTS: At the active dose, we found specific disruptions of functional network connectivity between the frontal-temporal-basal ganglia and the cerebellar circuits. The temporal connectivity between these 2 circuits was found to be less correlated (p < 0.05) when driving under the influence of alcohol. This disconnection was also associated with an abnormal driving behavior (unstable motor vehicle steering). CONCLUSIONS: Connections between frontal-temporal-basal ganglia and cerebellum have recently been explored; these may be responsible in part for maintaining normal motor behavior by integrating their overlapping motor control functions. These connections appear to be disrupted by alcohol intoxication, in turn associated with an explicit type of impaired driving behavior.

Approach bias for erotic stimuli among heterosexual female college students who use pornography.

Repeated engagement in addictive behaviors may lead to relatively automatic action tendencies whereby individuals approach rather than avoid addictive stimuli. This study assessed whether an approach bias for erotic stimuli exists among heterosexual college-aged females who report using pornography. We tested 121 female undergraduates using an approach-avoidance task (AAT) employing both erotic and neutral stimuli, during which participants were instructed to push or pull a gaming joystick in response to image orientation. To simulate approach and avoidance movements, pulling the joystick enlarged the image and pushing shrunk the image. Severity of pornography use was assessed using the Brief Pornography Screener (BPS) and the Problematic Pornography Use Scale (PPUS). Participants demonstrated a significant approach bias of 24.81 ms for erotic stimuli as compared to neutral stimuli, and this approach bias significantly positively correlated with PPUS scores. Moreover, approach bias scores were significantly positively correlated with anhedonia (as assessed by the Snaith-Hamilton Pleasure Scale), indicating that the stronger the degree of approach for erotic stimuli, the more anhedonia that was observed. Anhedonia was not significantly associated with pornography use severity, however. Findings implicate both similarities and differences in problematic pornography use among female and male users. A limitation of the current study is that it assessed approach biases among only heterosexual females due to the erotic stimuli employed during the AAT. Future studies should examine approach biases among females of varying sexual orientations.

Alcohol dose effects on brain circuits during simulated driving: an fMRI study.

Driving while intoxicated remains a major public health hazard. Driving is a complex task involving simultaneous recruitment of multiple cognitive functions. The investigators studied the neural substrates of driving and their response to different blood alcohol concentrations (BACs), using functional magnetic resonance imaging (fMRI) and a virtual reality driving simulator. We used independent component analysis (ICA) to isolate spatially independent and temporally correlated driving-related brain circuits in 40 healthy, adult moderate social drinkers. Each subject received three individualized, separate single-blind doses of beverage alcohol to produce BACs of 0.05% (moderate), 0.10% (high), or 0% (placebo). 3 T fMRI scanning and continuous behavioral measurement occurred during simulated driving. Brain function was assessed and compared using both ICA and a conventional general linear model (GLM) analysis. ICA results replicated and significantly extended our previous 1.5T study (Calhoun et al. [2004a]: Neuropsychopharmacology 29:2097-2017). GLM analysis revealed significant dose-related functional differences, complementing ICA data. Driving behaviors including opposite white line crossings and mean speed independently demonstrated significant dose-dependent changes. Behavior-based factors also predicted a frontal-basal-temporal circuit to be functionally impaired with alcohol dosage across baseline scaled, good versus poorly performing drivers. We report neural correlates of driving behavior and found dose-related spatio-temporal disruptions in critical driving-associated regions including the superior, middle and orbito frontal gyri, anterior cingulate, primary/supplementary motor areas, basal ganglia, and cerebellum. Overall, results suggest that alcohol (especially at high doses) causes significant impairment of both driving behavior and brain functionality related to motor planning and control, goal directedness, error monitoring, and memory.

Absence of established sex differences in patients with schizophrenia on a two-dimensional object array task.

Sex differences are pervasive in schizophrenia, ranging from differences in the age of onset and symptoms of the illness to structural brain differences. Yet, there has been very little research on the interaction of these differences with established cognitive sex differences that exist in healthy populations. We tested 25 patients with schizophrenia and 17 healthy controls on a two-dimensional task of object location memory. It has been previously shown that healthy females outperform healthy males on this task, a result that was upheld in this experiment. However, the female advantage is completely absent in patients with schizophrenia. This finding has important implications for the interpretation of clinical and physiological sex differences present in schizophrenia.

Approach bias for erotic stimuli in heterosexual male college students who use pornography.

BACKGROUND AND AIMS: Addicted individuals often demonstrate relatively automatic action tendencies in response to addiction-related stimuli, whereby they approach rather than avoid addictive stimuli. This study assessed whether an approach bias for erotic stimuli exists among heterosexual college-aged males who report using pornography. METHODS: We tested 72 male undergraduate students using an approach-avoidance task employing erotic stimuli, during which participants were instructed to push or pull a joystick in response to image orientation. To simulate approach and avoidance movements, pulling the joystick enlarged the image and pushing shrunk the image. Frequency and severity of pornography use was assessed using a Brief Pornography Screener and the Problematic Pornography Use Scale (PPUS). RESULTS: Participants demonstrated a significant approach bias for erotic stimuli as compared to neutral stimuli, and this approach bias significantly correlated with pornography-use measures. Moreover, individuals with problematic pornography use (as classified by the PPUS) showed more than double the approach bias than did non-problematic users. DISCUSSION AND CONCLUSION: The observation of cognitive biases for erotic stimuli in individuals with problematic pornography use indicate similarities between behavioral and substance addictions.

Relationships between drinking quantity and frequency and behavioral and hippocampal BOLD responses during working memory performance involving allocentric spatial navigation in college students.

BACKGROUND: Quantity and frequency of drinking may be used to effectively quantify the severity of alcohol-use. Drinking-severity has been related to neurocognitive impairments in such domains as spatial working memory (SWM). Youth drinking has been associated with altered neurofunctional underpinnings of SWM. The current study examined the relationship between drinking-severity and SWM processing. METHODS: One-hundred-and-seventy college drinkers reported the maximum number of drinks in a 24 -h period in the last six-months (quantity) and average number of drinking weeks in the last six-months (frequency). All participants performed a virtual Morris Water Task during fMRI which included trials where the target platform was visible or hidden. RESULTS: Greater quantity was associated with reduced SWM-related activity in the dorsolateral prefrontal cortex (F(1, 167) = 4.15, p = .04). Greater frequency was associated with reduced SWM-related activity in the hippocampus (F(1, 167) = 4.34, p = 0.039). Greater quantity was associated with longer search times (r = 0.21, p = .005) and greater platforms found (r = 0.19, p = .01) in VISIBLE trials. We did not find a relationship between drinking quantity or frequency and gender on SWM-related activity, although men found more platforms in both HIDDEN (F(1, 168) = 11.7, p = 0.0008) and VISIBLE (F(1, 168) = 23.0, p < .0001) trials compared to women. CONCLUSIONS: Altered SWM-related hippocampal function relating to alcohol use in young adults raises questions regarding the impact on young adult health and the nature of the findings. Future studies should examine whether these differences may lead to cognitive deficits later in life.

Factors affecting the hippocampal BOLD response during spatial memory.

The hippocampus has long been implicated in spatial memory, from work in rodents to imaging and brain lesion studies in humans. However, recent evidence has pointed to the recruitment of areas outside the hippocampus proper on spatial memory tasks, including the parahippocampal gyrus and precuneus, possibly suggesting a more focused role for the hippocampus proper. In this study, a virtual version of the standard rodent spatial memory assessment, the Morris water task, has been employed during fMRI to investigate the differential involvement of these distinct brain areas. Twenty-eight healthy participants completed a block designed version of the virtual Morris water task (vMWT) which consisted of three conditions: (1) a hippocampal dependent condition during which the participants were forced to use distal room cues in the virtual environment to navigate to a hidden platform; (2) a non-hippocampal dependent condition during which participants were to navigate to a visible platform; (3) a fixation period. Activations of the BOLD signal were evident in the hidden condition as compared to the visible condition in the parahippocampal gyrus, precuneus, and fusiform when analyzed using to a blocked analysis. Moreover, this blocked analysis revealed increases in the right hippocampal BOLD signal during fixation. However, when hidden trials were compared to visible trials using a post hoc event-related analysis focused on the beginning of each trial, activations of the right hippocampus are evident. These results support the theory that extra-hippocampal structures contribute to spatial memory behavior and identify a temporally specific involvement of the hippocampus. Furthermore, they substantiate previous results reporting hippocampal BOLD increases during fixation.

The effects of nicotine on conditioning, extinction, and reinstatement in humans.

Nicotine has been shown to enhance the reinforcement and reward-responsiveness of non-nicotine stimuli. To determine whether nicotine enhances the strength of conditioning to context, undergraduate participants with varying levels of nicotine dependence were recruited for a two-day study and tested on a virtual reality (VR) conditioned place preference (CPP) paradigm. On day one, participants explored two virtual rooms where they received multiple pairings of M&M rewards in one room and no rewards in the other room, followed by a free-access test session with no rewards. On day two, participants received three test sessions to assess extinction. Subsequently, participants received M&Ms. in a novel context and were then tested for reinstatement. Prior to testing on each day, subjects were administered either nicotine (4mg) or placebo lozenges, in a between-subjects, four-group, 2×2 design (nicotine or placebo on days 1 and 2). After conditioning on day one, only participants who received placebo exhibited a CPP by spending significantly more time in the room previously-paired with M&Ms. Contrary to our hypothesis, nicotine-treated participants did not display a significant CPP, and there were no significant differences between treatment groups. However, post hoc analysis indicated that in a subset of participants with greater nicotine dependence, the nicotine group displayed a CPP by rating the M&M-paired room as significantly more enjoyable than those who received placebo. Additionally, while neither treatment group showed significant place preferences during the first two extinction sessions on Day 2, individuals who received nicotine on Day 1 or placebo on Day 2 spent significantly more time in the M&M-paired room during the final extinction session. Finally, those who received nicotine on Day 2 exhibited significantly greater reinstatement compared to placebo-treated participants. These results partially support preclinical evidence that nicotine can affect learning, extinction, and reinstatement.

Sex differences in visual-spatial learning using a virtual water maze in pre-pubertal children.

Gonadal steroid effects during puberty are often hypothesized to account for the male advantage seen in certain spatial tasks. One spatial task where males consistently show better performance than females is the Morris Water Task in which subjects must navigate to a goal location in a pool. We examined whether sex differences exist in pre-pubertal children completing a Virtual Morris Water Task, which has previously shown strong sex differences in adults. Pre-pubertal boys show superior performance to similar-aged girls, as evidenced by shorter latencies to find the platform and stronger preferences for the platform location during a probe trial. These results suggest that sex differences in spatial learning and memory exist prior to puberty and do not appear to require the effects of sex hormones at puberty. Rather, these differences may reflect early-life hormonal effects on hippocampal-dependent processes and may suggest different preferential learning strategies by boys and girls.

A virtual reality apartment as a measure of medication management skills in patients with schizophrenia: a pilot study.

Performance on a novel, virtual reality (VR) assessment of medication management skills, the Virtual Reality Apartment Medication Management Assessment (VRAMMA), was investigated in 25 patients with schizophrenia and 18 matched healthy controls. The VRAMMA is a virtual 4-room apartment consisting of a living room with an interactive clock and TV, a bedroom, a kitchen, and a bathroom with an interactive medicine cabinet. After an exploratory phase, participants were given a mock prescription regimen to be taken 15 minutes later from pill bottles located in the medicine cabinet in the bathroom of the virtual environment. The VRAMMA was administered with a validated measure of medication management skills, several neurocognitive tests, and a symptom scale. Results revealed that (1) schizophrenic patients made significantly more quantitative errors in the number of pills taken, were less accurate at taking the prescribed medications at the designated time, and checked the interactive clock less frequently than healthy controls; (2) in patients with schizophrenia, there was significant agreement in classification of adherence vs nonadherence between a validated measure of medication management skills and the VRAMMA; and (3) in patients with schizophrenia, years of education and a measure of verbal learning and memory were linked to quantitative errors on the VRAMMA, while positive symptoms, specifically delusional symptoms, were inversely linked to distance traveled within the VRAMMA. This is the first study, to our knowledge, to provide evidence for the utility of VR technology in the assessment of instrumental role functioning in patients with schizophrenia.

Virtual reality conditioned place preference using monetary reward.

Computerized tasks based on conditioned place preference (CPP) methodology offer the opportunity to study learning mechanisms involved in conditioned reward in humans. In this study, we examined acquisition and extinction of a CPP for virtual environments associated with monetary reward ($). Healthy men and women (N=57) completed a computerized CPP task in which they controlled an avatar within a virtual environment. On day 1, subjects completed 6 conditioning trials in which one room was paired with high $ and another with low $. Acquisition of place conditioning was assessed by measuring the time spent in each room during an exploration test of the virtual environments and using self-reported ratings of room liking and preference. Twenty-four hours later, retention and extinction of CPP were assessed during 4 successive exploration tests of the virtual environments. Participants exhibited a place preference for (spent significantly more time in) the virtual room paired with high $ over the one paired with low $ (p=0.015). They also reported that they preferred the high $ room (p<0.001) and liked it significantly more than the low $ room (p<0.001). However, these preferences were short-lived: 24h later subjects did not exhibit a behavioral or subjective preference for the high $ room. These findings show that individuals exhibit transient behavioral and subjective preferences for a virtual environment paired with monetary reward. Variations on this task may be useful to study mechanisms and brain substrates involved in conditioned reward and to examine the influence of drugs upon appetitive conditioning.

A functional magnetic resonance imaging study of working memory abnormalities in schizophrenia.

BACKGROUND: Previous neuroimaging studies of working memory (WM) in schizophrenia, typically focusing on dorsolateral prefrontal cortex, yield conflicting results, possibly because of varied choice of tasks and analysis techniques. We examined neural function changes at several WM loads to derive a more complete picture of WM dysfunction in schizophrenia. METHODS: We used a version of the Sternberg Item Recognition Paradigm to test WM function at five distinct loads. Eighteen schizophrenia patients and 18 matched healthy controls were scanned with functional magnetic resonance imaging at 3 Tesla. RESULTS: Patterns of both overactivation and underactivation in patients were observed depending on WM load. Patients' activation was generally less responsive to load changes than control subjects', and different patterns of between-group differences were observed for memory encoding and retrieval. In the specific case of successful retrieval, patients recruited additional neural circuits unused by control subjects. Behavioral effects were generally consistent with these imaging results. CONCLUSIONS: Differential findings of overactivation and underactivation may be attributable to patients' decreased ability to focus and allocate neural resources at task-appropriate levels. Additionally, differences between encoding and retrieval suggest that WM dysfunction may be manifested differently during the distinct phases of encoding, maintenance, and retrieval.

Simulated driving and brain imaging: combining behavior, brain activity, and virtual reality.

INTRODUCTION: Virtual reality in the form of simulated driving is a useful tool for studying the brain. Various clinical questions can be addressed, including both the role of alcohol as a modulator of brain function and regional brain activation related to elements of driving. OBJECTIVE: We reviewed a study of the neural correlates of alcohol intoxication through the use of a simulated-driving paradigm and wished to demonstrate the utility of recording continuous-driving behavior through a new study using a programmable driving simulator developed at our center. METHODS: Functional magnetic resonance imaging data was collected from subjects while operating a driving simulator. Independent component analysis (ICA) was used to analyze the data. Specific brain regions modulated by alcohol, and relationships between behavior, brain function, and alcohol blood levels were examined with aggregate behavioral measures. Fifteen driving epochs taken from two subjects while also recording continuously recorded driving variables were analyzed with ICA. RESULTS: Preliminary findings reveal that four independent components correlate with various aspects of behavior. An increase in braking while driving was found to increase activation in motor areas, while cerebellar areas showed signal increases during steering maintenance, yet signal decreases during steering changes. Additional components and significant findings are further outlined. CONCLUSION: In summary, continuous behavioral variables conjoined with ICA may offer new insight into the neural correlates of complex human behavior.

Virtual reality assessment of medication compliance in patients with schizophrenia.

Medication compliance is essential to treating the symptoms of schizophrenia effectively. This study utilized a virtual reality (VR) apartment paradigm to assess medication compliance behaviors in 25 patients with schizophrenia and in 16 healthy control subjects. Participants were assigned a prescription consisting of three medications and were asked to self-administer this regimen in 15 min. Results demonstrate that patients had considerably more difficulty in complying with the medication regimen than did controls. They manifested significantly more quantitative errors, and were much less accurate in consuming the medications at the assigned time. Significant differences in performance between these groups were also evidenced by a variety of validated neuropsychological measures. Correlations between the data may suggest a convergent validity for this new VR task. Future research will investigate the validity of this task in predicting additional measures of psychosocial functioning.