Psychostimulants like cocaine and amphetamine are commonly abused by young adults who often state that they take these drugs to increase social or cognitive performance. The current study tested the hypothesis that individuals at early stages of occasional stimulant use show subtle executive dysfunctions such as verbal fluency deficits. 155 young (age 18-25), non-dependent occasional users of stimulants and 49 stimulant naïve comparison subjects performed the Delis-Kaplan Verbal Fluency test. Correlation and median split analyses were conducted to account for stimulant history and co-drug use. Compared to stimulant naïve subjects, occasional stimulant users generated significantly more responses on an over-learned verbal fluency task (Category Fluency), but at the expense of increased error rates (Set Loss and Repetition Errors). These performance differences were not related to lifetime uses of stimulants or marijuana. Taken together, these results support the hypothesis that individuals who are using stimulants occasionally exhibit subtle executive dysfunctions when required to generate verbal sets under time pressure. In particular, occasional stimulant users apply quickly but inaccurately verbal rules, which may represent a mix of diminished cognitive flexibility along with increased rigidity and impulsivity. This specific executive dysfunction may help to identify individuals at risk for stimulant use or dependence.
stimulant; cocaine; amphetamine; executive function; verbal fluency
Sensation seeking has been linked to increased risk taking and is therefore crucial in influencing behavioral outcomes of risk-taking behavior. Using functional magnetic resonance imaging (fMRI), the neural underpinnings of risk appraisal were studied in a large subject sample (n=188), stratified according to thrill and adventure seeking (TAS) ratings. As defined by a median split of the sample, low and high TAS groups were compared on a simple decision-making task completed during fMRI. The task was designed such that risk (i.e., magnitude of outcome) and gains (i.e., direction of outcome) could be mapped independently. Behavioral analysis indicated that high TAS individuals are more sensitive to rewards but less discriminating between risk with and without punishment and that low TAS individuals are less sensitive to rewards but quite sensitive to receiving punishments in risky situations. Imaging results on the group differences for the interaction between level of risk and level of gain showed differences in the right superior frontal gyrus (BA6), left insula (BA21), right nucleus accumbens, left lentiform nucleus, and left precuneus (BA7). The presented data suggest a neural model of risk processing in sensation seeking individuals such that the positive response to reward outweighs the impact of equivalent loss. This imbalance in approach/avoidance is evident in differences in the underlying neural substrates in TAS individuals and leads to greater risk behavior in the face of potential loss.
sensation seeking; fMRI; SFG; neural correlates; decision making; risk taking
A low level of response (i.e., a low LR) to alcohol is a genetically influenced phenotype that predicts later alcoholism. While the low LR reflects, at least in part, a low brain response to alcohol, the physiological underpinnings of the low LR have only recently been addressed.
Forty-nine drinking but not yet alcoholic matched pairs of 18-25-year-old subjects (N = 98; 53% female) with low and high LRs as established in separate alcohol challenges were evaluated in two event-related functional magnetic resonance imaging (fMRI) sessions (placebo and ~ 0.7 ml/kg of alcohol) while performing a validated stop signal task. The high and low LR groups had identical blood alcohol levels during the alcohol session.
Significant high versus low LR group and LR group × condition effects were observed in blood oxygen level dependent (BOLD) signal during error and inhibitory processing, despite similar LR-group performance on the task. In most clusters with significant (corrected p<.05, clusters >1344 μl) LR group × alcohol/placebo condition interactions, the low LR group demonstrated relatively less, whereas the high LR group demonstrated more, error and inhibition-related activation after alcohol compared to placebo.
This is one of the first fMRI studies to demonstrate significant differences between healthy groups with different risks for a future life threatening disorder. The results may suggest a brain mechanism that contributes to how a low LR might enhance the risk for future heavy drinking and alcohol dependence.
alcohol; reaction; risk; fMRI
Problems inhibiting non-adaptive behaviors have been linked to an increased risk for substance use and other risk taking behaviors in adolescence. This study examines the hypothesis that abnormalities in neural activation during inhibition in early adolescence may predict subsequent substance involvement.
Thirty eight adolescents from local area middle schools, ages 12–14, with very limited histories of substance use, underwent functional magnetic resonance imaging (fMRI) as they performed a go/no-go task of response inhibition and response selection. Adolescents and their parents were then followed annually with interviews covering substance use and other behaviors. Based on follow-up data, youth were classified as transitioning to heavy use of alcohol (TU; n=21), or as healthy controls (CON; n=17).
At baseline, prior to the onset of use, youth who later transitioned into heavy use of alcohol showed significantly less activation than those who went on to remain non to minimal users throughout adolescence. Activation reductions in TU at baseline were seen on no-go trials in 12 brain regions, including right inferior frontal gyrus, left dorsal and medial frontal areas, bilateral motor cortex, cingulate gyrus, left putamen, bilateral middle temporal gyri, and bilateral inferior parietal lobules (corrected p < .01, each cluster ≥ 32 contiguous voxels).
These results support the hypothesis that less neural activity during response inhibition demands predicts future involvement with problem behaviors such as alcohol and other substance use.
alcohol; adolescence; fMRI; inhibition; go/no-go
Animal approach-avoidance conflict paradigms have been used extensively to characterize effects of anxiolytic agents and probe neural circuitry related to anxiety. However, there are few behavioral approaches to measure conflict in human populations, limiting the translation of findings from animal conflict tasks to human clinical research. We developed a novel approach-avoidance conflict (AAC) paradigm involving situations in which the same decision is associated with “reward” (points) and “punishment” (negative affective stimuli). The AAC task was completed by 95 young adults (56 female) with varying levels of self-reported trait anxiety. As expected, conflict-related approach behavior correlated with self-reported motivation to approach reward and avoid punishment and greater reward level increased approach behavior. Additionally, females exhibited less approach behavior than males. Anxiety Sensitivity Index (Physical subscale) scores related negatively to approach behavior for males, while Behavioral Activation Scale (BAS, Fun Seeking subscale) scores related positively to approach behavior for females. Results support the utility of the AAC task as a behavioral test that has strong reverse translational features. Findings indicate that approach drives and anxiety sensitivity may be important in determining conflict behavior for females and males respectively. The approach-avoidance conflict task offers a novel, translational measure to probe neural systems underlying conflict behavior, motivational processes, and anxiety disorders.
Conflict; Reward; Anxiety; Avoidance; Decision making; Translational research
Prior neuroimaging studies support the hypothesis that anticipation, an important component of anxiety, may be mediated by activation within the insular and medial prefrontal cortices including the anterior cingulate cortex. However, there is an insufficient understanding of how affective anticipation differs across anxiety groups in emotional brain loci and networks. We examined 14 anxiety positive (AP) and 14 anxiety normative (AN) individuals completing an affective picture anticipation task during functional magnetic resonance imaging (fMRI). Brain activation was examined across groups for cued anticipation (to aversive or pleasant stimuli). Both groups showed greater activation in the bilateral anterior insula during cued differential anticipation (i.e., aversive vs. pleasant) and activation on the right was significantly higher in AP compared to AN subjects. Functional connectivity showed that the left anterior insula was involved in a similar network during pleasant anticipation in both groups. The left anterior insula during aversive and the right anterior insula during all anticipation conditions co-activated with a cortical network consisting of frontal and parietal lobes in the AP group to a greater degree. These results are consistent with the hypothesis that anxiety is related to greater anticipatory reactivity in the brain and that there may be functional asymmetries in the brain that interact with psychiatric traits.
Stimulants are used increasingly to enhance social (cocaine) or cognitive performance (stimulants normally prescribed, prescription stimulants, e.g. methylphenidate, amphetamines). Chronic use, on the other hand, has been associated with significant verbal memory and learning deficits. This study sought to determine whether subtle learning and memory problems characterize individuals who exhibit occasional but not chronic use of stimulants.
154 young (age 18–25) occasional, non-dependent stimulant users and 48 stimulant naïve comparison subjects performed the California Verbal Learning test (CVLT-II). Lifetime uses of stimulants and co-use of marijuana were considered in correlation and median split analyses.
Compared to stimulant naïve subjects, occasional stimulant users showed significant performance deficits, most pronounced in the verbal recall and recognition domains. Lifetime uses of stimulants and marijuana did not affect CVLT-II performance. The type of stimulant used, however, was of major relevance: users of cocaine only were less impaired, while cumulative use of prescription stimulants was associated with impaired verbal learning and memory capacities.
These results support the hypothesis of subtle and possibly pre-existing neurocognitive deficiencies in occasional users of stimulants, which may be related to the motivation of using these drugs. More importantly, despite beneficial short-term effects, cumulative use, particularly of prescription amphetamines and methylphenidate, intensifies these deficits.
Stimulant; cocaine; amphetamine; executive function; verbal learning; verbal memory
Aims: Alcohol acutely reduces agitation and is widely used in social situations, but the neural substrates of emotion processing during its intoxication are not well understood. We examine whether alcohol's social stress dampening effect may be via reduced activity in the cortical systems that subserve awareness of bodily sensations, and are associated with affective distress. Methods: Blood oxygen level-dependent activation was measured through 24 functional magnetic resonance imaging sessions in 12 healthy volunteers during an emotional face-processing task following ingestion of a moderate dose of alcohol and a placebo beverage. Results: Results revealed that bilateral anterior insula response to emotional faces was significantly attenuated following consumption of alcohol, when compared with placebo (clusters >1472 μl; corrected P < 0.05). Conclusion: Attenuated response in the anterior insula after alcohol intake may explain some of the decreased interoceptive awareness described during intoxication.
Several studies provide empirical evidence for the association between impulsivity and time perception. However, little is known about the neural substrates underlying this function. This investigation examined the influence of impulsivity on neural activation patterns during the encoding and reproduction of intervals with durations of 3, 9 and 18 seconds using event-related functional magnetic resonance imaging (fMRI). Twenty-seven subjects participated in this study, including 15 high impulsive subjects that were classified based on their self-rating. FMRI activation during the duration reproduction task was correlated with measures of two self-report questionnaires related to the concept of impulsivity (Barratt Impulsiveness Scale, BIS; Zimbardo Time Perspective Inventory, ZTPI). Behaviorally, those individuals who under-reproduced temporal intervals also showed lower scores on the ZTPI future perspective subscale and higher scores on the BIS. FMRI activation revealed an accumulating pattern of neural activity peaking at the end of the 9- and 18-s interval within right posterior insula. Activations of brain regions during the reproduction phase of the timing task, such as those related to motor execution as well as to the ‘core control network’ – encompassing the inferior frontal and medial frontal cortex, the anterior insula as well as the inferior parietal cortex – were significantly correlated with reproduced duration, as well as with BIS and ZTPI subscales. In particular, the greater activation in these regions the shorter were the reproduced intervals, the more impulsive was an individual and the less pronounced the future perspective. Activation in the core control network, thus, may form a biological marker for cognitive time management and for impulsiveness.
time perception; duration reproduction; impulsivity; time perspective; fMRI
This review presents a novel conceptualization of addiction, integrating the concepts of interoception (i.e., the CNS representation of visceral feelings) and alliesthesia (i.e., that rewarding properties of stimuli are dependent on the internal state of the individual) with existing theories. It is argued that the body state, as defined by the integration of interoceptive information, is a crucial arbiter of the risk for initiation of and transition to compulsive use of addictive compounds. Overall, individuals at risk for drug dependence are characterized by an altered internal bodily state that leads to a change in hedonic and incentive motivational properties of addictive drugs. Specifically, drug dependent individuals experience alliesthesia of interoceptive processing, leading to increased incentive motivational properties of the drug over time and thereby increasing the probability of subsequent use. This extension of previous theories of addiction to include interoception and alliesthesia is based upon a clearly delineated set of neural substrates mediating interoception, key elements of which also recently have been implicated in drug addiction. The model thereby provides new potential targets for interventions that are aimed at changing the internal state that puts the individual at risk for continued substance use.
Addiction; Insula; Interoception; Alliesthesia; Reward
Pregabalin (PGB) has shown potential as an anxiolytic for treatment of generalized and social anxiety disorder. PGB binds to voltage-dependent calcium channels, leading to upregulation of GABA inhibitory activity and reduction in the release of various neurotransmitters. Previous functional magnetic resonance imaging (fMRI) studies indicate that selective serotonin reuptake inhibitors and benzodiazepines attenuate amygdala, insula, and medial prefrontal cortex activation during anticipation and emotional processing in healthy controls. The aim of this study was to examine whether acute PGB administration would attenuate activation in these regions during emotional anticipation. In this double-blind, placebo-controlled, randomized crossover study, 16 healthy controls completed a paradigm involving anticipation of negative and positive affective images during fMRI approximately 1 h after administration of placebo, 50, or 200 mg PGB. Linear mixed model analysis revealed that PGB was associated with (1) decreases in left amygdala and anterior insula activation and (2) increases in anterior cingulate (ACC) activation, during anticipation of positive and negative stimuli. There was also a region of the anterior amygdala in which PGB dose was associated with increased activation during anticipation of negative and decreased activation during anticipation of positive stimuli. Attenuation of amygdala and insula activation during anticipatory or emotional processing may represent a common regional brain mechanism for anxiolytics across drug classes. PGB induced increases in ACC activation could be a unique effect related to top–down modulation of affective processing. These results provide further support for the viability of using pharmaco-fMRI to determine the anxiolytic potential of pharmacologic agents.
pregabalin; neuroimaging; insula; amygdala; anticipation; psychopharmacology; neuropharmacology; psychopharmacology; mood/anxiety/stress disorders; imaging; clinical or preclinical; pregabalin; anxiety; insula; prefrontal cortex; amygdala
Although there are multiple indications that alcohol can alter many physiological brain functions, including cerebral blood flow (CBF), studies of the latter have generally used small or modest sized samples. Few investigations have yet evaluated how CBF changes after alcohol relate to subsets of subjects with elevated alcoholism risks, such as those with lower levels of response (LR) to alcohol. This study used arterial spin labeling (ASL) after alcohol administration to evaluate a large sample of healthy young men and women with low and high alcohol responses, and, thus, varying risks for alcohol use disorders (AUD).
Healthy young adult social drinkers with low and high LR (N=88, 50% female) matched on demography and drinking histories were imaged with whole brain resting ASL ~1 hour after ingesting ~3 drinks of ethanol and after a placebo beverage (i.e., 178 ASL sessions). The relationships of CBF changes from placebo to alcohol for subjects with low and high LR were evaluated.
CBF increased after alcohol as compared to placebo in five frontal brain regions. Despite identical BACs, these increases with alcohol were less prominent in individuals who required more drinks to experience alcohol-related effects (i.e., had a lower LR to alcohol). The LR group differences remained significant after covarying for recent drinking quantities.
The results confirm that alcohol intake is associated with acute increases in CBF, particularly in frontal regions. Less intense CBF changes were seen in subjects with a genetically influenced characteristic, a low LR to alcohol, that relates to the future risk of heavy drinking and alcohol problems.
alcohol; arterial spin labeling; level of response to alcohol; alcoholism risk
In this review, we survey the state of the field of functional magnetic resonance imaging (fMRI) as it relates to drug discovery and drug development. We highlight the advantages and limitations of fMRI for this purpose and suggest ways to improve the use of fMRI for developing new therapeutics, with emphasis on treatments for anxiety disorders. Fundamentally, pharmacological studies with standard psychiatric treatments using standardized behavioral probes during fMRI will need to be carried out to determine characteristic brain signatures that could be used to predict whether novel compounds are likely to have specific therapeutic effects.
The purpose of this review is to highlight some of the issues that need to be addressed in order to optimally utilize functional neuroimaging as a clinical tool to predict outcomes in substance use disorders. First, the importance of recognizing the clinical heterogeneity of substance use disorders population is highlighted. We also emphasize that empirical and theoretical analyses support the idea that the courses of substance use disorders are relatively independent of the types of substance being used. Second, various approaches to the measurement and characterization of the longitudinal courses of substance use disorders are summarized. Third, predictors of outcomes are reviewed and their limitations are discussed. Within this context, we describe aspects of our work that focus on using functional magnetic resonance imaging (fMRI) to predict outcomes. Fourth, we discuss future directions, critical experiments and the utility of functional neuroimaging as a clinical tool.
Addiction; Stimulants; Outcomes; Prediction; fMRI; Neuroimaging
It is unclear whether and how elite athletes process physiological or psychological challenges differently than healthy comparison subjects. In general, individuals optimize exercise level as it relates to differences between expected and experienced exertion, which can be conceptualized as a body prediction error. The process of computing a body prediction error involves the insular cortex, which is important for interoception, i.e. the sense of the physiological condition of the body. Thus, optimal performance may be related to efficient minimization of the body prediction error. We examined the hypothesis that elite athletes, compared to control subjects, show attenuated insular cortex activation during an aversive interoceptive challenge.
Elite adventure racers (n = 10) and healthy volunteers (n = 11) performed a continuous performance task with varying degrees of a non-hypercapnic breathing load while undergoing functional magnetic resonance imaging. The results indicate that (1) non-hypercapnic inspiratory breathing load is an aversive experience associated with a profound activation of a distributed set of brain areas including bilateral insula, dorsolateral prefrontal cortex and anterior cingulated; (2) adventure racers relative to comparison subjects show greater accuracy on the continuous performance task during the aversive interoceptive condition; and (3) adventure racers show an attenuated right insula cortex response during and following the aversive interoceptive condition of non-hypercapnic inspiratory breathing load.
These findings support the hypothesis that elite athletes during an aversive interoceptive condition show better performance and an attenuated insular cortex activation during the aversive experience. Interestingly, differential modulation of the right insular cortex has been found previously in elite military personnel and appears to be emerging as an important brain system for optimal performance in extreme environments.
Previous neuroimaging studies suggest that prefrontal cortex (PFC) modulation of the amygdala and related limbic structures is an underlying neural substrate of effortful emotion regulation. Anxiety-prone individuals experience excessive negative emotions, signaling potential dysfunction of systems supporting down-regulation of negative emotions. We examined the hypothesis that anxious individuals require increased recruitment of lateral and medial PFC to decrease negative emotions. An emotion regulation task that involved viewing moderately negative images was presented during functional magnetic resonance imaging (fMRI). Participants with elevated trait anxiety scores (n = 13) and normal trait anxiety scores (n = 13) were trained to reduce negative emotions using cognitive reappraisal. Blood oxygenation level-dependent (BOLD) changes were contrasted for periods when participants were reducing emotions versus when they were maintaining emotions. Compared to healthy controls, anxious participants showed greater activation of brain regions implicated in effortful (lateral PFC) and automatic (subgenual anterior cingulate cortex) control of emotions during down-regulation of negative emotions. Left ventrolateral PFC activity was associated with greater self-reported reduction of distress in anxious participants, but not in healthy controls. These findings provide evidence of altered functioning of neural substrates of emotion regulation in anxiety-prone individuals. Anxious participants required greater engagement of lateral and medial PFC in order to successfully reduce negative emotions.
Emotion; Emotion Regulation; fMRI; Anxiety; Prefrontal Cortex; Anterior Cingulate Cortex
Pregabalin has shown promise in the treatment of anxiety disorders. Previous functional magnetic resonance imaging (fMRI) studies indicate agents used to treat anxiety, e.g., SSRIs and benzodiazepines, attenuate amygdala, insula, and medial prefrontal cortex (mPFC) activation during emotional processing. Our prior study has shown that during anticipation of an emotional stimulus, pregabalin attenuates amygdala and insula activation but increases medial PFC activation. In this study, we examined whether, similar to SSRIs and benzodiazepines, pregabalin attenuates amygdala, insula, and medial PFC during emotional face processing. Sixteen healthy volunteers underwent a double-blind within-subjects fMRI study investigating effects of placebo, 50 mg, and 200 mg pregabalin on neural activation during an emotional face-matching task. Linear mixed model analysis revealed that pregabalin dose-dependently attenuated left amygdala activation during fearful face-matching and left anterior insula activation during angry face-matching. The 50 mg dose exhibited more robust effects than the 200 mg dose in the right anterior insula and ventral ACC. Thus, pregabalin shares some similarity to SSRIs and benzodiazepines in attenuating anger and fear-related insula and amygdala activation during emotional face processing. However, there is evidence that a subclinical 50 mg dose of pregabalin produced more robust and widespread effects on neural responses in this paradigm than the more clinically relevant 200 mg dose. Taken together, pregabalin has a slightly different effect on brain activation as it relates to anticipation and emotional face processing, which may account for its unique characteristic as an agent for the treatment of anxiety disorders.
anxiety; anxiolytic; benzodiazepine; emotion; fMRI; pharmaco-imaging; pregabalin
Personality and alcohol expectancies have been examined as risk factors for the initiation and maintenance of alcohol use in adolescents and young adults. Differences in processing appetitive stimuli are seen as a mechanism for personality's influence on behavior, and that mechanism predisposes individuals to form more positive expectancies for alcohol. The go/no-go task has been used to show how personality differences influence responding to appetitive stimuli in adolescents and adults, and functional magnetic resonance imaging (fMRI) has been used to examine the relation of go/no-go responding to personality in adult males. However, no study to date has examined the relation between fMRI responding, personality and alcohol expectancies in adolescents.
Forty-six adolescents (ages 12−14 years; 61% male) with minimal substance use histories completed measures of neuroticism, extraversion, and alcohol expectancies, and performed a go/no-go task during fMRI acquisition.
Greater blood oxygen level-dependent (BOLD) response to inhibition predicted fewer expectancies of cognitive and motor improvements but more expectancies of cognitive and motor impairment from alcohol. In addition, extraverted youths reported more positive alcohol expectancies. However, BOLD response did not predict neuroticism or extraversion.
These preliminary results suggest that decreased inhibitory neural processing may contribute to more positive and less negative expectancies, which can eventually lead to problem drinking. Further, extraversion may also yield more positive expectancies and could underlie a vulnerability to disordered alcohol use.
Imaging studies of posttraumatic stress disorder (PTSD) have identified functional differences in the amygdala and anterior cingulate (ACC)/medial prefrontal cortex during emotion processing. Recent investigations of the limbic sensory system and its associated neural substrate, the insular cortex, have demonstrated its importance for emotional awareness. Intimate-partner violence (IPV) is one of the most common causes of PTSD among women. This study examined the hypothesis that women with IPV-PTSD show a dysregulation of this limbic sensory system while processing threat-related emotional faces.
12 women with IPV-PTSD and 12 non-traumatized comparison women underwent BOLD functional magnetic resonance imaging while completing an emotional-face matching task.
IPV-PTSD subjects relative to comparison subjects displayed increased activation of the anterior insula and amygdala and decreased connectivity among the anterior insula, amygdalae, and ACC while matching to fearful vs. happy target faces. A similar pattern of activation differences was also observed for angry vs. happy target faces. IPV-PTSD subjects relative to comparison subjects also displayed increased dACC/mPFC activation and decreased vACC activation when matching to a male vs. a female target, and the extent of increased dACC activation correlated positively with hyperarousal symptoms.
Women with IPV-PTSD display hyperactivity and disconnection among affective and limbic sensory systems while processing threat-related emotion. Furthermore, hyperactivity of cognitive-appraisal networks in IPV-PTSD may promote hypervigilant states of awareness through an exaggerated sensitivity to contextual cues, i.e. male gender, which relate to past trauma.
posttraumatic stress; anxiety; emotion; insula; amygdala; anterior cingulate
Neuroticism is a core personality trait that profoundly affects how individuals interpret and interact with their environment. Understanding neuroticism at a neurobiological level will be an important step toward identifying novel vulnerability factors for psychiatric illnesses such as depression and anxiety. Along these lines, recent work has identified neural activation patterns within the right anterior insula that correlates with an individual's degree of neuroticism. The present study aims to further characterize the circumstances under which neuroticism modulates insular activity. Sixteen healthy participants underwent functional magnetic resonance imaging while playing a card game with varying degrees of outcome uncertainty. Activation within the bilateral anterior insula was found during all decisions, irrespective of uncertainty. However, a significant positive correlation between neuroticism and anterior insula activity was found only during ‘certain decisions’ (i.e. situations where the most probable outcome was clearly evident). Moreover, an increase in the right anterior insula activity during certain decisions was related to a behavioral mirroring effect such that the response latency for certain decisions approached the response latency for uncertain decisions. These findings suggest that increasing levels of neuroticism modulate neural activation in such a way that the brain interprets certainty as uncertain.
functional magnetic resonance imaging (fMRI); decision-making; uncertainty; personality; individual differences
A number of studies have examined the perception of time with durations ranging from milliseconds to a few seconds, however the neural basis of these processes are still poorly understood and the neural substrates underlying the perception of multiple-second intervals are unknown. Here we present evidence of neural systems activity in circumscribed areas of the human brain involved in the encoding of intervals with durations of 9 and 18 seconds in a temporal reproduction task using event-related functional magnetic resonance imaging (fMRI). During the encoding there was greater activation in more posterior parts of the medial frontal and insular cortex whereas the reproduction phase involved more anterior parts of these brain structures. Intriguingly, activation curves over time show an accumulating pattern of neural activity, which peaks at the end of the interval within bilateral posterior insula and superior temporal cortex when individuals are presented with 9- and 18-second tone intervals. This is consistent with an accumulator-type activity, which encodes duration in the multiple seconds range. Given the close connection between the dorsal posterior insula and ascending internal body signals, we suggest that the accumulation of physiological changes in body states constitutes our experience of time. This is the first time that an accumulation function in the posterior insula is detected that might be correlated with the encoding of time intervals.
time perception; duration reproduction; insular cortex; fMRI
Bipolar Disorder (BD) is a neuropsychiatric disorder characterized by symptoms ranging from a hyperactive manic state to depression, with periods of relative stability, known as euthymia, in between. Although prognosis for BD sufferers remains poor, treatment development has been restricted due to a paucity of validated animal models. Moreover, most models focus on the manic state of BD with little done to characterize the longitudinal behavior of these models. We recently presented two dopamine transporter (DAT) mouse models of BD mania: genetic (DAT knockdown; KD, mice) and pharmacological (the selective DAT inhibitor GBR 12909). These models exhibit an exploratory profile consistent with the quantified exploratory profile of manic BD patients observed in the cross-species translational test, the Behavioral Pattern Monitor (BPM).
To further explore the suitability of these models, we examined the effects of reduced DAT function on the behavior of mice testing after familiarization to the BPM environment. Testing with 16 mg/kg GBR 12909 in familiarized mice resulted in a consistent mania-like profile. In contrast, the mania-like profile of DAT KD mice disappears in a familiar environment, with partial reinstatement elicited by the introduction of novelty. In addition, we found that a sub-threshold dose of GBR 12909 (9 mg/kg) reinstated the mania-like profile in DAT KD mice without affecting wildtype behavior.
Thus, the mania-like exploratory profile of DAT KD mice is reduced in a familiar environment, partially reinstated with novelty, but is fully restored when administered a stimulant that is ineffective in wildtype mice. These mice may provide a model of BD from mania to euthymia and back again with stimulant treatment. Acute blockade of the DAT by GBR 12909 however, may provide a consistent model for BD mania.
Alterations in exploratory behavior are a fundamental feature of bipolar mania, typically characterized as motor hyperactivity and increased goal-directed behavior in response to environmental cues. In contrast, abnormal exploration associated with schizophrenia and depression can manifest as prominent withdrawal, limited motor activity, and inattention to the environment. While motor abnormalities are cited frequently as clinical manifestations of these disorders, relatively few empirical studies have quantified human exploratory behavior. This article reviews the literature characterizing motor and exploratory behavior associated with bipolar disorder and genetic and pharmacological animal models of the illness. Despite sophisticated assessment of exploratory behavior in rodents, objective quantification of human motor activity has been limited primarily to actigraphy studies with poor cross-species translational value. Furthermore, symptoms that reflect the cardinal features of bipolar disorder have proven difficult to establish in putative animal models of this illness. Recently, however, novel tools such as the Human Behavioral Pattern Monitor provide multivariate translational measures of motor and exploratory activity, enabling improved understanding of the neurobiology underlying psychiatric disorders.
bipolar disorder; animal models; rodent; open field test; exploration; hyperactivity; behavior pattern monitor; dopamine
Medial cortex is critically involved in self-referential processing. Little is known about how SSRIs affect medial cortical activity during self-assessment. We hypothesized that 3 week oral administration of escitalopram 10mg per day would alter activity related to self-referential processing in medial cortex. Fifteen healthy females performed a self-assessment task during fMRI on two occasions – once after 3 weeks of placebo and once at the end of 3 weeks of escitalopram. Task conditions involved responding “yes” or “no” to whether various positive and negative adjectives described the subject (i.e., “self” evaluation trials) or the subject’s best friend (i.e., “other” evaluation trials), whereas the comparison condition involved responding whether the valence of various adjectives was positive or negative (i.e., “word” evaluation trials). Behaviorally after escitalopram, subjects less frequently endorsed that negative adjectives described themselves. Three main neuroimaging results were observed: (1) increased activation in medial prefrontal cortex and posterior cingulate related to self minus word evaluation trials, (2) increased activation in posterior cingulate related to escitalopram minus placebo for self and word evaluation trials, (3) drug by task interactions in the insula, cerebellum and prefrontal cortex. These results show that SSRIs change medial cortical activity and may alter self-evaluation.
SSRI; medial cortex; fMRI; self; cingulate; emotion processing
Neuroimaging studies on delay discounting tasks that use reward delays ranging from minutes to days have implicated the insula and striatum in the processing of inter-temporal decisions. This study aimed at assessing whether these brain regions would also be involved in decision-making when subjects have to wait through the delays within the range of seconds. Employing functional magnetic resonance imaging (fMRI) in thirteen healthy volunteers, we repeatedly presented monetaryoptions with delays that differed within the range of multiple seconds. Using a region of interest approach, we found significant activation in the bilateral anterior insula and striatum when subjects chose either the immediate (smaller) or delayed (larger) option. In particular, insular activation was observed after the response and the delay, when the outcome of the immediate or the delayed choice was shown. Significantly greater activation was observed in the ventroanterior striatum while subjects chose the immediate, as opposed to the delayed, options, and also after receiving the outcome of waiting through the longer delay option. The evidence presented here indicates that both the ventral striatum and the insula are involved in the processing of choosing delay options as well as the consequences of choices with delays in the seconds’ range.
delay discounting; decision making; time perception; reward; fMRI