Failures in cortical control of fronto-striatal neural circuits may underpin impulsive and compulsive acts. In this narrative review, we explore these behaviors from the perspective of neural processes and consider how these behaviors and neural processes contribute to mental disorders such as obsessive–compulsive disorder (OCD), obsessive–compulsive personality disorder, and impulse-control disorders such as trichotillomania and pathological gambling. We present findings from a broad range of data, comprising translational and human endophenotypes research and clinical treatment trials, focussing on the parallel, functionally segregated, cortico-striatal neural projections, from orbitofrontal cortex (OFC) to medial striatum (caudate nucleus), proposed to drive compulsive activity, and from the anterior cingulate/ventromedial prefrontal cortex to the ventral striatum (nucleus accumbens shell), proposed to drive impulsive activity, and the interaction between them. We suggest that impulsivity and compulsivity each seem to be multidimensional. Impulsive or compulsive behaviors are mediated by overlapping as well as distinct neural substrates. Trichotillomania may stand apart as a disorder of motor-impulse control, whereas pathological gambling involves abnormal ventral reward circuitry that identifies it more closely with substance addiction. OCD shows motor impulsivity and compulsivity, probably mediated through disruption of OFC-caudate circuitry, as well as other frontal, cingulate, and parietal connections. Serotonin and dopamine interact across these circuits to modulate aspects of both impulsive and compulsive responding and as yet unidentified brain-based systems may also have important functions. Targeted application of neurocognitive tasks, receptor-specific neurochemical probes, and brain systems neuroimaging techniques have potential for future research in this field.
impulsive; compulsive; endophenotypes; serotonin; dopamine; Cognition; Psychiatry & Behavioral Sciences; Animal models; Biological Psychiatry; OCD; impulsivity; compulsivity; translational
Obsessive-compulsive disorder (OCD) has been associated with impairments in
stop-signal inhibition, a measure of motor response suppression. The study
used a novel paradigm to examine both thought suppression and response
inhibition in OCD, where the modulatory effects of stimuli relevant to OCD
could also be assessed. Additionally, the study compared inhibitory
impairments in OCD patients with and without co-morbid depression, as
depression is the major co-morbidity of OCD.
Volitional response suppression and unintentional thought suppression to
emotive and neutral stimuli were examined using a novel thought stop-signal
task. The thought stop-signal task was administered to non-depressed OCD
patients, depressed OCD patients and healthy controls (n=20
Motor inhibition impairments were evident in OCD patients, while motor
response performance did not differ between patients and controls. Switching
to a new response but not motor inhibition was affected by stimulus
relevance in OCD patients. Additionally, unintentional thought suppression
as measured by repetition priming was intact. OCD patients with and without
depression did not differ on any task performance measures, though there
were significant differences in all self-reported measures.
Results support motor inhibition deficits in OCD that remain stable
regardless of stimulus meaning or co-morbid depression. Only switching to a
new response was influenced by stimulus meaning. When response inhibition
was successful in OCD patients, so was the unintentional suppression of the
Depression; inhibition; obsessive-compulsive disorder; stop-signal
Obsessive-compulsive disorder (OCD) is highly heritable. Attempts to delineate precise genetic contributions have met with limited success. There is an ongoing search for intermediate cognitive brain markers (endophenotypes) that may help clarify genetic contributions. The aim was to assess inhibitory control processes in unaffected first-degree relatives of OCD patients for the first time with objective tests.
The Intradimensional/Extradimensional Shift, Stop-Signal, and Cambridge Gamble tasks were administered to 20 unaffected first-degree relatives, 20 OCD patient probands with washing/checking symptoms, and 20 healthy matched comparison subjects without a family history of OCD.
Unaffected first-degree relatives and OCD patient probands showed cognitive inflexibility (extradimensional set shifting) and motor impulsivity (stop-signal reaction times). Decision making (Cambridge Gamble task) was intact.
Deficits in cognitive flexibility and motor inhibition may represent cognitive endophenotypes for OCD. Such measures will play a key role in understanding genotype/phenotype associations for OCD and related spectrum conditions.
To describe, in the context of DSM-V, how a focus on addiction and compulsion is emerging in the consideration of pathological gambling (PG).
A systematic literature review of evidence for the proposed re-classification of PG as an addiction.
Findings include: 1. Phenomenological models of addiction highlighting a motivational shift from impulsivity to compulsivity associated with a protracted withdrawal syndrome and blurring of the ego-syntonic/ego-dystonic dichotomy; 2. Common neurotransmitter (dopamine, serotonin) contributions to PG and substance use disorders (SUDs); 3. Neuroimaging support for shared neurocircuitries between “behavioral” and substance addictions and differences between obsessive-compulsive disorder (OCD), impulse control disorders (ICDs) and SUDs; 4. Genetic findings more closely related to endophenotypic constructs like compulsivity and impulsivity than to psychiatric disorders; 5. Psychological measures such as harm avoidance identifying a closer association between SUDs and PG than with OCD; 6. Community and pharmaco-therapeutic trials data supporting a closer association between SUDs and PG than with OCD. Adapted behavioral therapies, such as exposure therapy appear applicable to OCD, PG, or SUDs, suggesting some commonalities across disorders.
PG shares more similarities with SUDs than with OCD. Similar to the investigation of impulsivity, studies of compulsivity hold promising insights concerning the course, differential diagnosis and treatment of PG, SUDs, and OCD.
Compulsivity; Impulsivity; Addiction; Pathological Gambling; Endophenotypes
Dopamine and dopamine-receptor function are often implicated in behavioral inhibition, and deficiencies within behavioral inhibition processes linked to ADHD, schizophrenia, obsessive-compulsive disorder and drug addiction. In the stop-signal task, which measures the speed of the process of inhibition (stop-signal reaction time, SSRT), psychostimulant-related improvement of SSRT in ADHD is linked with dopamine function. However, the precise nature of dopaminergic control over SSRT remains unclear.
This study examined region- and receptor-specific modulation of SSRT in the rat using direct infusions, into the dorsomedial striatum (DMStr) or nucleus accumbens core (NAcbC), of the dopamine D1-receptor (DRD1) antagonist SCH 23390 or dopamine D2-receptor (DRD2) antagonist sulpiride. DRD1 and DRD2 antagonists had contrasting effects on SSRT that were specific to the DMStr. SCH 23390 decreased SSRT with little effect on the go response. Conversely, sulpiride increased SSRT but also increased go-trial reaction time and reduced trial completion at the highest doses. These results suggest that DRD1 and DRD2 function within the DMStr, but not the NAcbC, may act to balance behavioral inhibition in a manner that is independent of behavioral activation.
stopping; SSRT; caudate; ADHD; schizophrenia; OCD
The stop-signal paradigm measures the ability to stop a motor response after its execution has been initiated. Impairments in inhibiting inappropriate behavior and prolonged stop-signal reaction times (SSRTs) are characteristic of several psychiatric disorders, most notably attention deficit/hyperactivity disorder. While there is relative consensus regarding the anatomical substrates of behavioral inhibition, the neurochemical imbalance responsible for the deficits in stopping displayed by impulsive individuals is still a matter of debate.
The aim of this study was to investigate the effects of manipulating brain monoamine levels on stop task parameters.
Lister-hooded rats were trained on the rodent version of the stop-signal task and administered different monoamine transporter inhibitors: citalopram, which selectively blocks the serotonin transporter; atomoxetine, which selectively blocks the noradrenaline transporter; and GBR-12909, which selectively blocks the dopamine transporter (DAT), and the alpha-2 adrenergic agonist guanfacine.
Atomoxetine speeded SSRT and increased accuracy for go-trials. Citalopram slowed go reaction time and decreased go accuracy at the highest dose (1 mg/kg). GBR-12909 speeded go reaction time and impaired both go and stop accuracy. Guanfacine negatively modulated all principal stop and go measures at the highest dose used (0.3 mg/kg).
The results suggest that atomoxetine exerts its beneficial effects on SSRT via its action on noradrenaline re-uptake, as the specific DAT blocker GBR-12909 and serotonin reuptake blockade had only minor effects on SSRT. The speeding of the go reaction time by dopamine reuptake blockade is consistent with the hypothesis that the hypothetical stop and go processes are modulated by distinct monoaminergic systems.
Stop-signal task; Response inhibition; SSRT; Dopamine; Noradrenaline; Serotonin; GBR-12909; Atomoxetine; Citalopram; Guanfacine
Abnormalities in the orbital prefrontal cortex and its ventral striatal target fields are believed to be involved in causing obsessive and compulsive symptoms. Lesions to this brain circuitry result in a selective disturbance in suppressing responses to irrelevant stimuli. This disturbance might underlie the apparent inhibitory deficit suggested by the symptomatology of obsessive-compulsive disorder (OCD). Oculomotor tests were administered to 12 medication-free, nondepressed patients with OCD aged 18 to 44 y and 12 matched healthy controls to assess the ability to suppress responses and to execute delayed responses volitionally. Patients with OCD had more response-suppression failures than controls when peripheral visual targets were presented close to central fixation. No significant case-control differences were observed on the delayed-response task. A basic disturbance of neurobehavioral inhibition in OCD may underlie the repetitive behavior that characterizes the illness and be related to abnormalities in orbital prefrontal ventral striatal circuits.
Pathological Gambling (PG) is an impulse control disorder often comorbid with other psychopathology, particularly bipolar spectrum disorders, attention deficit/hyperactivity disorder, obsessive-compulsive disorder (OCD) and substance abuse. This paper reviews the published literature on the pharmacological management of PG, highlighting how clinical and subclinical comorbid psychopathology influences the choice of pharmacological treatment.
Using Medline, the authors reviewed relevant articles published on this topic from1995 to 2005, focusing on the best-designed studies for inclusion.
Much of the literature on PG-treatment presupposes different theories regarding this disorder. Data suggest the utility of differentiating the pharmacotherapy of pathological gamblers in light of their comorbid profile, specifically assessing for comorbid bipolar, ADHD, OCD, and substance abuse disorders.
Decisions about pharmacological treatment of PG should take into account current and previous comorbid disorders which influence treatment selection.
Pathological Gambling; Impulse Control Disorders; Comorbidity; Compulsive-Impulsive Spectrum; Subthreshold symptoms
The article reviews the current knowledge about the impulse control disorders (ICDs) with specific emphasis on epidemiological and pharmacological advances. In addition to the traditional ICDs present in the DSM-IV—pathological gambling, trichotillomania, kleptomania, pyromania and intermittent explosive disorder—a brief description of the new proposed ICDs—compulsive–impulsive (C–I) Internet usage disorder, C–I sexual behaviors, C–I skin picking and C–I shopping—is provided. Specifically, the article summarizes the phenomenology, epidemiology and comorbidity of the ICDs. Particular attention is paid to the relationship between ICDs and obsessive–compulsive disorder (OCD). Finally, current pharmacological options for treating ICDs are presented and discussed.
impulse control disorders (ICDs); obsessive–compulsive disorder (OCD); pathological gambling (PG); kleptomania; compulsive–impulsive (C–I) shopping; trichotillomania (TTM); intermittent explosive disorder (IED); C–I Internet usage disorder; C–I sexual behaviors (C–ISBs); C–I skin picking; pyromania
Pathological gambling (PG) and obsessive-compulsive disorder (OCD) are conceptualized as a behavioral addiction, with a dependency on repetitive gambling behavior and rewarding effects following compulsive behavior, respectively. However, no neuroimaging studies to date have examined reward circuitry during the anticipation phase of reward in PG compared with in OCD while considering repetitive gambling and compulsion as addictive behaviors.
To elucidate the neural activities specific to the anticipation phase of reward, we performed event-related functional magnetic resonance imaging (fMRI) in young adults with PG and compared them with those in patients with OCD and healthy controls. Fifteen male patients with PG, 13 patients with OCD, and 15 healthy controls, group-matched for age, gender, and IQ, participated in a monetary incentive delay task during fMRI scanning. Neural activation in the ventromedial caudate nucleus during anticipation of both gain and loss decreased in patients with PG compared with that in patients with OCD and healthy controls. Additionally, reduced activation in the anterior insula during anticipation of loss was observed in patients with PG compared with that in patients with OCD which was intermediate between that in OCD and healthy controls (healthy controls < PG < OCD), and a significant positive correlation between activity in the anterior insula and South Oaks Gambling Screen score was found in patients with PG.
Decreased neural activity in the ventromedial caudate nucleus during anticipation may be a specific neurobiological feature for the pathophysiology of PG, distinguishing it from OCD and healthy controls. Correlation of anterior insular activity during loss anticipation with PG symptoms suggests that patients with PG fit the features of OCD associated with harm avoidance as PG symptoms deteriorate. Our findings have identified functional disparities and similarities between patients with PG and OCD related to the neural responses associated with reward anticipation.
The ability to withhold reinforced responses—behavioral inhibition—is impaired in various psychiatric conditions including Attention Deficit Hyperactivity Disorder (ADHD). Methodological and analytical limitations have constrained our understanding of the effects of pharmacological and environmental factors on behavioral inhibition.
To determine the effects of acute methylphenidate (MPH) administration and rearing conditions (isolated vs. pair-housed) on behavioral inhibition in adult rats.
Inhibitory capacity was evaluated using two response-withholding tasks, differential reinforcement of low rates (DRL) and fixed minimum interval (FMI) schedules of reinforcement. Both tasks made sugar pellets contingent on intervals longer than 6 s between consecutive responses. Inferences on inhibitory and timing capacities were drawn from the distribution of withholding times (interresponse times, or IRTs).
MPH increased the number of intervals produced in both tasks. Estimates of behavioral inhibition increased with MPH dose in FMI and with social isolation in DRL. Nonetheless, burst responding in DRL and the divergence of DRL data relative to past studies, among other limitations, undermined the reliability of DRL data as the basis for inferences on behavioral inhibition.
Inhibitory capacity was more precisely estimated from FMI than from DRL performance. Based on FMI data, MPH, but not a socially enriched environment, appears to improve inhibitory capacity. The highest dose of MPH tested, 8 mg/kg, did not reduce inhibitory capacity but reduced the responsiveness to waiting contingencies. These results support the use of the FMI schedule, complemented with appropriate analytic techniques, for the assessment of behavioral inhibition in animal models.
Impulsivity; Methylphenidate; Housing; Fixed minimum interval; Differential reinforcement of low rates; Temporal regulation; Model; Reinforcement; Stimulants; Timing
Hoarding Disorder (HD), defined as the acquisition of and failure to discard large volumes of possessions, resulting in clutter that precludes normal use of living spaces, is a common and debilitating condition. Although hoarding has historically been conceptualized as a variant of obsessive-compulsive disorder (OCD), increasing evidence suggests that hoarding might be more closely associated with the symptoms of attention deficit-hyperactivity disorder (ADHD). The aim of the present study was to clarify the relationship between the core features of hoarding (clutter, difficulty discarding, acquiring), OCD symptoms, and ADHD symptoms. HD (N = 39), non-hoarding OCD (N = 26), and healthy control (N = 36) participants underwent careful diagnostic interviewing and completed standardized self-report measures of the core features of hoarding (clutter, difficulty discarding, acquiring), OCD symptoms, negative affect, and the inattentive and hyperactive/impulsive symptoms of ADHD. Multiple linear regressions demonstrated that after controlling for global negative affect, OCD symptoms did not significantly predict any of the core features of HD. Conversely, the inattentive (but not hyperactive/impulsive) symptoms of ADHD significantly predicted severity of clutter, difficulty discarding, and acquiring. These results challenge current conceptualizations of hoarding as a subtype of OCD, and suggest an association with neurocognitive impairment.
Hoarding; OCD; ADHD; attention
Pathological impulsivity is a prominent feature in several psychiatric disorders, but detailed understanding of the specific neuronal processes underlying impulsive behavior is as yet lacking.
As recent findings have suggested involvement of the brain cannabinoid system in impulsivity, the present study aimed at further elucidating the role of cannabinoid CB1 receptor activation in distinct measures of impulsive behavior.
Materials and methods
The effects of the selective cannabinoid CB1 receptor antagonist, rimonabant (SR141716A) and agonist WIN55,212-2 were tested in various measures of impulsive behavior, namely, inhibitory control in a five-choice serial reaction time task (5-CSRTT), impulsive choice in a delayed reward paradigm, and response inhibition in a stop-signal paradigm.
In the 5-CSRTT, SR141716A dose-dependently improved inhibitory control by decreasing the number of premature responses. Furthermore, SR141716A slightly improved attentional function, increased correct response latency, but did not affect other parameters. The CB1 receptor agonist WIN55,212-2 did not change inhibitory control in the 5-CSRTT and only increased response latencies and errors of omissions. Coadministration of WIN55,212-2 prevented the effects of SR141716A on inhibitory control in the 5-CSRTT. Impulsive choice and response inhibition were not affected by SR141716A at any dose, whereas WIN55,212-2 slightly impaired response inhibition but did not change impulsive choice.
The present data suggest that particularly the endocannabinoid system seems involved in some measures of impulsivity and provides further evidence for the existence of distinct forms of impulsivity that can be pharmacologically dissociated.
Cannabinoid; Cognition; Inhibitory control; Impulsive choice; Response inhibition; SR141716A; WIN55,212-2
Impulsivity is a central feature of drug addiction and may arise as a result of impaired inhibitory control. The extent to which inhibitory deficits arise as a consequence of drug exposure or relate to pre-existing addiction vulnerability is unknown.
Materials and methods
This study compared measures of impulsivity in outpatients with alcohol dependence (n = 23) and problem gambling (n = 21), a putative behavioural addiction where direct effects of drug exposure may be minimal. Healthy controls (n = 27) were also tested, in a cross-sectional design. Subjects completed the stop-signal test as a neurocognitive probe of response inhibition, alongside self-report ratings of impulsivity, adult ADHD and OCD.
On the stop-signal test, Go reaction time and stop-signal reaction time were significantly slower in the alcohol-dependent group, compared with healthy controls. Healthy controls slowed their responding after successful and failed stop trials. Slowing after failed stop trials was significantly attenuated in the alcohol-dependent subjects. Go reaction time and post-error slowing were correlated with chronicity and severity, respectively, in the alcohol-dependent subjects. Problem gamblers did not differ significantly from controls on the stop-signal test, despite trait elevations in impulsivity ratings.
Inhibitory control is impaired in alcohol dependence but occurs in the context of psychomotor slowing. In addition, alcohol-dependent individuals failed to show behavioral adjustment following failed stops. These deficits may represent direct effects of chronic alcohol administration on fronto-striatal circuitry.
Compulsivity; Executive function; Post-error adjustment; Pathological gambling; Alcoholism
Disturbances in impulse control are key features of substance abuse disorders, and conversely, many drugs of abuse are known to elicit impulsive behavior both clinically and preclinically. To date, little is known with respect to the involvement of the opioid system in impulsive behavior, although recent findings have demonstrated its involvement in delay discounting processes. The aim of the present study was to further investigate the role of the opioid system in varieties of impulsivity.
Materials and methods
To this end, groups of rats were trained in the five-choice serial reaction time task (5-CSRTT) and stop-signal task (SST), operant paradigms that provide measures of inhibitory control and response inhibition, respectively. In addition, another group of rats was trained in the delayed reward paradigm, which measures the sensitivity towards delay of gratification and as such assesses impulsive choice.
Results and discussion
Results demonstrated that morphine, a selective µ-opioid receptor agonist, primarily impaired inhibitory control in the 5-CSRTT by increasing premature responding. In addition, in keeping with previous data, morphine decreased the preference for the large over small reward in the delayed reward paradigm. The effects of morphine on measures of impulsivity in both the 5-CSRTT and delayed reward paradigm were blocked by naloxone, a µ-opioid receptor antagonist. Naloxone by itself did not alter impulsive behavior, suggesting limited involvement of an endogenous opioid tone in impulsivity. Response inhibition measured in the SST was neither altered by morphine nor naloxone, although some baseline-dependent effects of morphine on response inhibition were observed.
In conclusion, the present data demonstrate that acute challenges with morphine modulate distinct forms of impulsive behavior, thereby suggesting a role for the opioid system in impulsivity.
Cognition; Inhibitory control; Impulsive choice; Morphine; Naloxone
Maladaptive impulsivity is a core symptom in various psychiatric disorders. However, there is only limited evidence available on whether different measures of impulsivity represent largely unrelated aspects or a unitary construct. In a cross-species translational study, thirty rats were trained in impulsive choice (delayed reward task) and impulsive action (five-choice serial reaction time task) paradigms. The correlation between those measures was assessed during baseline performance and after pharmacological manipulations with the psychostimulant amphetamine and the norepinephrine reuptake inhibitor atomoxetine. In parallel, to validate the animal data, 101 human subjects performed analogous measures of impulsive choice (delay discounting task, DDT) and impulsive action (immediate and delayed memory task, IMT/DMT). Moreover, all subjects completed the Stop Signal Task (SST, as an additional measure of impulsive action) and filled out the Barratt impulsiveness scale (BIS-11). Correlations between DDT and IMT/DMT were determined and a principal component analysis was performed on all human measures of impulsivity. In both rats and humans measures of impulsive choice and impulsive action did not correlate. In rats the within-subject pharmacological effects of amphetamine and atomoxetine did not correlate between tasks, suggesting distinct underlying neural correlates. Furthermore, in humans, principal component analysis identified three independent factors: (1) self-reported impulsivity (BIS-11); (2) impulsive action (IMT/DMT and SST); (3) impulsive choice (DDT). This is the first study directly comparing aspects of impulsivity using a cross-species translational approach. The present data reveal the non-unitary nature of impulsivity on a behavioral and pharmacological level. Collectively, this warrants a stronger focus on the relative contribution of distinct forms of impulsivity in psychopathology.
Obsessive-compulsive disorder (OCD) is a significant public health problem. Selective serotonin reuptake inhibitors (SSRIs) are the only FDA-approved medications for OCD. However, SSRIs are of limited efficacy in clinical practice. Given the persistence of symptoms and levels of treatment response, it is clear that the serotonin paradigm of OCD does not fully account for the neurobiology of the disorder, and that further translational research is needed. In this review, the glutamate hypothesis of pediatric OCD is explored, the neuroimaging evidence reviewed, and the translational impact highlighted. The traditional strategy of going from pharmacology to pathophysiology has failed to show real progress in our understanding of the neurobiology of psychiatric illness and, while still in the early stages, this work demonstrates the clear benefit of approaching psychiatric illness from the opposite direction.
adolescent; child; glutamate; magnetic resonance imaging; obsessive-compulsive disorder
Evidence for a relationship between cigarette smoking and Attention-Deficit/Hyperactivity Disorder (ADHD) has prompted investigations into nicotinic treatments for this disorder. Impulsivity is a hallmark of ADHD and is measured in the laboratory as behavioral inhibition (BI) using the Stop Signal Task (SST). Acute nicotine improves SST performance in adolescents and young adults with ADHD and impaired baseline SST performance, raising questions about the role of nicotinic acetylcholine receptor function in BI. The specificity of this effect to those with ADHD, the component processes of the SST affected by nicotine, and the effects of nicotinic antagonism are yet unknown.
This study investigated the effects of both a nicotinic receptor agonist and antagonist on the SST and choice reaction time task (CRT) in highly impulsive (HI) and control (CTRL) subjects.
This was a within-subjects, double blind study of: 7 mg transdermal nicotine, 20 mg oral mecamylamine and placebo. Subjects were recruited into HI (n=11) and CTRL (n=14) groups based on both SST and clinical criteria.
BI was significantly improved by nicotine compared to placebo in the HI group and impaired by mecamylamine in the CTRL group. Reaction time on the SST was improved by nicotine compared to placebo in the CTRL group and was unchanged in both groups on the CRT.
These findings demonstrate nicotinic modulation of BI in subjects with both normal and disordered baseline performance. The effects on BI are consistent with cholinergic enhancement of signal detection processes and/or modulation of noradrenaline by nicotine.
Cholinergic; nicotine; mecamylamine; ADHD; stop signal task; impulsivity; behavioral inhibition; reaction time; acetylcholine
The X-linked gene STS encodes the steroid hormone-modulating enzyme steroid sulfatase. Loss-of-function of STS, and variation within the gene, have been associated with vulnerability to developing Attention Deficit Hyperactivity Disorder (ADHD), a neurodevelopmental condition characterised by inattention, severe impulsivity, hyperactivity and motivational deficits. ADHD is commonly co-morbid with a variety of disorders, including Obsessive Compulsive Disorder (OCD). The neurobiological role of steroid sulfatase, and therefore its potential role in ADHD and associated co-morbidities, is currently poorly understood. The 39,XY*O mouse, which lacks the Sts gene, exhibits several behavioral abnormalities relevant to ADHD including inattention and hyperactivity. Here, we show that, unexpectedly, 39,XY*O mice achieve higher ratios than wildtype mice on a progressive ratio task thought to index motivation, but that there is no difference between the two groups on a behavioral task thought to index compulsivity (marble burying). High performance liquid chromatography (HPLC) analysis of monoamine levels in wildtype and 39,XY*O brain tissue regions (frontal cortex, striatum, thalamus, hippocampus and cerebellum) revealed significantly higher levels of 5-hydroxytryptamine (5-HT) in the striatum and hippocampus of 39,XY*O mice. Significant correlations between hippocampal 5-HT levels and progressive ratio performance, and between striatal 5-HT levels and locomotor activity strongly implicate regionally-specific perturbations of the 5-HT system as a neurobiological candidate for behavioral differences between 40,XY and 39,XY*O mice. These data suggest that inactivating mutations and functional variants within STS might exert their influence on ADHD vulnerability and disorder endophenotypes through modulation of the serotonergic system.
Attention Deficit Hyperactivity Disorder; dehydroepiandrosterone sulfate; hippocampus; Obsessive Compulsive Disorder; progressive ratio; striatum
Obsessive compulsive disorder (OCD) is a psychiatric condition defined by intrusive thoughts (obsessions) associated with compensatory and repetitive behavior (compulsions). However, advancement in our understanding of this disorder has been hampered by the absence of effective animal models, and correspondingly analysis of the physiological changes that may be present in these models To address this, we have evaluated two current rodent models of OCD; repeated injection of dopamine D2 agonist quinpirole and repeated adolescent injection of the tricyclic agent clomipramine in combination with a behavioral paradigm designed to produce compulsive lever pressing. These results were then compared with their relative impact on the state of activity of the mesolimbic dopaminergic system using extracellular recoding of spontaneously active dopamine (DA) neurons in the ventral tegmental area (VTA). The clomipramine model failed to exacerbate compulsive lever pressing, and VTA DA neurons in clomipramine-treated rats had mildly diminished bursting activity. In contrast, quinpirole treated animals showed significant increases in compulsive lever pressing, which was concurrent with a substantial diminution of bursting activity of VTA DA neurons. Therefore, VTA DA activity correlated with the behavioral response in these models. Taken together, these data support the view that compulsive behaviors likely reflect, at least in part, a disruption of the dopaminergic system, more specifically by a decrease in baseline phasic dopamine signaling mediated by burst firing of DA neurons.
Obsessive compulsive disorder; phasic dopamine; animal models; compulsive lever pressing
Compulsive behaviors in obsessive–compulsive disorder (OCD) may be related to deficits in reward processing mediated by corticostriatal circuitry, a brain network implicated in the pathophysiology of OCD. Performing compulsive actions can be perceived as a reward to OCD patients because it temporarily reduces the anxiety provoked by obsessions. Although most OCD literature provides evidence of altered regional activity in these corticostriatal circuits, very little is known about the connectivity between individual regions of the corticostriatal-limbic circuits, including the cognitive and affective neural circuitry associated with OCD. Thus, this study investigated the differences in functional connectivity (FC) patterns in this network during resting-state and incentive processing. Nineteen patients with OCD and 18 well-matched healthy controls were scanned during resting-state and a monetary incentive delay task (task state). FC was assessed using both voxel-wise and region-of-interest (ROI)-wise analyses. Voxel-wise FC analysis with the nucleus accumbens seed revealed that patients with OCD exhibited increased FC between the nucleus accumbens and the lateral orbitofrontal cortex during resting-state. Additionally, these patients showed decreased FC between the nucleus accumbens and limbic areas such as the amygdala during incentive processing. Exploratory ROI-wise FC analysis revealed that OCD patients demonstrated enhanced FC between the nucleus accumbens and the lateral orbitofrontal cortex and increased total connectivity of the lateral orbitofrontal cortex during resting-state. Additionally, patients showed alterations in FC between resting and task state. This study provides evidence that patients with OCD have altered FC in the corticostriatal-limbic network, particularly in striatal-amygdala and striatal-orbitofrontal circuitry, during incentive processing and resting-state. These findings also emphasize that functional connections in the network are modulated by affective/motivational states and further suggest that OCD patients may have abnormalities of such modulation in this network.
•Corticostriatal-limbic FC analysis of task-based and resting-state fMRI data in OCD•Dysfunctional connectivity in striatal–amygdala during reward task in OCD•Dysfunctional connectivity in striatal–orbitofrontal cortex at rest in OCD•FC levels in corticostriatal-limbic network are modulated by affective state.•OCD patients have deficits in this modulation of the corticostriatal-limbic network.
Corticostriatal circuitry; Functional connectivity; Obsessive–compulsive disorder; Reward; Resting-state
Deficits in inhibitory control, the ability to suppress ongoing or planned motor or cognitive processes, contribute to many psychiatric and neurological disorders. The rehabilitation of inhibition-related disorders may therefore benefit from neuroplasticity-based training protocols aiming at normalizing inhibitory control proficiency and the underlying brain networks. Current literature on training-induced behavioral and brain plasticity in inhibitory control suggests that improvements may follow either from the development of automatic forms of inhibition or from the strengthening of top-down, controlled inhibition. Automatic inhibition develops in conditions of consistent and repeated associations between inhibition-triggering stimuli and stopping goals. Once established, the stop signals directly elicit inhibition, thereby bypassing slow, top-down executive control and accelerating stopping processes. In contrast, training regimens involving varying stimulus-response associations or frequent inhibition failures prevent the development of automatic inhibition and thus strengthen top-down inhibitory processes rather than bottom-up ones. We discuss these findings in terms of developing optimal inhibitory control training regimens for rehabilitation purposes.
plasticity; inhibitory control; training; rehabilitation; frontal
This study focused on hypotheses regarding the source of incompleteness in obsessive-compulsive disorder (OCD). For this, we had to document the behavioral manifestation of incompleteness in compulsive rituals, predicting that an exaggerated focus on acts that are appropriate for the task will support the hypothesis on heightened responsibility/perfectionism. In contrast, activity past the expected terminal act for the motor task would support the “stop signal deficiency” hypothesis.
Methodology and Principal Findings
We employed video-telemetry to analyze 39 motor OCD rituals and compared each with a similar task performed by a non-OCD individual, in order to objectively and explicitly determine the functional end of the activity. We found that 75% of OCD rituals comprised a “tail,” which is a section that follows the functional end of the task that the patients ascribed to their activity. The other 25% tailless rituals comprised a relatively high number and higher rate of repetition of non-functional acts. Thus, in rituals with tail, incompleteness was manifested by the mere presence of the tail whereas in tailless rituals, incompleteness was manifested by the reduced functionality of the task due to an inflated execution and repetition of non-functional acts.
The prevalence of activity after the functional end (“tail”) and the elevated non-functionality in OCD motor rituals support the “lack of stop signal” theories as the underlying mechanism in OCD. Furthermore, the presence and content of the tail might have a therapeutic potential in cognitive-behavior therapy.
Obsessive-compulsive disorder (OCD) is characterized by recurrent and persistent thoughts (obsessions), and repetitive behaviors or mental acts (compulsions). In Korea, an epidemiological study reported that the lifetime prevalence of OCD in the population was greater than two percent. The exact cause of OCD is still unknown. Evidence from familial, twin and segregation studies supports the role of a genetic component in the etiology of OCD. In addition, there is growing evidence that OCD has a specific neurochemical and neuroanatomical basis. According to this evidence, researchers have selected various candidate genes which have been implicated in the neurophysiology of OCD, and differences of allelic variants in OCD patients and controls have been analyzed. In this review we will introduce the results of previous genetic studies of OCD which have been performed in other populations, including twin studies, family studies, segregation analyses, linkage analyses, and association studies. In addition to these studies, we will present the results of our genetic studies of OCD performed in Korea.
Obsessive-compulsive disorder; genetic component
Although poor decision-making is a hallmark of psychiatric conditions such as attention deficit/hyperactivity disorder, pathological gambling or substance abuse, a fraction of healthy individuals exhibit similar poor decision-making performances in everyday life and specific laboratory tasks such as the Iowa Gambling Task. These particular individuals may provide information on risk factors or common endophenotypes of these mental disorders. In a rodent version of the Iowa gambling task – the Rat Gambling Task (RGT), we identified a population of poor decision makers, and assessed how these rats scored for several behavioral traits relevant to executive disorders: risk taking, reward seeking, behavioral inflexibility, and several aspects of impulsivity. First, we found that poor decision-making could not be well predicted by single behavioral and cognitive characteristics when considered separately. By contrast, a combination of independent traits in the same individual, namely risk taking, reward seeking, behavioral inflexibility, as well as motor impulsivity, was highly predictive of poor decision-making. Second, using a reinforcement-learning model of the RGT, we confirmed that only the combination of extreme scores on these traits could induce maladaptive decision-making. Third, the model suggested that a combination of these behavioral traits results in an inaccurate representation of rewards and penalties and inefficient learning of the environment. Poor decision-making appears as a consequence of the over-valuation of high-reward-high-risk options in the task. Such a specific psychological profile could greatly impair clinically healthy individuals in decision-making tasks and may predispose to mental disorders with similar symptoms.