Loss Of Inhibitory Control Research Articles

The Role of Metabotropic Glutamate Receptor Subtype 5 in Mouse Models of Cocaine Addiction

Cocaine is a psychostimulant that is one of the most widely used illicit drugs, particularly in America. Cocaine addiction is a chronic relapsing disease that is characterized by drug craving and loss of inhibitory control. Animal models of psychiatric diseases are essential to identify underlying neural circuitry and to test the effectiveness of novel pharmacotherapies to prevent relapse. Current research using animal models indicates that type 5 metabotropic glutamate receptors may be of particular importance to the onset and maintenance of cocaine addiction. This literature review provides a general overview of the glutamate system, and the animal models frequently used in the study of addiction and summarizes peer-reviewed research focused on cocaine-induced adaptations to the type 5 metabotropic glutamate receptors in mice. Cocaine administration in mouse models induces a range of neural changes in the brain, reflecting the neuroadaptations associated with cocaine addiction. Cocaine-induced adaptations to type 5 metabotropic glutamate receptor vary by brain region and by methodological constraints. Key neural changes that occur in the mouse brain following cocaine administration include adaptations in the dopaminergic and glutamatergic systems. The interplay between mGluR5 and the dopamine system plays a significant role in the neurobiological adaptations that drive cocaine addiction. Lastly, we cover the potential efficacy of targeting this receptor as a novel therapeutic option to prevent cocaine relapse. Selective antagonists of this receptor have been studied for their potential therapeutic effects in mouse models of cocaine addiction. These compounds reduce the conditioned responses to drug-associated cues and reduce the motivation to seek cocaine, thereby inhibiting relapse-like behavior, and have been found to modulate synaptic plasticity in brain regions involved in addiction, such as the nucleus accumbens and prefrontal cortex. Overall, these compounds demonstrate promising effects in mouse models of cocaine addiction.

C-Maf-positive spinal cord neurons are critical elements of a dorsal horn circuit for mechanical hypersensitivity in neuropathy

Corticospinal tract (CST) neurons innervate the deep spinal dorsal horn to sustain chronic neuropathic pain. The majority of neurons targeted by the CST are interneurons expressing the transcription factor c-Maf. Here, we used intersectional genetics to decipher the function of these neurons in dorsal horn sensory circuits. We find that excitatory c-Maf (c-MafEX) neurons receive sensory input mainly from myelinated fibers and target deep dorsal horn parabrachial projection neurons and superficial dorsal horn neurons, thereby connecting non-nociceptive input to nociceptive output structures. Silencing c-MafEX neurons has little effect in healthy mice but alleviates mechanical hypersensitivity in neuropathic mice. c-MafEX neurons also receive input from inhibitory c-Maf and parvalbumin neurons, and compromising inhibition by these neurons caused mechanical hypersensitivity and spontaneous aversive behaviors reminiscent of c-MafEX neuron activation. Our study identifies c-MafEX neurons as normally silent second-order nociceptors that become engaged in pathological pain signaling upon loss of inhibitory control.

Cognitive inflexibility and repetitive habitual actions are associated with problematic use of the internet

Classification of Problematic Use of the Internet (PUI) remains contentious, and differing conceptualisations define PUI as a behavioural addiction, an impulse-control disorder, or an artefact of in-person social difficulties. However, these divergent conceptualisations share two commonalities: an emphasis on loss of inhibitory control (a central component of impulsivity) over internet-related urges, and repetitive habitual patterns of internet use that persist despite maladaptive outcomes (a central component of compulsivity). To date, no study has concurrently investigated impulsive and compulsive mechanisms as possible cognitive drivers of PUI. To address this gap, the study aimed to predict PUI through assessment of multiple dimensions of impulsivity and compulsivity: response inhibition, risky decision-making, reward valuation, reward-related attentional bias, cognitive flexibility, and habit formation. Ninety-one Australian university students (52 problematic internet users and 38 healthy controls) were sampled via online group-testing. Using logistic regression analysis, the model was able to predict individuals with PUI with 83.3% accuracy. Significant predictors within the model were two dimensions of compulsivity: cognitive flexibility and habitual actions, with each unit increase (i.e., towards inflexibility and perseverance) predicting an increase in likelihood of PUI of 134% and 17% respectively. The results suggest that individuals with PUI may have difficulty inhibiting previously rewarding learned responses when these reward contingencies are reversed, as well as an excessive tendency towards habit formation. Dysfunction in action-outcome and stimulus-response learning mechanisms may be mechanistic drivers of PUI, signifying possible transdiagnostic cognitive similarities between PUI and addictive disorders.

ANKRD26-Related Thrombocytopenia and Predisposition to Myeloid Neoplasms.

This review describes ANKRD26-related thrombocytopenia (RT) from a molecular, clinical, and laboratory perspective, with a focus on the clinical decision-making that takes place in the diagnosis and management of families with ANKRD26-RT. ANKRD26-related thrombocytopenia (ANKRD26-RT) is a non-syndromic autosomal dominant thrombocytopenia with predisposition to hematologic neoplasm. The clinical presentation is variable with moderate thrombocytopenia with normal platelet size and absent to mild bleeding being the hallmark which makes it difficult to distinguish from other inherited thrombocytopenias. The pathophysiology involves overexpression of ANKRD26 through loss of inhibitory control by transcription factors RUNX1 and FLI1. The great majority of disease-causing variants are in the 5' untranslated region. Acute myeloid leukemia, myelodysplastic syndrome, and chronic myelomonocytic leukemia have been reported to occur in the context of germline variants in ANKRD26, with the development of somatic driver mutations in hematopoietic regulators playing an important role in malignant transformation. In the absence of clear risk estimates of development of malignancy, optimal surveillance strategies and interventions to reduce risk of evolution to a myeloid disorder, multidisciplinary evaluation, with a strong genetic counseling framework is essential in the approach to these patients and their families. Gene-specific expertise and a multidisciplinary approach are important in the diagnosis and treatment of patients and families with ANKRD26-RT. These strategies help overcome the challenges faced by clinicians in the evaluation of individuals with a rare, non-syndromic, inherited disorder with predisposition to hematologic malignancy for which large data to guide decision-making is not available.

Structural and Functional Correlates of Higher Cortical Brain Regions in Chronic Refractory Cough

Chronic refractory cough significantly impairs the psychological and social aspects of quality of life. Loss of inhibitory control is suggested as a potential central neurobiological mechanism underlying chronic refractory cough. Do structural and functional changes related to chronic cough occur in higher cortical brain regions? The structural and resting-state functional alterations in the brains of 15 patients with chronic refractory cough and 15 age- and sex-matched healthy control participants were evaluated. Gray matter volumes of the whole brain were measured using voxel-based morphometry based on T1-weighted MRI. Intrinsic functional connectivity within large-scale brain networks was examined on resting-state functional MRI. Correlation analyses were performed to examine the relationships of these brain changes with duration, severity, and impact of cough. Compared with healthy control participants, patients with chronic refractory cough demonstrated a lower gray matter volume in the left frontal cluster and enhanced functional connectivity within the left frontoparietal network, which were associated with greater cough scores. Furthermore, enhanced functional connectivity within the left frontoparietal network was associated with a greater psychological and social impact of coughing. Lower left frontal gray matter volume was associated with longer cough duration. Structural and functional alterations in the left frontal brain regions may be implicated in the psychological and social impact and disease duration of chronic refractory cough. Our findings provide new perspectives on developing interventional approaches targeting the cognitive modulation of chronic coughing.

Emerging Roles for Mammalian Target of Rapamycin (mTOR) Complexes in Bladder Cancer Progression and Therapy.

Simple SummaryThe mammalian target of rapamycin (mTOR) pathway promotes cell growth and metabolism in response to growth factors, nutrients, and cellular energy status. Dysregulation and mutation of the mTOR pathway can contribute to tumor initiation and progression. mTOR pathway abnormalities have been found in approximately 70% of urothelial carcinomas (UCs). This review summarizes recent advances in knowledge of the mTOR pathway, highlights the role of the mTOR pathway in UC, and explores the potential of the mTOR pathway as a therapeutic target in UC. This review also explores current preclinical studies and clinical trials targeting the mTOR pathway, and concludes with future directions of research that could more robustly define and target aberrant mTOR activity in bladder cancer.The mammalian target of rapamycin (mTOR) pathway regulates important cellular functions. Aberrant activation of this pathway, either through upstream activation by growth factors, loss of inhibitory controls, or molecular alterations, can enhance cancer growth and progression. Bladder cancer shows high levels of mTOR activity in approximately 70% of urothelial carcinomas, suggesting a key role for this pathway in this cancer. mTOR signaling initiates through upstream activation of phosphatidylinositol 3 kinase (PI3K) and protein kinase B (AKT) and results in activation of either mTOR complex 1 (mTORC1) or mTOR complex 2 (mTORC2). While these complexes share several key protein components, unique differences in their complex composition dramatically alter the function and downstream cellular targets of mTOR activity. While significant work has gone into analysis of molecular alterations of the mTOR pathway in bladder cancer, this has not yielded significant benefit in mTOR-targeted therapy approaches in urothelial carcinoma to date. New discoveries regarding signaling convergence onto mTOR complexes in bladder cancer could yield unique insights the biology and targeting of this aggressive disease. In this review, we highlight the functional significance of mTOR signaling in urothelial carcinoma and its potential impact on future therapy implications.

Reduced Inhibitory Inputs On Basolateral Amygdala Principal Neurons Following Long-Term Alcohol Consumption

Recent studies have shown that manipulating basolateral amygdala (BLA) activity can affect alcohol consumption, particularly following chronic and/or long-term intake. Although the mechanisms underlying these effects remain unclear, the BLA is highly sensitive to emotional stimuli including stress and anxiety. Negative emotional states facilitate alcohol craving and relapse in patients with alcohol use disorders. Consequently, the aim of this study was to determine the effect of long-term (10 weeks) alcohol drinking on synaptic activity in BLA principal neurons. We utilized an intermittent drinking paradigm in rats, which facilitated escalating, binge-like alcohol intake over the 10 week drinking period. We then recorded spontaneous excitatory and inhibitory postsynaptic currents of BLA principal neurons from long-term alcohol drinking rats and aged-matched water drinking controls. Excitatory postsynaptic current properties from long-term alcohol drinking rats were unchanged compared to those from age-matched water drinking controls. Conversely, we observed significant reductions of inhibitory postsynaptic current amplitude and frequency in long-term ethanol drinking rats compared to age-matched water drinking controls. These results highlight substantive decreases in basal inhibitory synaptic activity of BLA principal neurons following long-term alcohol consumption. A loss of inhibitory control in the BLA could explain the high incidence of compulsive drinking and stress- or anxiety-induced relapse in patients with alcohol use disorders.

An Operant Conditioning Model Combined with a Chemogenetic Approach to Study the Neurobiology of Food Addiction in Mice.

The study of food addiction comprises 3 hallmarks that include the persistence to response without an outcome, the strong motivation for palatable food, and the loss of inhibitory control over food intake that leads to compulsive behavior in addicted individuals. The complex multifactorial nature of this disorder and the unknown neurobiological mechanistic correlation explains the lack of effective treatments. Our operant conditioning model allows deciphering why some individuals are vulnerable and develop food addiction while others are resilient and do not. It is a translational approach since it is based on the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) and the Yale Food Addiction Scale (YFAS 2.0). This model allows to evaluate the addiction criteria in 2 time-points at an early and a late period by grouping them into 1) persistence to response during a period of non-availability of food, 2) motivation for food with a progressive ratio, and 3) compulsivity when the reward is associated with a punishment such as an electric foot-shock. The advantage of this model is that it allows us to measure 4 phenotypic traits suggested as predisposing factors related to vulnerability to addiction. Also, it is possible to evaluate the long food addiction mouse model with mice genetically modified. Importantly, the novelty of this protocol is the adaptation of this food addiction model to a short protocol to evaluate genetic manipulations targeting specific brain circuitries by using a chemogenetic approach that could promote the rapid development of this addictive behavior. These adaptations lead to a short food addiction mouse protocol, in which mice follow the same behavioral procedure of the early period in the long food addiction protocol with some variations due to the surgical viral vector injection. To our knowledge, there is no paradigm in mice allowing us to study the combination of such a robust behavioral approach that allows uncovering the neurobiology of food addiction at the brain circuit level. We can study using this protocol if modifying the excitability of a specific brain network confers resilience or vulnerability to developing food addiction. Understanding these neurobiological mechanisms is expected to help to find novel and efficient interventions to battle food addiction.

Human motor fatigability as evoked by repetitive movements results from a gradual breakdown of surround inhibition.

Motor fatigability emerges when demanding tasks are executed over an extended period of time. Here, we used repetitive low-force movements that cause a gradual reduction in movement speed (or 'motor slowing') to study the central component of fatigability in healthy adults. We show that motor slowing is associated with a gradual increase of net excitability in the motor network and, specifically, in primary motor cortex (M1), which results from overall disinhibition. Importantly, we link performance decrements to a breakdown of surround inhibition in M1, which is associated with high coactivation of antagonistic muscle groups. This is consistent with the model that a loss of inhibitory control might broaden the tuning of population vectors such that movement patterns become more variable, ill-timed and effortful. We propose that the release of inhibition in M1 is an important mechanism underpinning motor fatigability and, potentially, also pathological fatigue as frequently observed in patients with brain disorders.

Towards a Dynamic Exploration of Vision, Cognition and Emotion in Alcohol-Use Disorders.

: Visuoperceptive impairments are among the most frequently reported deficits in alcohol-use disorders, but only very few studies have investigated their origin and interactions with other categories of dysfunctions. Besides, these deficits have generally been interpreted in a linear bottom-up perspective, which appears very restrictive with respect to the new models of vision developed in healthy populations. Indeed, new theories highlight the predictive nature of the visual system and demonstrate that it interacts with higher-level cognitive functions to generate top-down predictions. These models nota-bly posit that a fast but coarse visual analysis involving magnocellular pathways helps to compute heuristic guesses regard-ing the identity and affective value of inputs, which are used to facilitate conscious visual recognition. Building on these new proposals, the present review stresses the need to reconsider visual deficits in alcohol-use disorders as they might have cru-cial significance for core features of the pathology, such as attentional bias, loss of inhibitory control and emotion decoding impairments. Centrally, we suggest that individuals with severe alcohol-use disorders could present with magnocellular dam-age and we defend a dynamic explanation of the deficits. Rather than being restricted to high-level processes, deficits could start at early visual stages and then extend and potentially intensify during following steps due to reduced cerebral connec-tivity and dysfunctional cognitive/emotional regions. A new research agenda is specifically provided to test these hypotheses.

Attenuation of dopamine-induced GABA release in problem gamblers.

IntroductionWe have previously shown that an interaction between medial prefrontal and parietal cortices is instrumental in promoting self‐awareness via synchronizing oscillations in the gamma range. The synchronization of these oscillations is modulated by dopamine release. Given that such oscillations result from intermittent GABA stimulation of pyramidal cells, it is of interest to determine whether the dopaminergic system regulates GABA release directly in cortical paralimbic regions. Here, we test the hypothesis that the regulation of the GABA‐ergic system by the dopaminergic system becomes attenuated in problem gamblers resulting in addictive behaviors and impaired self‐awareness.Methods[11C]Ro15‐4513 PET, a marker of benzodiazepine α1/α5 receptor availability in the GABA receptor complex, was used to detect changes in synaptic GABA levels after oral doses of 100mg L‐dopa in a double‐blind controlled study of male problem gamblers (N = 10) and age‐matched healthy male controls (N = 10).ResultsThe mean reduction of cortical gray matter GABA/BDZ receptor availability induced by L‐dopa was significantly attenuated in the problem gambling group compared to the healthy control group (p = 0.0377).ConclusionsOur findings demonstrate that: (a) Exogenous dopamine can induce synaptic GABA release in healthy controls. (b) This release is attenuated in frontal cortical areas of males suffering from problem gambling, possibly contributing to their loss of inhibitory control. This suggests that dysfunctional dopamine regulation of GABA release may contribute to problem gambling and gambling disorder.

Modeling Contextual Modulation of Memory Associations in the Hippocampus.

We present a computational model of how memories can be contextually acquired and recalled in the hippocampus. Our adaptive contextual memory model comprises the lateral entorhinal cortex (LEC), the dentate gyrus (DG) and areas CA3 and CA1 in the hippocampus, and assumes external inputs about context that originate in the prefrontal cortex (PFC). Specifically, we propose that there is a top-down bias on the excitability of cells in the DG of the hippocampus that recruits a sub-population of cells to differentiate contexts, independent of experienced stimuli, expanding the “pattern separation” role typically attributed to the DG. It has been demonstrated in rats that if PFC is inactivated, both acquisition and recall of memory associations are impaired. However, PFC inactivation during acquisition of one set of memory associations surprisingly leads to subsequent facilitation of the acquisition of a conflicting set of memory associations in the same context under normal PFC operation. We provide here the first computational and algorithmic account of how the absence or presence of the top-down contextual biases on the excitability of DG cells during different learning phases of these experiments explains these data. Our model simulates PFC inactivation as the loss of inhibitory control on DG, which leads to full or partial activation of DG cells related to conflicting memory associations previously acquired in different contexts. This causes context-inappropriate memory traces to become active in the CA3 recurrent network and thereby the output CA1 area within the hippocampus. We show that these incongruous memory patterns proactively interfere with and slow the acquisition of new memory associations. Further, we demonstrate that pattern completion within CA3 in response to a partial cue for the recall of previously acquired memories is also impaired by PFC inactivation for the same reason. Pre-training the model with interfering memories in contexts different from those used in the experiments, simulating a lifetime of experiences, was crucial to reproduce the rat behavioral data. Finally, we made several testable predictions based on the model that suggest future experiments to deepen our understanding of brain-wide memory processes.

Multisensory Integration Strategy for Modality-Specific Loss of Inhibition Control in Older Adults.

Older adults are known to have lesser cognitive control capability and greater susceptibility to distraction than young adults. Previous studies have reported age-related problems in selective attention and inhibitory control, yielding mixed results depending on modality and context in which stimuli and tasks were presented. The purpose of the study was to empirically demonstrate a modality-specific loss of inhibitory control in processing audio-visual information with ageing. A group of 30 young adults (mean age = 25.23, Standard Deviation (SD) = 1.86) and 22 older adults (mean age = 55.91, SD = 4.92) performed the audio-visual contour identification task (AV-CIT). We compared performance of visual/auditory identification (Uni-V, Uni-A) with that of visual/auditory identification in the presence of distraction in counterpart modality (Multi-V, Multi-A). The findings showed a modality-specific effect on inhibitory control. Uni-V performance was significantly better than Multi-V, indicating that auditory distraction significantly hampered visual target identification. However, Multi-A performance was significantly enhanced compared to Uni-A, indicating that auditory target performance was significantly enhanced by visual distraction. Additional analysis showed an age-specific effect on enhancement between Uni-A and Multi-A depending on the level of visual inhibition. Together, our findings indicated that the loss of visual inhibitory control was beneficial for the auditory target identification presented in a multimodal context in older adults. A likely multisensory information processing strategy in the older adults was further discussed in relation to aged cognition.

P040 Restoration of abnormal muscular cramping in musicians’ dystonia through bihemispheric transcranial direct current stimulation and bimanual motor retraining

Question Task-specific focal dystonia (TSFD) is typically characterized by involuntary and abnormal muscular cramping, which compromises fine motor control. Previous neurophysiological studies have identified loss of inhibitory control at the motor cortex as a possible pathophysiology of the dystonic cramping. A recent study demonstrated that bi-hemispheric transcranial direct current stimulation (tDCS) over the motor cortices during performing bimanual mirrored finger movements ameliorated impairment of dexterous finger movements in pianists with TSFD. However, little has been uncovered about its underlying neurophysiological mechanism. Here we tested a hypothesis that the bi-hemispheric tDCS with motor retraining normalizes abnormal co-contraction between antagonistic pairs of extrinsic finger muscles in pianists with TSFD. Methods Eight pianists suffering from TSFD at the right hand and eight healthy pianists performed the bimanual mirrored finger movements for twenty-four minutes with two conditions; either with 2 mA tDCS over the motor cortices (cathodal over the left and anodal over the right) for twenty-four minutes (real condition) or thirty seconds (sham condition). Results The results demonstrated changes in pattern of muscular co-contraction only following the real stimulation condition, in which tonic activity turned into more phasic pattern. In addition, the amount of muscular co-contraction was significantly decreased after the real stimulation in the patients, which was the case neither at the sham condition of the patients nor at both conditions of the healthy controls. Conclusions The results provide physiological evidences of restoration of both abnormal pattern and amount of muscular co-activation of musicians’ dystonia through the bi-hemispheric tDCS with bimanual motor retraining.

Impaired Decision Making and Loss of Inhibitory-Control in a Rat Model of Huntington Disease.

Cognitive deficits associated with Huntington disease (HD) are generally dominated by executive function disorders often associated with disinhibition and impulsivity/compulsivity. Few studies have directly examined symptoms and consequences of behavioral disinhibition in HD and its relation with decision-making. To assess the different forms of impulsivity in a transgenic model of HD (tgHD rats), two tasks assessing cognitive/choice impulsivity were used: risky decision-making with a rat gambling task (RGT) and intertemporal choices with a delay discounting task (DD). To assess waiting or action impulsivity the differential reinforcement of low rate of responding task (DRL) was used. In parallel, the volume as well as cellular activity of the amygdala was analyzed. In contrast to WT rats, 15 months old tgHD rats exhibited a poor efficiency in the RGT task with difficulties to choose advantageous options, a steep DD curve as delays increased in the DD task and a high rate of premature and bursts responses in the DRL task. tgHD rats also demonstrated a concomitant and correlated presence of both action and cognitive/choice impulsivity in contrast to wild type (WT) animals. Moreover, a reduced volume associated with an increased basal cellular activity of the central nucleus of amygdala indicated a dysfunctional amygdala in tgHD rats, which could underlie inhibitory dyscontrol. In conclusion, tgHD rats are a good model for impulsivity disorder that could be used more widely to identify potential pharmacotherapies to treat these invasive symptoms in HD.

Lamina specific loss of inhibition may lead to distinct neuropathic manifestations: a computational modeling approach

Introduction It has been reported that inhibitory control at the superficial dorsal horn (SDH) can act in a regionally distinct manner, which suggests that regionally specific subpopulations of SDH inhibitory neurons may prevent one specific neuropathic condition. Methods In an attempt to address this issue, we provide an alternative approach by integrating neuroanatomical information provided by different studies to construct a network-model of the SDH. We use Neuroids to simulate each neuron included in that model by adapting available experimental evidence. Results Simulations suggest that the maintenance of the proper level of pain sensitivity may be attributed to lamina II inhibitory neurons and, therefore, hyperalgesia may be elicited by suppression of the inhibitory tone at that lamina. In contrast, lamina III inhibitory neurons are more likely to be responsible for keeping the nociceptive pathway from the mechanoreceptive pathway, so loss of inhibitory control in that region may result in allodynia. The SDH network-model is also able to replicate non-linearities associated to pain processing, such as Aβ-fiber mediated analgesia and frequency-dependent increase of the neural response. Discussion By incorporating biophysical accuracy and newer experimental evidence, the SDH network-model may become a valuable tool for assessing the contribution of specific SDH connectivity patterns to noxious transmission in both physiological and pathological conditions.

See it, grab it, or STOP! Relationships between trait impulsivity, attentional bias for pictorial food cues and associated response inhibition following in-vivo food cue exposure

Impulsivity is associated with appetitive behaviour such as heightened sensitivity to cues of reward. Impulsivity may thus confer a vulnerability to weight gain by virtue of over-responsiveness to rewarding appetitive cues. This vulnerability should be detectable as heightened cognitive and behavioural responsiveness to food cues, namely, an attentional bias to food-stimuli, subjective wanting, and loss of inhibitory control. We examined this proposition by measuring reactions to acute, in-vivo, food-cue exposure in low-impulsive and high-impulsive individuals. We expected that high-impulsive individuals would: (1) show a greater attentional bias towards pictorial food cues presented after in-vivo food cue exposure; (2) show a greater appetitive reaction to high-calorie snack foods; and (3) show poorer inhibitory control after in vivo exposure compared to control. Fifty female participants (25 yr ± 1.1; 24 kg/m2 ± 0.6) randomly allocated to either a high-calorie food-cue exposure or food-neutral control condition subsequently completed a food-cue visual probe reaction time task, subjective ratings of appetitive state and the Stop-Signal task. A significant Group-by-Duration interaction indicated that high-impulsives show slowed disengagement (longer RTs for 2000 ms duration) of pictorial food stimuli compared to their low-impulsive counterparts. Conversely, the low impulsive group show greater attentional bias than the high impulsive group (faster RTs) at the 500 ms duration, indicating speeded detection of pictorial food cues. High-impulsives showed poorer response inhibition compared to low-impulsives following in-vivo food-cue exposure. Impulsivity did not significantly moderate the effect of in-vivo cue-exposure on desire-to-eat ratings. The evidence we obtained regarding inhibitory control following in vivo food cue exposure suggests that high-impulsive individuals may be prone to overeat when their reward systems are activated, a hypothesis that requires further confirmation.

New insights into the mechanisms of itch: are pain and itch controlled by distinct mechanisms?

Itch and pain are closely related but distinct sensations. They share largely overlapping mediators and receptors, and itch-responding neurons are also sensitive to pain stimuli. Itch-mediating primary sensory neurons are equipped with distinct receptors and ion channels for itch transduction, including Mas-related G protein-coupled receptors (Mrgprs), protease-activated receptors, histamine receptors, bile acid receptor, toll-like receptors, and transient receptor potential subfamily V1/A1 (TRPV1/A1). Recent progress has indicated the existence of an itch-specific neuronal circuitry. The MrgprA3-expressing primary sensory neurons exclusively innervate the epidermis of skin, and their central axons connect with gastrin-releasing peptide receptor (GRPR)-expressing neurons in the superficial spinal cord. Notably, ablation of MrgprA3-expressing primary sensory neurons or GRPR-expressing spinal cord neurons results in selective reduction in itch but not pain. Chronic itch results from dysfunction of the immune and nervous system and can manifest as neural plasticity despite the fact that chronic itch is often treated by dermatologists. While differences between acute pain and acute itch are striking, chronic itch and chronic pain share many similar mechanisms, including peripheral sensitization (increased responses of primary sensory neurons to itch and pain mediators), central sensitization (hyperactivity of spinal projection neurons and excitatory interneurons), loss of inhibitory control in the spinal cord, and neuro-immune and neuro-glial interactions. Notably, painful stimuli can elicit itch in some chronic conditions (e.g., atopic dermatitis), and some drugs for treating chronic pain are also effective in chronic itch. Thus, itch and pain have more similarities in pathological and chronic conditions.

Neural network activation during a stop‐signal task discriminates cocaine‐dependent from non‐drug‐abusing men

Cocaine dependence is defined by a loss of inhibitory control over drug-use behaviors, mirrored by measurable impairments in laboratory tasks of inhibitory control. The current study tested the hypothesis that deficits in multiple subprocesses of behavioral control are associated with reliable neural-processing alterations that define cocaine addiction. While undergoing functional magnetic resonance imaging (fMRI), 38 cocaine-dependent men and 27 healthy control men performed a stop-signal task of motor inhibition. An independent component analysis on fMRI time courses identified task-related neural networks attributed to motor, visual, cognitive and affective processes. The statistical associations of these components with five different stop-signal task conditions were selected for use in a linear discriminant analysis to define a classifier for cocaine addiction from a subsample of 26 cocaine-dependent men and 18 controls. Leave-one-out cross-validation accurately classified 89.5% (39/44; chance accuracy = 26/44 = 59.1%) of subjects with 84.6% (22/26) sensitivity and 94.4% (17/18) specificity. The remaining 12 cocaine-dependent and 9 control men formed an independent test sample, for which accuracy of the classifier was 81.9% (17/21; chance accuracy = 12/21 = 57.1%) with 75% (9/12) sensitivity and 88.9% (8/9) specificity. The cocaine addiction classification score was significantly correlated with a measure of impulsiveness as well as the duration of cocaine use for cocaine-dependent men. The results of this study support the ability of a pattern of multiple neural network alterations associated with inhibitory motor control to define a binary classifier for cocaine addiction.

Hypertrophic Degeneration of the Inferior Olive Yields Erroneous Internal Estimates of Direction of Gravity (P02.255)

Objective: To investigate the role of the inferior olive (IO) for estimating direction of gravity. Background Central graviceptive pathways (CGP) connect the vestibular nuclei with cerebellar, brainstem and cortical areas. Acute lesions along the CGP lead to ocular torsion, skew deviation and subjective visual vertical (SVV) tilt. The IO is interconnected with the contralateral dentate nucleus and the ipsilateral red nucleus. Disruption of the central tegmental tract connecting the red nucleus with the IO may interfere with estimating direction of gravity. Design/Methods: We assessed the SVV in a 65yo man with a pontomesencephalic hemorrhage that included the medial vestibular nuclei, the right superior and lateral vestibular nucleus, the right interstitial nucleus of Cajal, the medial longitudinal fasciculus and central tegmental tract bilaterally. SVV was assessed at 16 days and 4 months after hemorrhage. Initially, he presented with gait ataxia, horizontal gaze palsy, impaired upgaze, and left-sided sensorimotor impairment. After four months he developed a vertical pendular nystagmus and increased gait ataxia. MR-imaging revealed a hypertrophic degeneration of the right IO. Results: Whereas SVV adjustments obtained at day 16 deviated 3.7° ipsilesional, large contralesional (-15.2°) deviations were found after four months. Conclusions: A shift from ipsilesional to contralesional SVV deviations in the presence of a hypertrophic degeneration of the IO was observed. We hypothesize that disrupted inhibitory GABA-ergic input from the red nucleus to the IO results in synchronized oscillations of IO neurons. These synchronized oscillations are signaled to the cerebellum, which results in a loss of inhibitory control that is normally provided through this pathway. This loss of inhibition could lead to hyperactivity of the dentate nucleus contralateral to the affected IO and consequently to a SVV tilt to the side of the overactive dentate nucleus. Such a mechanism would be in accordance to previous reports describing SVV tilts contralateral to an inhibited dentate nucleus. Supported by: Swiss National Science Foundation (3200B0-105434 and 32003B_130163/1), the Betty and David Koetser Foundation for Brain Research, Zurich, Switzerland, and the Center of Integrative Human Physiology, University of Zurich, Switzerland. Disclosure: Dr. Tarnutzer has nothing to disclose. Dr. Palla has nothing to disclose. Dr. Marti has nothing to disclose. Dr. Schuknecht has nothing to disclose. Dr. Straumann has nothing to disclose.