Neurons of the Ventral Tegmental Area Encode Individual Differences in Motivational "Wanting" for Reward Cues.

It has been argued that the dopaminergic system is involved in the attribution of motivational value to reward predictive cues as well as prediction error. To evaluate, dopamine neurons were recorded from male rats performing a Pavlovian approach task containing cues that have both "predictive" and "incentive" properties. All animals learned the predictive nature of the cue (illuminated lever entry into cage), but some also found the cue to be attractive and were motivated toward it ("sign-trackers," STs). "Goal-trackers" (GTs) predominantly approached the location of reward receptacle. Rats were implanted with tetrodes for neural electrophysiological recordings in the ventral tegmental area. Cells were characterized by spike waveform shape and firing rate. Firing rates and magnitudes of responses in relation to Pavlovian behaviors, cue presentation, and reward delivery were assessed. We identified 103 dopamine and 141 nondopamine neurons. GTs and STs both showed responses to the initial lever presentation (CS1) and lever retraction (CS2). However, higher firing rates were sustained during the lever interaction period only in STs. Further, dopamine cells of STs showed a significantly higher proportion of cells responding to both CS1 and CS2. These are the first results to show that neurons from the VTA encode both predictive and incentive cues, support an important role for dopamine neurons in the attribution of incentive salience to reward-paired cues, and underscore the consequences of potential differences in motivational behavior between individuals.SIGNIFICANCE STATEMENT This project serves to determine whether dopamine neurons encode differences in cued approach behaviors and incentive salience. How neurons of the VTA affect signaling through the NAcc and subsequent dopamine release is still not well known. All cues that precede a reward are predictive in nature. Some, however, also have incentive value, in that they elicit approach toward them. We quantified the attribution of incentive salience through cue approach behavior and cue interaction, and the corresponding magnitude of VTA neural firing. We found dopamine neurons of the VTA encode strength of incentive salience of reward cues. This suggests that dopamine neurons specifically in the VTA encode motivation.

Neural Activity in the Ventral Pallidum Encodes Variation in the Incentive Value of a Reward Cue.

UNLABELLED: There is considerable individual variation in the extent to which reward cues are attributed with incentive salience. For example, a food-predictive conditioned stimulus (CS; an illuminated lever) becomes attractive, eliciting approach toward it only in some rats ("sign trackers," STs), whereas others ("goal trackers," GTs) approach the food cup during the CS period. The purpose of this study was to determine how individual differences in Pavlovian approach responses are represented in neural firing patterns in the major output structure of the mesolimbic system, the ventral pallidum (VP). Single-unit in vivo electrophysiology was used to record neural activity in the caudal VP during the performance of ST and GT conditioned responses. All rats showed neural responses to both cue onset and reward delivery but, during the CS period, STs showed greater neural activity than GTs both in terms of the percentage of responsive neurons and the magnitude of the change in neural activity. Furthermore, neural activity was positively correlated with the degree of attraction to the cue. Given that the CS had equal predictive value in STs and GTs, we conclude that neural activity in the VP largely reflects the degree to which the CS was attributed with incentive salience. SIGNIFICANCE STATEMENT: Cues associated with reward can acquire motivational properties (i.e., incentive salience) that cause them to have a powerful influence on desire and motivated behavior. There are individual differences in sensitivity to reward-paired cues, with some individuals attaching greater motivational value to cues than others. Here, we investigated the neural activity associated with these individual differences in incentive salience. We found that cue-evoked neural firing in the ventral pallidum (VP) reflected the strength of incentive motivation, with the greatest neural responses occurring in individuals that demonstrated the strongest attraction to the cue. This suggests that the VP plays an important role in the process by which cues gain control over motivation and behavior.

Deep brain stimulation in the central nucleus of the amygdala decreases 'wanting' and 'liking' of food rewards.

We investigated the potential of deep brain stimulation (DBS) in the central nucleus of the amygdala (CeA) in rats to modulate functional reward mechanisms. The CeA is the major output of the amygdala with direct connections to the hypothalamus and gustatory brainstem, and indirect connections with the nucleus accumbens. Further, the CeA has been shown to be involved in learning, emotional integration, reward processing, and regulation of feeding. We hypothesized that DBS, which is used to treat movement disorders and other brain dysfunctions, might block reward motivation. In rats performing a lever-pressing task to obtain sugar pellet rewards, we stimulated the CeA and control structures, and compared stimulation parameters. During CeA stimulation, animals stopped working for rewards and rejected freely available rewards. Taste reactivity testing during DBS exposed aversive reactions to normally liked sucrose tastes and even more aversive taste reactions to normally disliked quinine tastes. Interestingly, given the opportunity, animals implanted in the CeA would self-stimulate with 500 ms trains of stimulation at the same frequency and current parameters as continuous stimulation that would stop reward acquisition. Neural recordings during DBS showed that CeA neurons were still active and uncovered inhibitory-excitatory patterns after each stimulus pulse indicating possible entrainment of the neural firing with DBS. In summary, DBS modulation of CeA may effectively usurp normal neural activity patterns to create an 'information lesion' that not only decreased motivational 'wanting' of food rewards, but also blocked 'liking' of rewards.

Disentangling pleasure from incentive salience and learning signals in brain reward circuitry.

Multiple signals for reward-hedonic impact, motivation, and learned associative prediction-are funneled through brain mesocorticolimbic circuits involving the nucleus accumbens and ventral pallidum. Here, we show how the hedonic "liking" and motivation "wanting" signals for a sweet reward are distinctly modulated and tracked in this circuit separately from signals for Pavlovian predictions (learning). Animals first learned to associate a fixed sequence of Pavlovian cues with sucrose reward. Subsequent intraaccumbens microinjections of an opioid-stimulating drug increased the hedonic liking impact of sucrose in behavior and firing signals of ventral pallidum neurons, and likewise, they increased incentive salience signals in firing to the reward-proximal incentive cue (but did not alter firing signals to the learned prediction value of a reward-distal cue). Microinjection of a dopamine-stimulating drug instead enhanced only the motivation component but did not alter hedonic impact or learned prediction signals. Different dedicated neuronal subpopulations in the ventral pallidum tracked signal enhancements for hedonic impact vs. incentive salience, and a faster firing pattern also distinguished incentive signals from slower hedonic signals, even for a third overlapping population. These results reveal separate neural representations of wanting, liking, and prediction components of the same reward within the nucleus accumbens to ventral pallidum segment of mesocorticolimbic circuitry.

Altered locus coeruleus-norepinephrine function following single prolonged stress.

Data from preclinical and clinical studies have implicated the norepinephrine system in the development and maintenance of post-traumatic stress disorder. The primary source of norepinephrine in the forebrain is the locus coeruleus (LC); however, LC activity cannot be directly measured in humans, and previous research has often relied upon peripheral measures of norepinephrine to infer changes in central LC-norepinephrine function. To directly assess LC-norepinephrine function, we measured single-unit activity of LC neurons in a validated rat model of post-traumatic stress disorder - single prolonged stress (SPS). We also examined tyrosine hydroxylase mRNA levels in the LC of SPS and control rats as an index of norepinephrine utilisation. For electrophysiological recordings, 92 LC neurons were identified from 19 rats (SPS, 12; control, 7), and spontaneous and evoked responses to a noxious event (paw compression) were recorded. Baseline and restraint stress-evoked tyrosine hydroxylase mRNA expression levels were measured in SPS and control rats (n = 16 per group) in a separate experiment. SPS rats showed lower spontaneous activity but higher evoked responses, leading to an enhanced signal-to-noise ratio of LC neurons, accompanied by impaired recovery from post-stimulus inhibition. In concert, tyrosine hydroxylase mRNA expression in the LC of SPS rats tended to be lower at baseline, but was exaggerated following restraint stress. These data demonstrate persistent changes in LC function following stress/trauma in a rat model of post-traumatic stress, as measured by differences in both the electrophysiological properties of LC neurons and tyrosine hydroxylase mRNA transcription.

Dynamic computation of incentive salience: "wanting" what was never "liked".

Pavlovian cues for rewards become endowed with incentive salience, guiding "wanting" to their learned reward. Usually, cues are "wanted" only if their rewards have ever been "liked," but here we show that mesocorticolimbic systems can recompute "wanting" de novo by integrating novel physiological signals with a cue's preexisting associations to an outcome that lacked hedonic value. That is, a cue's incentive salience can be recomputed adaptively. We demonstrate that this recomputation is encoded in neural signals coursing through the ventral pallidum. Ventral pallidum neurons do not ordinarily fire vigorously to a cue that predicts the previously "disliked" taste of intense salt, although they do fire to a cue that predicts the taste of previously "liked" sucrose. Yet we show that neural firing rises dramatically to the salt cue immediately and selectively when that cue is encountered in a never-before-experienced state of physiological salt depletion. Crucially, robust neural firing to the salt cue occurred the first time it was encountered in the new depletion state (in cue-only extinction trials), even before its associated intense saltiness has ever been tasted as positively "liked" (salt taste had always been "disliked" before). The amplification of incentive salience did not require additional learning about the cue or the newly positive salt taste. Thus dynamic recomputation of cue-triggered "wanting" signals can occur in real time at the moment of cue re-encounter by combining previously learned Pavlovian associations with novel physiological information about a current state of specific appetite.

A neural computational model of incentive salience.

Incentive salience is a motivational property with 'magnet-like' qualities. When attributed to reward-predicting stimuli (cues), incentive salience triggers a pulse of 'wanting' and an individual is pulled toward the cues and reward. A key computational question is how incentive salience is generated during a cue re-encounter, which combines both learning and the state of limbic brain mechanisms. Learning processes, such as temporal-difference models, provide one way for stimuli to acquire cached predictive values of rewards. However, empirical data show that subsequent incentive values are also modulated on the fly by dynamic fluctuation in physiological states, altering cached values in ways requiring additional motivation mechanisms. Dynamic modulation of incentive salience for a Pavlovian conditioned stimulus (CS or cue) occurs during certain states, without necessarily requiring (re)learning about the cue. In some cases, dynamic modulation of cue value occurs during states that are quite novel, never having been experienced before, and even prior to experience of the associated unconditioned reward in the new state. Such cases can include novel drug-induced mesolimbic activation and addictive incentive-sensitization, as well as natural appetite states such as salt appetite. Dynamic enhancement specifically raises the incentive salience of an appropriate CS, without necessarily changing that of other CSs. Here we suggest a new computational model that modulates incentive salience by integrating changing physiological states with prior learning. We support the model with behavioral and neurobiological data from empirical tests that demonstrate dynamic elevations in cue-triggered motivation (involving natural salt appetite, and drug-induced intoxication and sensitization). Our data call for a dynamic model of incentive salience, such as presented here. Computational models can adequately capture fluctuations in cue-triggered 'wanting' only by incorporating modulation of previously learned values by natural appetite and addiction-related states.

Dissecting components of reward: 'liking', 'wanting', and learning.

In recent years significant progress has been made delineating the psychological components of reward and their underlying neural mechanisms. Here we briefly highlight findings on three dissociable psychological components of reward: 'liking' (hedonic impact), 'wanting' (incentive salience), and learning (predictive associations and cognitions). A better understanding of the components of reward, and their neurobiological substrates, may help in devising improved treatments for disorders of mood and motivation, ranging from depression to eating disorders, drug addiction, and related compulsive pursuits of rewards.

Computing motivation: Incentive salience boosts of drug or appetite states.

Current computational models predict reward based solely on learning. Real motivation involves that but also more. Brain reward systems can dynamically generate incentive salience, by integrating prior learned values with even novel physiological states (e.g., natural appetites; drug-induced mesolimbic sensitization) to cause intense desires that were themselves never learned. We hope future computational models may capture this too.

DECISION UTILITY, THE BRAIN, AND PURSUIT OF HEDONIC GOALS.

How do brain representations of the utility of a hedonic goal guide decisions about whether to pursue it? Our focus here will be on brain mechanisms of reward utility operating at particular decision moments in life. Moments such as when you encounter an image, sound, scent or other cue associated in your past with a particular reward; or perhaps just vividly imagine that cue. Such a cue can often trigger a sudden motivational urge to pursue that goal, and sometimes a decision to do so. In drug addicts trying to quit, a cue for the addicted drug might trigger urges that rise to compulsive levels of intensity, despite prior commitments to abstain, leading to the decision to relapse into taking the drug again. Normal or addicted, the urge and decision may well have been lacking immediately before the cue was encountered. The decision to pursue the cued reward might never have happened if the cue had not been encountered. Why can such cues momentarily dominate decision making? The answer involves brain mesolimbic dopamine mechanisms that amplify the incentive salience of reward cues, selectively elevating decision utility to trigger "wanting" for the goal. We describe affective neuroscience studies of brain limbic generators of "wanting" that shed light on how cues trigger pursuit of their goals, both normally and even under intense conditions of irrational goal pursuit.

Dynamic Encoding of Incentive Salience in the Ventral Pallidum: Dependence on the Form of the Reward Cue.

Some rats are especially prone to attribute incentive salience to a cue (conditioned stimulus, CS) paired with food reward (sign-trackers, STs), but the extent they do so varies as a function of the form of the CS. Other rats respond primarily to the predictive value of a cue (goal-trackers, GTs), regardless of its form. Sign-tracking is associated with greater cue-induced activation of mesolimbic structures than goal-tracking; however, it is unclear how the form of the CS itself influences activity in neural systems involved in incentive salience attribution. Thus, our goal was to determine how different cue modalities affect neural activity in the ventral pallidum (VP), which is known to encode incentive salience attribution, as rats performed a two-CS Pavlovian conditioned approach task in which both a lever-CS and a tone-CS predicted identical food reward. The lever-CS elicited sign-tracking in some rats (STs) and goal-tracking in others (GTs), whereas the tone-CS elicited only goal-tracking in all rats. The lever-CS elicited robust changes in neural activity (sustained tonic increases or decreases in firing) throughout the VP in STs, relative to GTs. These changes were not seen when STs were exposed to the tone-CS, and in GTs there were no differences in firing between the lever-CS and tone-CS. We conclude that neural activity throughout the VP encodes incentive signals and is especially responsive when a cue is of a form that promotes the attribution of incentive salience to it, especially in predisposed individuals.

A Computerized Microelectrode Recording to Magnetic Resonance Imaging Mapping System for Subthalamic Nucleus Deep Brain Stimulation Surgery.

BACKGROUND: Accurate electrode placement is critical to the success of deep brain stimulation (DBS) surgery. Suboptimal targeting may arise from poor initial target localization, frame-based targeting error, or intraoperative brain shift. These uncertainties can make DBS surgery challenging. OBJECTIVE: To develop a computerized system to guide subthalamic nucleus (STN) DBS electrode localization and to estimate the trajectory of intraoperative microelectrode recording (MER) on magnetic resonance (MR) images algorithmically during DBS surgery. METHODS: Our method is based upon the relationship between the high-frequency band (HFB; 500-2000 Hz) signal from MER and voxel intensity on MR images. The HFB profile along an MER trajectory recorded during surgery is compared to voxel intensity profiles along many potential trajectories in the region of the surgically planned trajectory. From these comparisons of HFB recordings and potential trajectories, an estimate of the MER trajectory is calculated. This calculated trajectory is then compared to actual trajectory, as estimated by postoperative high-resolution computed tomography. RESULTS: We compared 20 planned, calculated, and actual trajectories in 13 patients who underwent STN DBS surgery. Targeting errors for our calculated trajectories (2.33 mm ± 0.2 mm) were significantly less than errors for surgically planned trajectories (2.83 mm ± 0.2 mm; P = .01), improving targeting prediction in 70% of individual cases (14/20). Moreover, in 4 of 4 initial MER trajectories that missed the STN, our method correctly indicated the required direction of targeting adjustment for the DBS lead to intersect the STN. CONCLUSION: A computer-based algorithm simultaneously utilizing MER and MR information potentially eases electrode localization during STN DBS surgery.

Improved signal and reduced noise in neural recordings from close-spaced electrode arrays using independent component analysis as a preprocessor.

Noise can greatly complicate the isolation of individual cell action potential waveforms for the sake of electrophysiological analysis. For an experiment involving recording in the thalamus/subthalamus areas of a rat brain, a hybrid hardware/software method was utilized to improve the signal-to-noise quality of the recorded signal on each recording channel. The procedure uses closely spaced recording electrode arrays and independent component analysis (ICA) to fortify the signal energy of a single spike by combining input from several channels, and concurrently to reduce the noise on each channel by isolating common mode components such as artifacts, slow waves, and correlated distant spike activation. In the next step, a wavelet denoising-based signal-to-noise assessment is used to quantify the improvement in data quality for each data record. The data presented here demonstrate that this method, which can be applied off-line as a preprocessor to other time domain or transform domain spike sorting methods, is consistently effective at improving data quality and facilitating subsequent detection and classification of neurons.

Persistent neurochemical and behavioral abnormalities in adulthood despite early iron supplementation for perinatal iron deficiency anemia in rats.

BACKGROUND: Iron deficiency anemia (IDA) has been associated with altered cognitive, motor, and social-emotional outcomes in human infants. We recently reported that rats with chronic perinatal IDA, had altered regional brain iron, monoamines, and sensorimotor skill emergence during early development. OBJECTIVE: To examine the long-term consequences of chronic perinatal IDA on behavior, brain iron and monoamine systems after dietary iron treatment in rats. METHODS: Sixty dams were randomly assigned to iron-sufficient (CN) or low-iron (EID) diets during gestation and lactation. Thereafter, all offspring were fed the iron-sufficient diet, assessed for hematology and behavior after weaning and into adulthood and for brain measures as adults (regional brain iron, monoamines, dopamine and serotonin transporters, and dopamine receptor). Behavioral assessments included sensorimotor function, general activity, response to novelty, spatial alternation, and spatial water maze performance. RESULTS: Hematology and growth were similar for EID and CN rats by postnatal day 35. In adulthood, EID thalamic iron content was lower. Monoamines, dopamine transporter, and dopamine receptor concentrations did not differ from CN. EID serotonin transporter concentration was reduced in striatum and related regions. EID rats had persisting sensorimotor deficits (delayed vibrissae-evoked forelimb placing, longer sticker removal time, and more imperfect grooming chains), were more hesitant in novel settings, and had poorer spatial water maze performance than CN. General activity and spatial alternation were similar for EID and CN. CONCLUSION: Rats that had chronic perinatal IDA showed behavioral impairments that suggest persistent striatal dopamine and hippocampal dysfunction despite normalization of hematology, growth and most brain measures.

Sequential super-stereotypy of an instinctive fixed action pattern in hyper-dopaminergic mutant mice: a model of obsessive compulsive disorder and Tourette's.

BACKGROUND: Excessive sequential stereotypy of behavioral patterns (sequential super-stereotypy) in Tourette's syndrome and obsessive compulsive disorder (OCD) is thought to involve dysfunction in nigrostriatal dopamine systems. In sequential super-stereotypy, patients become trapped in overly rigid sequential patterns of action, language, or thought. Some instinctive behavioral patterns of animals, such as the syntactic grooming chain pattern of rodents, have sufficiently complex and stereotyped serial structure to detect potential production of overly-rigid sequential patterns. A syntactic grooming chain is a fixed action pattern that serially links up to 25 grooming movements into 4 predictable phases that follow 1 syntactic rule. New mutant mouse models allow gene-based manipulation of brain function relevant to sequential patterns, but no current animal model of spontaneous OCD-like behaviors has so far been reported to exhibit sequential super-stereotypy in the sense of a whole complex serial pattern that becomes stronger and excessively rigid. Here we used a hyper-dopaminergic mutant mouse to examine whether an OCD-like behavioral sequence in animals shows sequential super-stereotypy. Knockdown mutation of the dopamine transporter gene (DAT) causes extracellular dopamine levels in the neostriatum of these adult mutant mice to rise to 170% of wild-type control levels. RESULTS: We found that the serial pattern of this instinctive behavioral sequence becomes strengthened as an entire entity in hyper-dopaminergic mutants, and more resistant to interruption. Hyper-dopaminergic mutant mice have stronger and more rigid syntactic grooming chain patterns than wild-type control mice. Mutants showed sequential super-stereotypy in the sense of having more stereotyped and predictable syntactic grooming sequences, and were also more likely to resist disruption of the pattern en route, by returning after a disruption to complete the pattern from the appropriate point in the sequence. By contrast, wild-type mice exhibited weaker forms of the fixed action pattern, and often failed to complete the full sequence. CONCLUSIONS: Sequential super-stereotypy occurs in the complex fixed action patterns of hyper-dopaminergic mutant mice. Elucidation of the basis for sequential super-stereotypy of instinctive behavior in DAT knockdown mutant mice may offer insights into neural mechanisms of overly-rigid sequences of action or thought in human patients with disorders such as Tourette's or OCD.

Ventral pallidal coding of a learned taste aversion.

The hedonic value of a sweet food reward, or how much a taste is 'liked', has been suggested to be encoded by neuronal firing in the posterior ventral pallidum (VP). Hedonic impact can be altered by psychological manipulations, such as taste aversion conditioning, which can make an initially pleasant sweet taste become perceived as disgusting. Pairing nausea-inducing LiCl injection as a Pavlovian unconditioned stimulus (UCS) with a novel taste that is normally palatable as the predictive conditioned stimulus (CS+) suffices to induce a learned taste aversion that changes orofacial 'liking' responses to that sweet taste (e.g., lateral tongue protrusions) to 'disgust' reactions (e.g., gapes) in rats. We used two different sweet tastes of similar initial palatability (a sucrose solution and a polycose/saccharin solution, CS ± assignment was counterbalanced across groups) to produce a discriminative conditioned aversion. Only one of those tastes (arbitrarily assigned and designated as CS+) was associatively paired with LiCl injections as UCS to form a conditioned aversion. The other taste (CS-) was paired with mere vehicle injections to remain relatively palatable as a control sweet taste. We recorded the neural activity in VP in response to each taste, before and after aversion training. We found that the safe and positively hedonic taste always elicited excitatory increases in firing rate of VP neurons. By contrast, aversion learning reversed the VP response to the 'disgusting' CS+ taste from initial excitation into a conditioned decrease in neuronal firing rate after training. Such neuronal coding of hedonic impact by VP circuitry may contribute both to normal pleasure and disgust, and disruptions of VP coding could result in affective disorders, addictions and eating disorders.

Ventral pallidal representation of pavlovian cues and reward: population and rate codes.

We recorded neural activity in the ventral pallidum (VP) while rats learned a pavlovian reward association. Rats learned to distinguish a tone that predicted sucrose pellets (CS+) from a different tone that predicted nothing (CS-). Many VP units became responsive to CS+, but few units responded to CS-. When two CS+ were encountered sequentially, the earliest predictor of reward became most potent. Many VP units were also activated when the sucrose reward was received [unconditioned stimulus (UCS)]. These VP units for UCS remained responsive to sucrose reward after learning, even when sucrose was already predicted by CS+. Neural representation of reward learning and reward itself was characterized by population codes. The population of units that responded to CS+ increased with learning, whereas the population that responded to UCS did not change. A relative firing rate code also represented the identities of conditioned stimuli and UCS. Firing rate differences among stimuli were acquired early and remained stable during subsequent training, whereas population codes and behavioral conditioned responses continued to develop during subsequent training. Thus, the VP makes use of dynamic CS population and rate codes to encode pavlovian reward cues in reward learning and uses stable UCS population and firing codes to encode sucrose reward itself.

Hyperdopaminergic mutant mice have higher "wanting" but not "liking" for sweet rewards.

What is the role of dopamine in natural rewards? A genetic mutant approach was taken to examine the consequences of elevated synaptic dopamine on (1) spontaneous food and water intake, (2) incentive motivation and learning to obtain a palatable sweet reward in a runway task, and (3) affective "liking" reactions elicited by the taste of sucrose. A dopamine transporter (DAT) knockdown mutation that preserves only 10% of normal DAT, and therefore causes mutant mice to have 70% elevated levels of synaptic dopamine, was used to identify dopamine effects on food intake and reward. We found that hyperdopaminergic DAT knockdown mutant mice have higher food and water intake. In a runway task, they demonstrated enhanced acquisition and greater incentive performance for a sweet reward. Hyperdopaminergic mutant mice leave the start box more quickly than wild-type mice, require fewer trials to learn, pause less often in the runway, resist distractions better, and proceed more directly to the goal. Those observations suggest that hyperdopaminergic mutant mice attribute greater incentive salience ("wanting") to a sweet reward in the runway test. But sucrose taste fails to elicit higher orofacial "liking" reactions from mutant mice in an affective taste reactivity test. These results indicate that chronically elevated extracellular dopamine facilitates "wanting" and learning of an incentive motivation task for a sweet reward, but elevated dopamine does not increase "liking" reactions to the hedonic impact of sweet tastes.

The anatomical and electrophysiological subthalamic nucleus visualized by 3-T magnetic resonance imaging.

BACKGROUND: Accurate localization of the subthalamic nucleus (STN) is critical to the success of deep brain stimulation surgery for Parkinson disease. Recent developments in high-field-strength magnetic resonance imaging (MRI) have made it possible to visualize the STN in greater detail. However, the relationship of the MR-visualized STN to the anatomic, electrophysiological, or atlas-predicted STN remains controversial. OBJECTIVE: To evaluate the size of the STN visualized on 3-T MRI compared with anatomic measurements in cadaver studies and to compare the predictions of 3-T MRI and those of the Schaltenbrand-Wahren (SW) atlas for intraoperative STN microelectrode recordings. METHODS: We evaluated the STN by 3-T MRI and intraoperative microelectrode recordings in 20 Parkinson disease patients undergoing deep brain stimulation surgery. We compared our findings with anatomic cadaver studies and with the individually scaled SW atlas-based predictions for each patient. RESULTS: The dimensions of the 3-T MR-visualized STN were very similar to those of the largest anatomic study (MRI length, width, and height: 9.8 ± 1.6, 11.5 ± 1.6, and 3.7 ± 0.7 mm, respectively; n = 40; cadaver length, width, and height: 9.3 ± 0.7, 10.6 ± 0.9, and 3.1 ± 0.5 mm, respectively; n = 100). The amount of STN traversed during intraoperative microelectrode recordings was better correlated to the 3-T MR-visualized STN than the SW atlas-predicted STN (R = 0.38 vs R = -0.17). CONCLUSION: The STN as visualized on 3-T MRI corresponds well with cadaveric anatomic studies and intraoperative electrophysiology. STN visualization with 3-T MRI may be an improvement over SW atlas-based localization for STN deep brain stimulation surgery in Parkinson disease.

Dopamine receptor modulation of repetitive grooming actions in the rat: potential relevance for Tourette syndrome.

Studies of rodent grooming can provide valuable insight for dopamine contributions to the initiation, organization, and repetition of motor patterns. This information is useful for understanding how brain dysfunctions contribute to movement disorders such as Tourette syndrome and obsessive compulsive disorder, in which patients are driven to reiterate particular movement patterns. In rodents, dopamine D1 receptor stimulation causes a complex behavioral super-stereotypy in the form of excessive production and rigid execution of whole sequences of movements known as syntactic grooming chains. Sequential super-stereotypy of grooming chains may be particularly advantageous for modeling movement sequences and treatments in Tourette syndrome and related disorders. Here, we report that co-administration of haloperidol, one available treatment for Tourette syndrome and primarily a D2 receptor antagonist, prevented D1 stimulation with SKF38393 from inducing sequential super-stereotypy, which manifests as an exaggeration of the tendency to complete all four phases of a syntactic chain in rigid serial order once the first phase has begun. In a separate experiment, we showed that in contrast to acute D1 agonist administration, 39h withdrawal from chronic (3weeks) administration of the D1 antagonist SCH23390 (which has been suggested to increase D1 receptor expression in the basal ganglia) did not elicit sequential super-stereotypy after drug cessation. Instead, rats suddenly removed from repeated SCH23390 spent more time performing simple stereotypies that included intense scratching and biting behaviors. Together, these results have implications for understanding how dopamine receptors facilitate particular stereotypies manifest in animal models of Tourette syndrome and obsessive compulsive disorder.