Rat anterior cingulate neurons responsive to rule or strategy changes are modulated by the hippocampal theta rhythm and sharp-wave ripples.

To better understand neural processing during adaptive learning of stimulus-response-reward contingencies, we recorded synchrony of neuronal activity in anterior cingulate cortex (ACC) and hippocampal rhythms in male rats acquiring and switching between spatial and visual discrimination tasks in a Y-maze. ACC population activity as well as single unit activity shifted shortly after task rule changes or just before the rats adopted different task strategies. Hippocampal theta oscillations (associated with memory encoding) modulated an elevated proportion of rule-change responsive neurons (70%), but other neurons that were correlated with strategy-change, strategy value and reward-rate were not. However, hippocampal sharp wave-ripples modulated significantly higher proportions of rule-change, strategy-change and reward-rate responsive cells during post-session sleep but not pre-session sleep. This suggests an underestimated mechanism for hippocampal mismatch and contextual signals to facilitate ACC to detect contingency changes for cognitive flexibility, a function that is attenuated after it is damaged.

Autonomy and competence satisfaction as resources for facing chronic pain disability in adolescence: a self-determination perspective.

This study aimed to test empirically the developmental goal pursuit model of paediatric chronic pain, which draws upon Self-Determination Theory for understanding risks and resources for living with chronic pain. This study examined the relationship between basic psychological need satisfaction (i.e. the satisfaction of the needs for autonomy, relatedness and competence) and the fear-avoidance model of pain in adolescents suffering from chronic pain. Hundred and twenty adolescents (mean age = 14.52, 71.6% female), receiving treatment through paediatric pain centres for chronic pain, were enrolled. Adolescents completed measures of basic psychological need satisfaction, fear and avoidance of pain, and pain-related functional impairment. Path analyses model indicated that higher levels of autonomy and competence satisfaction were associated with lower levels of functional disability, through the mediation of fear and avoidance of pain. Relatedness satisfaction was not significatively related to fear of pain, avoidance, and functional disability. The integration of Self-Determination Theory in the paediatric pain literature may further our understanding of potential resources for decreasing functional disability in children living with chronic pain.

Neuronal activity in the nucleus accumbens and hippocampus in rats during formation of seeking behavior in a radial maze.

Seeking behavior of rats in a radial maze with asymmetric reward was studied by means of synchronous recording of cell activity in the hippocampus and ventral striatum. The synchrony of cell activity in the hippocampus and nucleus accumbens was modulated by spatial position and reward; the important role in this synchronization can be played by theta rhythm. This is in line with the anatomical and physiological data on the convergence of hippocampal spatially organized positional and reward value information inputs from the amygdala and ventral segmental area to n. accumbens.

A case of acute cerebral ischemia following inhalation of a synthetic cannabinoid.

OBJECTIVE: Synthetic cannabinoids are increasingly used in the United States as marijuana substitutes. However, reports of severe toxicity, resulting from their use, are limited. We present the case of acute cerebral infarction following synthetic cannabinoid inhalation. CASE REPORT: A 33-year-old man with no significant medical history presented at the emergency department with right-sided weakness and aphasia. He had smoked a synthetic cannabinoid (SC) product called "WTF" prior to the onset of symptoms. Physical examination showed right hemiparesis, dysarthria, and aphasia. Laboratory evaluation, electrocardiography, and computed tomography (CT) of the head were unremarkable. Following administration of intravenous tissue plasminogen activator, his symptoms improved. A repeat head CT showed acute infarction in the left insular cortex. His hypercoagulability panel was unremarkable, and the patient was discharged neurologically intact. Urine toxicology results were unremarkable. Analysis of the product by gas chromatography-mass spectrometry (GC-MS) procedure confirmed the presence of a synthetic cannabinoid known as XLR-11. CONCLUSION: XLR-11 has previously been associated with acute kidney injury in humans. However, there are no reports of it causing acute cerebral ischemic events. The close temporal association between XLR-11 inhalation and his stroke is concerning. Acute cerebral infarction may occur after XLR-11 use in healthy patients.

Spatially selective reward site responses in tonically active neurons of the nucleus accumbens in behaving rats.

To study how hippocampal output signals conveying spatial and other contextual information might be integrated in the nucleus accumbens, tonically active accumbens neurons were recorded in three unrestrained rats as they performed spatial orientation tasks on an elevated round rotatable platform with four identical reward boxes symmetrically placed around the edge. The partially water-deprived rats were required to shuttle either between the pair of reward boxes indicated by beacon cues (lights in the boxes) or between the pair of boxes occupying particular locations in relation to environmental landmark cues. In 43/82 neurons, behaviorally correlated phasic modulations in discharge activity occurred, primarily prior to or after water was provided at the reward boxes. Twenty-two had inhibitory modulation, 12 excitatory, and nine were mixed excitatory and inhibitory. Although tonically active neurons (TANs) have rarely been reported in the rodent, the inhibitory and mixed responses correspond to previously reports in the macaque accumbens of tonically active neurons with activity correlated with reward delivery and, following conditioning, to sensory stimuli associated with rewards. Eighteen of the 43 tonically active accumbens neurons showed spatial selectivity, i.e., behaviorally correlated increases or decreases in firing rate were of different magnitudes at the respective reward boxes. This is the first demonstration that the configuration of environmental sensory cues associated with reward sites are also an effective stimulus for these neurons and that different neurons are selective for different places. These results are consistent with a role for the nucleus accumbens in the initiation of goal-directed displacement behaviors.

Reward value invariant place responses and reward site associated activity in hippocampal neurons of behaving rats.

To investigate the involvement of the hippocampal-accumbens system in goal-oriented displacement behaviors, hippocampal neuronal activity was recorded in rats learning and recalling new distributions of different volumes of liquid reward among the arms of a plus maze. Each arm had a reward box containing a water trough and identical visual cues that could be illuminated independently. As the water-restricted rat successively visited the respective boxes, it received 7, 5, and 3 drops of water, and then 1 drop, provided at 1-s intervals. (Reward distributions were reassigned daily and mid-session.) In the training phase, reward boxes were lit individually. In the recall phase, the lamps on all arms were lit and then turned off as the rat visited the boxes in order of descending value. Neuronal firing rates were analyzed for changes related to reward value or to shifts between learning and recall phases. The principal finding is that place responses remained unchanged after these manipulations and that these neurons showed no evidence of explicit coding of reward value. In addition, two other types of responses appeared while the rat was stationary at the reward boxes awaiting multiple rewards. These were observed primarily in neurons within the dentate gyrus, but also in CA1. Position-selective reward site responses were regular at 20-60 impulses per second, while position-independent discharges bursted irregularly at about 5 impulses per second. Such responses could explain controversial reports of reward dependence in hippocampal neurons. The higher incidence of the latter responses in the temporal ("ventral") hippocampus is consistent with the distinctive anatomical and functional properties of this subregion.

Position sensitivity in phasically discharging nucleus accumbens neurons of rats alternating between tasks requiring complementary types of spatial cues.

To determine how hippocampal location-selective discharges might influence downstream structures for navigation, nucleus accumbens neurons were recorded in rats alternating between two tasks guided respectively by lit cues in the maze or by extramaze room cues. Of 144 phasically active neurons, 80 showed significant behavioral correlates including displacements, immobility prior to, or after reward delivery, as well as turning, similar to previous reports. Nine neurons were position-selective, 22 were sensitive to task and platform changes and 40 others were both. Although the accumbens neurons showed the same behavioral correlate in two or four functionally equivalent locations, these responses were stronger at some of these places, evidence for position sensitivity. To test whether position responses were selective for room versus platform cues, the experimental platform was rotated while the rat performed each of the two tasks. This revealed responses to changes in position relative to both platform and room cues, despite the fact that previous studies had shown that place responses of hippocampal neurons recorded in the same task are anchored to room cues only. After these manipulations and shifts between the two tasks, the responses varied among simultaneously recorded neurons, and even in single neurons in alternating visits to reward sites. Again this contrasts with the uniformity of place responses of hippocampal neurons recorded in this same task. Thus accumbens position responses may derive from hippocampal inputs, while responses to context changes are more likely to derive from other signals or intrinsic processing. Considering the accumbens as a limbic-motor interface, we conclude that position-modulated behavioral responses in the accumbens may be intermediate between the allocentric reference frame of position-selective discharges in the hippocampus and the egocentric coding required to organize movement control. The conflicting responses among simultaneously recorded neurons could reflect competition processes serving as substrates for action selection and learning.

Active locomotion increases peak firing rates of anterodorsal thalamic head direction cells.

Head direction (HD) cells discharge selectively in macaques, rats, and mice when they orient their head in a specific ("preferred") direction. Preferred directions are influenced by visual cues as well as idiothetic self-motion cues derived from vestibular, proprioceptive, motor efferent copy, and command signals. To distinguish the relative importance of active locomotor signals, we compared HD cell response properties in 49 anterodorsal thalamic HD cells of six male Long-Evans rats during active displacements in a foraging task as well as during passive rotations. Since thalamic HD cells typically stop firing if the animals are tightly restrained, the rats were trained to remain immobile while drinking water distributed at intervals from a small reservoir at the center of a rotatable platform. The platform was rotated in a clockwise/counterclockwise oscillation to record directional responses in the stationary animals while the surrounding environmental cues remained stable. The peak rate of directional firing decreased by 27% on average during passive rotations (r(2) = 0.73, P < 0.001). Individual cells recorded in sequential sessions (n = 8) reliably showed comparable reductions in peak firing, but simultaneously recorded cells did not necessarily produce identical responses. All of the HD cells maintained the same preferred directions during passive rotations. These results are consistent with the hypothesis that the level of locomotor activity provides a state-dependent modulation of the response magnitude of AD HD cells. This could result from diffusely projecting neuromodulatory systems associated with motor state.

Background, but not foreground, spatial cues are taken as references for head direction responses by rat anterodorsal thalamus neurons.

Two populations of limbic neurons are likely neurophysiological substrates for cognitive operations required for spatial orientation and navigation: hippocampal pyramidal cells discharge selectively when the animal is in a certain place (the "firing field") in the environment, whereas head direction cells discharge when the animal orients its head in a specific, "preferred" direction. Cressant et al. (1997) showed that the firing fields of hippocampal place cells reorient relative to a group of three-dimensional objects only if these are at the periphery, but not the center of an enclosed platform. To test for corresponding responses in head direction cells, three objects were equally spaced along the periphery of a circular platform. Preferred directions were measured before and after the group of objects was rotated. (The rat was disoriented in total darkness between sessions). This was repeated in the presence or absence of a cylinder enclosing the platform. When the enclosure was present, the preferred directions of all 30 cells recorded shifted by the same angle as the objects. In the absence of the enclosure, the preferred directions did not follow the objects, remaining fixed relative to the room. These results provide a possible neurophysiological basis for observations from psychophysical experiments in humans that background, rather than foreground, cues are preferentially used for spatial orientation.

Lesions of the medial shell of the nucleus accumbens impair rats in finding larger rewards, but spare reward-seeking behavior.

The goal of this study was to help better understand the importance of the nucleus accumbens (Nacc) in the processing of position and reward value information for goal-directed orientation behaviors. Sixteen male Long-Evans rats, under partial water deprivation, were trained in a plus-maze to find water rewards in the respective arms which were lit in pseudo-random sequence (training trials). Each day one reward arm was selected to deliver six drops of water (at 1 s intervals) the others provided only one drop per visit. After 32 visits, probe trials were intermittently presented among training trials. Here, all four arms were lit and offered the previously assigned reward. The rats rapidly learned to go to the highly rewarded arm. Six trained rats were given bilateral electrolytic lesions in the Nacc shell, two others had unilateral lesions and eight had sham operations (with approved protocols). Field potentials evoked by fornix stimulation were recorded in lesion electrodes to guide placements. Only the lesioned rats showed significant impairments (P<0.05) in selecting the greater reward on probe trials. However on training trials, lesioned (and sham-operated) rats made only rare errors. While the motivation to drink and the capacity for cue-guided goal-directed orientation behavior was spared, lesioned rats were impaired in learning the location of the larger reward. The accumbens lesions apparently impaired integration of position and reward value information, consistent with anatomical and electrophysiological data showing the convergence of hippocampal, amygdalar, ventral tegmental area (VTA) and prefrontal cortical inputs there.

Influence of conflicting visual, inertial and substratal cues on head direction cell activity.

In order to navigate efficiently, animals can benefit from internal representations of their moment-to-moment orientation. Head-direction (HD) cells are neurons that discharge maximally when the head of a rat is oriented in a specific ("preferred") direction in the horizontal plane, independently from position or ongoing behavior. This directional selectivity depends on environmental and inertial cues. However, the mechanisms by which these cues are integrated remain unknown. This study examines the relative influence of visual, inertial and substratal cues on the preferred directions of HD cells when cue conflicts are produced in the presence of the rats. Twenty-nine anterior dorsal thalamic (ATN) and 19 postsubicular (PoS) HD cells were recorded from 7 rats performing a foraging task in a cylinder (76 cm in diameter, 60 cm high) with a white card attached to its inner wall. Changes in preferred directions were measured after the wall or the floor of the cylinder was rotated separately or together in the same direction by 45 degrees, 90 degrees or 180 degrees, either clockwise or counterclockwise. Linear regression analyses showed that the preferred directions of the HD cells in both structures shifted by approximately =90% of the angle of rotation of the wall, whether rotated alone or together with the floor (r2>0.87, P<0.001). Rotations of the floor alone did not trigger significant shifts in preferred directions. These results indicate that visual cues exerted a strong but incomplete control over the preferred directions of the neurons, while inertial cues had a small but significant influence, and substratal cues were of no consequence.

Manometric changes during retrograde biliary infusion in mice.

The manometric, ultrastructural, radiographic, and physiological consequences of retrograde biliary infusion were determined in normostatic and cholestatic mice. Intraluminal biliary pressure changed as a function of infusion volume, rate, and viscosity. Higher rates of constant infusion resulted in higher peak intraluminal biliary pressures. The pattern of pressure changes observed was consistent with biliary ductular and/or canalicular filling followed by leakage at a threshold pressure. Retrograde infusion with significant elevations in pressure led to paracellular leakage of lanthanum chloride, radiopaque dye, and [(14)C]sucrose with rapid systemic redistribution via sinusoidal and subsequent hepatic venous drainage. Chronic extrahepatic bile duct obstruction resulted in significantly smaller peak intrabiliary pressures and lower levels of paracellular leakage. These findings indicate that under both normostatic and cholestatic conditions elevated intrabiliary volumes/pressures result in an acute pressure-dependent physical opening of tight junctions, permitting the movement of infusate from the intrabiliary space into the subepithelial tissue compartment. Control of intraluminal pressure may potentially permit the selective delivery of macromolecules >18-20 A in diameter to specific histological compartments.

Position and behavioral modulation of synchronization of hippocampal and accumbens neuronal discharges in freely moving rats.

To understand how hippocampal signals are processed by downstream neurons, we analyzed the relative timing between neuronal discharges in simultaneous recordings in the hippocampus and nucleus accumbens of rats performing in a plus maze. In all, 154 pairs of cells (composed of 65 hippocampal and 56 accumbens neurons) were examined during the 1 s period prior to reward delivery. Cross-correlation analyses over a +/- 300-ms window with 10-ms bins revealed that 108 pairs had at least one significant histogram bin (P < 0.01). The most frequently occurring peaks of hippocampal firing prior to accumbens discharges appeared at latencies from -30-0 ms, corresponding to published values of the latency of the hippocampal pathway to the nucleus accumbens. Other peaks appeared most often at latencies multiples of about 110 ms prior to and after this, corresponding to theta rhythmicity. Since firing synchronization can result from several types of connectivity patterns (such as common inputs), a group of 18 hippocampus-accumbens pairs was selected as those most likely to have monosynaptic connections. The criterion was the presence of at least one highly significant peak (P < 0.001) at latencies corresponding to field potentials evoked in the accumbens by hippocampal stimulation. A significant peak occurred on all four maze arms for only one of these cell pairs, indicating positional modulation for the others. In addition, behavior dependence of the synchrony between these nucleus accumbens and hippocampus neurons was examined by studying data in relation to three different synchronization points: reward box arrival, box departure, and arrival at the center of the maze. This indicates that the functional connectivity between hippocampal and accumbens neurons was stronger when the rat was near reward areas. Ten of the hippocampal neurons in these 18 cell pairs showed 9-Hz (theta) rhythmic activity in autocorrelation analyses. Of these 10 cells, cross-correlograms from eight hippocampal-accumbens pairs also showed theta rhythmicity. Overall, these results indicate that the synchrony between hippocampus and nucleus accumbens neurons is modulated by spatial position and behavior, and theta rhythm may play an important role for this synchronization.

Evaluation of transmyocardial laser revascularization (TMLR) by gated myocardial perfusion scintigraphy.

TMLR is a novel treatment for patients with coronary artery disease. It comprises the creation of transmyocardial channels thought to improve myocardial perfusion. Gated Tc-99m sestamibi scintigraphy was used to evaluate changes in myocardial perfusion after TMLR. Twelve patients underwent TMLR using a carbon dioxide laser. Sestamibi scans were carried out following a standard protocol prior to and 1, 3, 6, and 12 months after TMLR. Both visual and semi-quantitative assessment showed improvement in 4 patients, deterioration in 2 patients, and no change in the remaining 6 patients each. However, visual and semi-quantitative assessment were concordant in 6 patients and discordant in 6 patients. In 3 of these, semi-quantitative assessment suggested a better outcome, and in 3 patients visual assessment gave better results. Our findings in a small group of patients suggest that about a third benefited from TMLR. Gated myocardial perfusion scintigraphy using technetium-99m sestamibi is suitable for visual evaluation of changes in the lased area over time, but does not allow semi-quantitative evaluation in the patient population typically treated with TMLR. Further investigations using optimized imaging protocols, including positron emission tomography and three dimensional image presentation, are warranted.

Hippocampal neuronal position selectivity remains fixed to room cues only in rats alternating between place navigation and beacon approach tasks.

To study the relationship between brain representations and behaviour, we recorded hippocampal neuronal activity in rats repeatedly alternating between two different tasks on a circular platform with four reward boxes along the edge. In the beacon approach task, rewards were provided only at the pair of diametrically opposite boxes that was illuminated. In the place navigation task, rewards were available only at the boxes positioned near the north-east and south-west corners of the room. Performance levels were high and rats rapidly reoriented to changes in lamp cues in the beacon approach task. Neuropsychological studies show that rats with hippocampal lesions readily employ beacon approach strategies, while place navigation is severely impaired. Previous studies suggested that the neurons might change their behavioural correlates as the rat performed the respective tasks. However, of 34 hippocampal 'place cells' recorded, all showed position selectivity fixed with respect to room cues, even in the beacon approach task where coding the position of the rat in the room was of no use for locating rewards. Whether or not hippocampal signals are actually employed for ongoing behaviour would then be decided by structures downstream from the hippocampus. If this is the case, then the 'counterproductive' room referred place-related discharges in the beacon approach task would be a background representation. This would provide support for proposals of multiple memory systems underlying different types of information processing and contrasts with the popular notion that local neuronal activity levels are selectively increased to the degree that the brain region is required for the ongoing function.

Mesenteric blood flow is related to disease activity and risk of relapse in Crohn's disease: a prospective follow-up study.

OBJECTIVE: The diagnostic significance of increased splanchnic blood flow in Crohn's disease is unclear. This prospective study was therefore undertaken to define the role of Doppler sonography in the assessment of disease activity and in the prediction of early relapse. METHODS: Splanchnic flowmetry was performed in 59 patients with Crohn's disease and 20 healthy volunteers during fasting and 30 min after ingestion of a standardized meal. Twenty-one patients measured during the active state and in clinical remission were followed-up for 6 months. Hemodynamic parameters of the superior and inferior mesenteric arteries and the portal vein were related to clinical (Crohn's disease activity index [CDAI]), laboratory (C-reactive protein), and endoscopic (Crohn's Disease Endoscopic Index of Severity) parameters of disease activity. RESULTS: The postprandial mean velocity of the superior mesenteric artery correlated closest with clinical activity (CDAI, p < 0.005) and C-reactive protein (p < 0.01), but was unrelated to endoscopic activity. All patients in remission after 6 months (9/9) showed an increase in postprandial pulsatility index of the superior mesenteric artery, compared with an initial measurement during active disease (+28%). In contrast, the majority of patients with later relapse or surgery (11/12) had decreased pulsatility index during initial remission (-20%). The positive predictive value of this index for maintenance of remission was 0.82. CONCLUSIONS: Postprandial flow measurements in the superior mesenteric artery are closely related to clinical but not endoscopic disease activity in patients with Crohn's disease. The repeated measurement of the postprandial pulsatility index allows estimation of the risk of recurrence.

Mesenteric blood flow is related to disease activity and risk of relapse in ulcerative colitis: a prospective follow up study.

BACKGROUND: The diagnostic significance of increased splanchnic blood flow in ulcerative colitis is unclear. This prospective study was therefore undertaken to define the role of Doppler sonography in the assessment of disease activity and in the prediction of early relapse. SUBJECTS/METHODS: Splanchnic flowmetry was performed in 76 patients with ulcerative colitis (47 with active disease and 29 in remission), six with infectious colitis, and 13 healthy controls during fasting and 30 minutes after ingestion of a standardised meal. Twenty seven of the patients with ulcerative colitis and all patients with infectious colitis were investigated during the active state as well as in clinical remission and followed up for six months. Flow velocity and pulsatility index (PI) of the superior (SMA) and inferior (IMA) mesenteric arteries and the portal vein were related to clinical (Truelove index), laboratory (C-reactive protein), and endoscopic (Sutherland index) parameters of disease activity. RESULTS: The mean flow velocity of the IMA correlated closest with clinical activity (Truelove, r = 0.41, p<0.005), the PI with C-reactive protein (r = 0.30, p<0.05), and endoscopic activity (r = 0.45, p<0.001). All patients in remission after six months (14/14) or with infectious colitis (6/6) showed an increase in PI of the IMA compared with the initial measurement during active disease (mean increase for ulcerative colitis +36% and for infectious colitis +77%). In contrast, most patients with later relapse or surgery (11/13) had decreased PI during initial remission (mean decrease -12%). The positive predictive value of this index for maintenance of remission was 0.77. Flow variables of the SMA and portal vein displayed weaker correlations. CONCLUSIONS: Flow measurements in the IMA are closely related to clinical and endoscopic disease activity in patients with ulcerative colitis. Repeated measurement of the PI allows estimation of the risk of recurrence.

Discharge correlates of hippocampal complex spike neurons in behaving rats passively displaced on a mobile robot.

This study investigated location-, movement-, and directional-selectivity of action potential discharges of hippocampal neurons in awake rats subjected to passive displacements in order to estimate vestibular contributions to this activity. Water-deprived rats were habituated to being restrained in a sling mounted on a moving robot. The extracellular activity of single complex-spike cells in area CA1 of the hippocampus was recorded with glass micropipettes in the rats during passive translations, rotations, and immobility. The robot made a standardized series of trajectories starting from each of four corners of a square enclosure surrounded by black curtains. A drop of water was delivered to the rat each time the robot arrived at one designated corner of the arena. The activities of 29 neurons were investigated in 45 recording sessions (16 of which were in total darkness) in four rats. Hippocampal neurons recorded in 31 sessions (9 sessions in the dark) had significant location-selective increases or decreases in firing rate as the rat was passively displaced or immobile within the experimental arena. In 20 sessions (6 in the dark) direction-selective discharges were found when the rat was in the corners. In six sessions, cells discharged selectively during movement initiation or termination. These data suggest that information essential for path integration is present in the hippocampus and that inertial cues could play a vital role in hippocampal spatial functions. These results resemble those of O'Mara et al. ([1994] J Neurosci 14:6511) using the same protocol in macaques, suggesting similarities in hippocampal processing and function.