Early-childhood social reticence predicts SCR-BOLD coupling during fear extinction recall in preadolescent youth.

Social Reticence (SR) is a temperament construct identified in early childhood that is expressed as shy, anxiously avoidant behavior and, particularly when stable, robustly associated with risk for anxiety disorders. Threat circuit function may develop differently for children high on SR than low on SR. We compared brain function and behavior during extinction recall in a sample of 11-to-15-year-old children characterized in early childhood on a continuum of SR. Three weeks after undergoing fear conditioning and extinction, participants completed a functional magnetic resonance imaging extinction recall task assessing memory and threat differentiation for conditioned stimuli. Whereas self-report and psychophysiological measures of differential conditioning, extinction, and extinction recall were largely similar across participants, SR-related differences in brain function emerged during extinction recall. Specifically, childhood SR was associated with a distinct pattern of hemodynamic-autonomic covariation in the brain when recalling extinguished threat and safety cues. SR and attention focus impacted associations between trial-by-trial variation in autonomic responding and in brain activation. These interactions occurred in three main brain areas: the anterior insular cortex (AIC), the anterior subdivision of the medial cingulate cortex (aMCC), and the dorsolateral prefrontal cortex (dlPFC). This pattern of SCR-BOLD coupling may reflect selective difficulty tracking safety in a temperamentally at-risk population.

Oxytocin by intranasal and intravenous routes reaches the cerebrospinal fluid in rhesus macaques: determination using a novel oxytocin assay.

Oxytocin (OT) is a potential treatment for multiple neuropsychiatric disorders. As OT is a peptide, delivery by the intranasal (IN) route is the preferred method in clinical studies. Although studies have shown increased cerebrospinal fluid (CSF) OT levels following IN administration, this does not unequivocably demonstrate that the peripherally administered OT is entering the CSF. For example, it has been suggested that peripheral delivery of OT could lead to central release of endogenous OT. It is also unknown whether the IN route provides for more efficient entry of the peptide into the CSF compared to the intravenous (IV) route, which requires blood-brain barrier penetration. To address these questions, we developed a sensitive and specific quantitative mass spectrometry assay that distinguishes labeled (d5-deuterated) from endogenous (d0) OT. We administered d5 OT (80 IU) to six nonhuman primates via IN and IV routes as well as IN saline as a control condition. We measured plasma and CSF concentrations of administered and endogenous OT before (t=0) and after (t=10, 20, 30, 45 and 60 min) d5 OT dosing. We demonstrate CSF penetrance of d5, exogenous OT delivered by IN and IV administration. Peripheral administration of d5 OT did not lead to increased d0, endogenous OT in the CSF. This suggests that peripheral administration of OT does not lead to central release of endogenous OT. We also did not find that IN administration offered an advantage compared to IV administration with respect to achieving greater CSF concentrations of OT.

Outpatient diabetes clinical decision support: current status and future directions.

Outpatient clinical decision support systems have had an inconsistent impact on key aspects of diabetes care. A principal barrier to success has been low use rates in many settings. Here, we identify key aspects of clinical decision support system design, content and implementation that are related to sustained high use rates and positive impacts on glucose, blood pressure and lipid management. Current diabetes clinical decision support systems may be improved by prioritizing care recommendations, improving communication of treatment-relevant information to patients, using such systems for care coordination and case management and integrating patient-reported information and data from remote devices into clinical decision algorithms and interfaces.

Impulsive and compulsive behaviors in Parkinson's disease.

Impulsive-compulsive behaviors (ICBs) in Parkinson's disease (PD) are a common and devastating side effect of dopamine replacement therapy. In this review we describe the phenomenology, prevalence, and risk factors of patients with PD. Results of behavioral studies assessing the neuropsychological profile of patients with PD emphasize that the ICBs, which are behavioral addictions, are not hedonically motivated. Rather, other factors such as the inability to cope with uncertainty may be triggering ICBs. New insights from functional imaging studies, strengthening the incentive salience hypothesis, are discussed, and therapeutic guidelines for the management of ICBs in PD are given.

Examining belief and confidence in schizophrenia.

BACKGROUND: People with psychoses often report fixed, delusional beliefs that are sustained even in the presence of unequivocal contrary evidence. Such delusional beliefs are the result of integrating new and old evidence inappropriately in forming a cognitive model. We propose and test a cognitive model of belief formation using experimental data from an interactive 'Rock Paper Scissors' (RPS) game. METHOD: Participants (33 controls and 27 people with schizophrenia) played a competitive, time-pressured interactive two-player game (RPS). Participants' behavior was modeled by a generative computational model using leaky integrator and temporal difference methods. This model describes how new and old evidence is integrated to form a playing strategy to beat the opponent and to provide a mechanism for reporting confidence in one's playing strategy to win against the opponent. RESULTS: People with schizophrenia fail to appropriately model their opponent's play despite consistent (rather than random) patterns that can be exploited in the simulated opponent's play. This is manifest as a failure to weigh existing evidence appropriately against new evidence. Furthermore, participants with schizophrenia show a 'jumping to conclusions' (JTC) bias, reporting successful discovery of a winning strategy with insufficient evidence. CONCLUSIONS: The model presented suggests two tentative mechanisms in delusional belief formation: (i) one for modeling patterns in other's behavior, where people with schizophrenia fail to use old evidence appropriately, and (ii) a metacognitive mechanism for 'confidence' in such beliefs, where people with schizophrenia overweight recent reward history in deciding on the value of beliefs about the opponent.

Thermal grill-evoked sensations of heat correlate with cold pain threshold and are enhanced by menthol and cinnamaldehyde.

BACKGROUND: Thunberg's thermal grill produces a sensation of strong heat upon skin contact with spatially interlaced innocuous warm and cool stimuli. METHODS: To examine the classes of peripheral axons that might contribute to this illusion, the effects of topical l-menthol, an activator of TRPM8, and cinnamaldehyde, a TRPA1 agonist, on the magnitude of thermal sensations were examined during grill stimulation in healthy volunteers. RESULTS: Under control conditions, cutaneous grill stimulation (interlaced 20/40 °C) evoked a sensation of heat, and for individual subjects, the magnitude of this heat sensation was positively correlated with cold pain threshold (CPT). Menthol increased the CPT and enhanced the magnitude of grill-evoked heat. Cinnamaldehyde intensified warm sensations, reduced heat pain threshold and also enhanced grill-evoked heat. CONCLUSIONS: Both TRPM8-expressing and TRPA1-expressing afferent axons can affect grill-evoked thermal sensations. The enhancement of grill-evoked sensations of temperature with menthol and cinnamaldehyde may provide an additional clinically relevant means of testing altered thermal sensitivity, which is often affected in neuropathic patient groups.

Emotion recognition and oxytocin in patients with schizophrenia.

BACKGROUND: Studies have suggested that patients with schizophrenia are impaired at recognizing emotions. Recently, it has been shown that the neuropeptide oxytocin can have beneficial effects on social behaviors. METHOD: To examine emotion recognition deficits in patients and see whether oxytocin could improve these deficits, we carried out two experiments. In the first experiment we recruited 30 patients with schizophrenia and 29 age- and IQ-matched control subjects, and gave them an emotion recognition task. Following this, we carried out a second experiment in which we recruited 21 patients with schizophrenia for a double-blind, placebo-controlled cross-over study of the effects of oxytocin on the same emotion recognition task. RESULTS: In the first experiment we found that patients with schizophrenia had a deficit relative to controls in recognizing emotions. In the second experiment we found that administration of oxytocin improved the ability of patients to recognize emotions. The improvement was consistent and occurred for most emotions, and was present whether patients were identifying morphed or non-morphed faces. CONCLUSIONS: These data add to a growing literature showing beneficial effects of oxytocin on social-behavioral tasks, as well as clinical symptoms.

Patients with schizophrenia show increased aversion to angry faces in an associative learning task.

BACKGROUND: We were interested in examining the relationship between socially relevant stimuli and decision processes in patients with schizophrenia. METHOD: We tested patients with schizophrenia and healthy controls on a stochastically rewarded associative learning task. Participants had to determine, through trial and error, which of two faces was associated with a higher chance of reward: one face was angry, the other happy. RESULTS: Both patients and healthy controls were able to perform the task at above-chance accuracy, and there was no significant difference in overall accuracy between the groups. Both groups also reliably preferred the happy face, such that they selected it more often than the angry face on the basis of the same amount of positive versus negative feedback. However, patients were significantly more averse to the angry face, such that they chose it less often than control participants when the reward feedback strongly supported the angry face as the best choice. CONCLUSIONS: Patients show an increased aversion to angry faces, in a task in which they must learn to associate rewards with expressions.

Can receptor potentials be detected with threshold tracking in rat cutaneous nociceptive terminals?

Threshold tracking of individual polymodal C- and Adelta-fiber terminals was used to assess membrane potential changes induced by de- or hyperpolarizing stimuli in the isolated rat skin-nerve preparation. Constant current pulses were delivered (1 Hz) through a tungsten microelectrode inserted in the receptive field, and the current amplitude was controlled by feedback with a laboratory computer programmed to serially determine the electrical threshold using the method of limits. During threshold tracking, the receptive fields of the fibers were heated (32-46 degrees C in 210 s) or superfused with modified synthetic interstitial fluid containing either 0, 20, 40, 50, or 60 mM [K+], phosphate buffer to pH 5.2 or 6.1, or bradykinin (BK, 10(-8)-10(-5) M). High [K+]e decreased the current threshold for activation by 6-14% over 120 s, whereas K+-free superfusion augmented the threshold by >5%, and after some delay, also induced ongoing discharge in 60% of units. pH 6.1 and 5.2 caused an increase in threshold of 6 and 18%, respectively, and 30% of the fibers were excited by low pH, although the change in threshold of pH responsive and unresponsive fibers did not differ significantly, suggesting a general excitability decrease induced by protons. Heat stimulation increased the mean threshold and conduction velocity of the fibers tested and resulted in activity in 78% of units. Additionally, for these units, activation was preceded by a significant decrease in threshold compared with the tracked thresholds of fibers unresponsive to heat. Bradykinin also led to a significant threshold decrease before activation. In conclusion, the technique of threshold tracking proved suitable to assess changes in excitability resulting from receptor currents evoked by noxious heat and bradykinin in the terminal arborization of cutaneous nociceptors.

[Molecular basis for pain mediating properties of extracorporeal shock waves]. / Molekulare Grundlagen zur schmerzvermittelnden Wirkung extrakorporaler Stosswellen.

The biologic action of extracorporeal shock wave application on the musculoskeletal system is understood poorly. To prove the hypothesis that alterations of tissue concentrations of substance P and prostaglandin E(2) are involved in the biologic action of shock waves, extracorporeal shock waves with energy flux density of 0.9 mJ/mm(2 )(1500 pulses at 1/s) were applied in vivo to the distal femur of rabbits. The concentrations of substance P and prostaglandin E(2) eluated from the periosteum of the femur were measured. Compared with the untreated contralateral hindlimbs, substance P release from the periosteum from the femur was increased 6 and 24 h after extracorporeal shock wave application, but was decreased 6 weeks after extracorporeal shock wave application. By contrast, extracorporeal shock wave application did not result in altered prostaglandin E(2) release from the periosteum from the femur. Remarkably, there was a close relationship between the time course of substance P release found here, and the well-known clinical time course of initial pain occurrence and subsequent pain relief after extracorporeal shock wave application to tendon diseases. Accordingly, substance P might be involved in the biologic action of extracorporeal shock wave application on tissue of the musculoskeletal system. This is the first study providing insights into the molecular mechanisms of extracorporeal shock wave application to the musculoskeletal system.

S+ -flurbiprofen but not 5-HT1 agonists suppress basal and stimulated CGRP and PGE2 release from isolated rat dura mater.

Neurogenic inflammation of the meninges, expressed in plasma extravasation and vasodilatation, putatively contributes to certain types of headache. Both, non-steroidal antiinflammatory drugs (NSAIDs) and serotonin-1 (5-HT1) receptor agonists are similarly effective antimigraine drugs but their mechanism of action is unclear. The clinical observation that sumatriptan lowered plasma levels of calcitonin gene-related peptide (CGRP), found increased during migraine attacks, drew attention to a possible inhibition of pro-inflammatory neuropeptide release from trigeminal afferents. An isolated preparation of fluid-filled rat skull cavities was used to study effects of NSAIDs and 5-HT(1B/D) agonists on the dura stimulated by inflammatory mediators (bradykinin, histamine and serotonin, 10(-5)M each). The release of immunoreactive CGRP (iCGRP) and immunoreactive PGE(2) (iPGE(2)) was measured in 5-min samples of superfusates using enzyme immunoassays. S(+)-flurbiprofen (10(-6)M) strongly reduced the basal and stimulated iCGRP release and abolished iPGE(2) release; R(-)-flurbiprofen showed much less effect on iPGE(2) liberation and did not influence iCGRP release. The 5-HT(1B/D) agonists naratriptan and CP93,129 were ineffective on both iCGRP and iPGE(2) release. Inspite of its weak COX blocking effect, R(-)-flurbiprofen is reported to exert antinociceptive effects, although it has not been tested in migraine. Only the potent COX blocker S(+)-flurbiprofen also suppressed iCGRP release while the 5-HT(1B/D) agonists were ineffective. Thus, inhibition of meningeal neuropeptide secretion is not a common action principle of the drugs that could be essential for their antimigraine effects.

Inflammatory mediators do not stimulate CGRP release if prostaglandin synthesis is blocked by S(+)-flurbiprofen in isolated rat skin.

OBJECTIVE: Nonsteroidal antiinflammatory drugs are well known as antipyretic analgesics, however, their mode of action is not yet fully understood. Besides their cyclooxygenase (COX) blocking effect other action principles are discussed. In the present study we investigated the effects of the flurbiprofen enantiomers on the stimulated release of calcitonin gene-related peptide (CGRP) from the isolated rat skin as an indirect measure of peripheral nociceptor activation and 'neurogenic inflammation'. METHODS: Stimulation was performed by a combination of inflammatory mediators (bradykinin, serotonin and histamine, all 10(-5) M). In addition, prostaglandin E(2) (PGE(2)) release was determined in order to verify the inhibitory effect of the tested drugs on prostaglandin production. RESULTS: S(+)-flurbiprofen (10(-7) and 10(-6) M), reported as the COX blocking enantiomer, completely blocked basal as well as stimulated PGE(2) release. Under R(-)-flurbiprofen a reduction of basal PGE(2) release was not significant; the stimulated PGE(2) release, was however significantly reduced at 10(-7) M and completely suppressed at 10(-6) M drug concentration. The stimulated CGRP release was not affected by R(-)-flurbiprofen (10(-7) or 10(-6) M). In contrast, S(+)-flurbiprofen - only at 10(-6) M - significantly reduced the inflammatory mediator-induced CGRP release. This reduction could be reversed by co-administration of PGE(2) (10(-5) M) suggesting that the effect was due to COX block and prostanoid deprivation. CONCLUSION: Although a higher concentration of the effective enantiomer was needed to inhibit stimulated CGRP than PGE(2) release, flurbiprofen seems to exert the antinociceptive/antiinflammatory effects observed by preventing the secondary cutaneous prostaglandin formation that appears necessary to enable activation by inflammatory mediators of the CGRP-releasing nerve fibers.

Impact of path parameters on maze solution time.

In order to compare spatial attention and visual processing capabilities of humans and rhesus macaques, we developed a visual maze task both could perform. Maze stimuli were constructed of orthogonal line segments displayed on a monitor. Each was octagonal in outline and contained a central square (the 'start box'). A single ('main') path, containing a random number of turns, extended outward from the start box, and either reached an exit in the maze's perimeter, or a blind ending within the maze. Subjects maintained ocular fixation within the start box, and indicated their judgment whether the path reached an exit or not by depressing one of two keys (humans) or foot pedals (monkeys). Successful maze solution by human subjects required a minimum viewing time. Replacing the maze with a masking stimulus after a variable interval revealed that the percent correct performance increased systematically with greater viewing time, reaching a plateau of approximately 85% correct if mazes were visible for 500 ms or more. A multiple linear regression analysis determined that the response time of both species depended upon several parameters of the main path, including the number of turns, total length, and exist status. Human and nonhuman primates required comparable time to process each turn in the path, whereas monkeys were faster than humans in processing each unit of path length. The data suggest that a covert analysis of the maze proceeds from the center outward along the main path in the absence of saccadic eye movements, and that both monkeys and humans undertake such an analysis during the solution of visual mazes.

ATP can enhance the proton-induced CGRP release through P2Y receptors and secondary PGE(2) release in isolated rat dura mater.

Trigeminal afferent neurons express ionotropic P2X receptors for extracellular ATP which are known to be sensitive to low interstitial pH. Both conditions - ATP release and tissue acidosis - may occur in the dura following the ischemia phase of migraine attacks. Aim of this study was to investigate whether and how ATP and protons may cooperate in exciting meningeal afferents. After removal of the cerebral hemispheres hemisected scull cavities of adult Wistar rats were used as organ bath of their own lining, the dura mater. The dura was chemically stimulated and the amounts of immunoreactive calcitonin gene-related peptide (iCGRP) and prostaglandin E(2) (PGE(2)) released into incubation fluid were measured using enzyme immunoassays. Stimulation with ATP (10(-4) and 10(-3)M) augmented iPGE(2) release dose-dependently whereas iCGRP secretion was minimally enhanced only if the dura had previously been depleted of extracellular ATP using hexokinase. Acid buffer solutions (pH 5.9 and 5.4) resulted in pH-dependent increase of iCGRP release but reduced iPGE(2) release. Purines (ATP 10(-3)>UTP 10(-4)M>ATP 10(-4)M) and PGE(2) (10(-5)M) were found to facilitate the proton-induced increase in iCGRP release. The proton-reduction of PGE(2) release was overcome by adding ATP (10(-3)M). S(+)-flurbiprofen (10(-6)M) suppressed both the basal and stimulated iPGE(2) release and prevented the ATP(10(-4)M)-induced facilitation of the proton response. The facilitating effect of ATP was also blocked under suramin, a non-selective P2 antagonist, and under reactive blue, an non-selective P2Y-antagonist, but not under pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid, a P2X-antagonist. The present results provide evidence that ATP has poor, if at all, direct excitatory effects on CGRP-containing trigeminal nerve endings in the isolated dura and its facilitatory action seems to depend on G-protein coupled P2Y receptors and secondary PGE(2) release. The UTP effect and the antagonist profile is indicative for the P2Y(2) receptor subtype.

Pro- and anti-inflammatory actions of ricinoleic acid: similarities and differences with capsaicin.

We have investigated the pro- and anti-inflammatory effects of ricinoleic acid (RA), the main active principle of castor oil, in an experimental model of blepharitis induced by intradermal injection of carrageenan in the guinea-pig eyelid and its possible capsaicin-like mode of action on acutely dissociated rat dorsal root ganglia (DRG) neurons in vitro. Topical treatment with RA (10-100 mg/guinea-pig) or capsaicin (1-10 mg/guinea-pig) caused eyelid reddening and oedema. At lower doses (0.3-3 mg/guinea-pig and 0.009-0.09 mg/guinea-pig for RA and capsaicin, respectively) both drugs significantly potentiated the eyelid oedema induced by carrageenan. The tachykinin NK1 receptor antagonist FK 888 (0.59 mg/kg s.c.) abolished the potentiation of carrageenan-induced eyelid oedema induced by either RA or capsaicin. The neutral endopeptidase inhibitor, thiorphan (1.3 mg/kg i.v.) significantly enhanced the potentiation of carrageenan-induced eyelid oedema produced by RA. This potentiating effect was abolished by FK 888. Repeated (8 days) topical application of RA (0.9 mg/guinea-pig) or capsaicin (0.09 mg/guinea-pig) inhibited the carrageenan-induced eyelid oedema. This anti-inflammatory effect was accompanied by a reduction (75%-80% of SP and 46%-51% of NKA) in tachykinin content of the eyelids, as determined by radioimmunoassay. In dissociated rat DRG neurons, RA (0.1 mM for 5 min) significantly inhibited the inward currents induced by application of capsaicin (1 microM) and/or low pH (5.8), without inducing any currents by itself or changing voltage-dependent currents. Moreover, after 24-h incubation, RA (0.1 mM) significantly decreased the capsaicin (1 microM)-induced calcitonin gene-related peptide (CGRP) release from rat DRG neurons, whereas acute drug superfusion did not evoke CGRP release by itself. Summarizing, RA possesses capsaicin-like dual pro-inflammatory and anti-inflammatory properties which are observed upon acute and repeated application, respectively. However, unlike capsaicin, RA does not induce inward current in DRG neurons and it is devoid of algesic properties in vivo.

Modulation of CGRP and PGE2 release from isolated rat skin by alpha-adrenoceptors and kappa-opioid-receptors.

Norepinephrine (NE) reduces the release of neuropeptides from central terminals of primary afferent neurones by presynaptic inhibition. We investigated whether NE also affects stimulus-induced intracutaneous calcitonin gene-related peptide (CGRP) and secondary prostaglandin E2 (PGE2) release. For comparison, kappa-opioid effects were examined. Antidromic electrical nerve stimulation resulted in significant increases in the release of CGRP and PGE2. The PGE2 release was prevented by selective activation of alpha2-adrenoceptors whereas the CGRP release was not changed. In contrast, selective kappa-opioid receptor activation diminished electrically evoked release of both CGRP and PGE2. We conclude that NE affected stimulated PGE2 release via alpha2-adrenoceptors on cells other than cutaneous afferents while kappa-opioid receptors are expressed in peripheral terminals of cutaneous afferents and their activation reduced CGRP release and secondary PGE2 formation.

Is there a correlation between spreading depression, neurogenic inflammation, and nociception that might cause migraine headache?

The time course of propagation of scotoma and blood flow changes during migraine aura parallels the phenomenon of cortical spreading depression (CSD). It was proposed that CSD generates a sterile neurogenic inflammation in the meninges, which may then lead to the activation or sensitization of nociceptors, thus generating headache. We performed rat experiments in which the effect of CSD on plasma extravasation in the dura mater and on neuronal activity in deep laminae of the trigeminal nucleus was assessed in vivo. CSD did not alter dural plasma extravasation measured by means of bovine serum albumin-coupled flourescein (n = 17 rats) compared to the CSD-free contralateral side. In an in vitro model, the application of KCl to the dura at concentrations extracellularly found during CSD did not alter the release of calcitonin gene-related peptide and prostaglandin E2 from the dura. In 33 rats, neither single CSDs nor a series of CSDs altered ongoing neuronal activity or mechanical and/or thermal sensitivity of the deeply located neurons to stimulation of their receptive fields in the dura mater. These results are at variance with data that showed increased c-Fos labeling in superficial laminae of the trigeminal nucleus following CSD. They do not suggest that CSD initiates migraine headache via neurogenic inflammation.

Interactions of inflammatory mediators stimulating release of calcitonin gene-related peptide, substance P and prostaglandin E(2) from isolated rat skin.

Inflammatory mediators acting directly on nociceptive primary afferents induce neuropeptide release. In this study we investigated interactions between bradykinin, serotonin, histamine, prostaglandin and acid pH in stimulating the release of substance P (SP), calcitonin gene-related peptide (CGRP) and prostaglandin E(2) (PGE(2)) from isolated flaps of rat back skin using enzyme immunoassays. Stimulation with bradykinin (10(-5) M) augmented the release of SP, CGRP and PGE(2) significantly. Serotonin, histamine and PGE(2) individually tested (10(-5) M) had no effect on neuropeptide release but they facilitated the bradykinin-evoked neuropeptide release. When bradykinin was combined with both serotonin and histamine, neither additional PGE(2) nor acid pH showed any further effect, suggesting that the facilitation had reached a maximum. Exposure of the skin to acid pH (6.1 or 5.2) significantly increased CGRP release. SP release was only slightly enhanced and PGE(2) release, in contrast, was suppressed by low pH stimulation, probably due to pH-dependent inhibition of phospholipase A(2). Treatment of the rats with flurbiprofen (25 mg/kg i.p.) one hour before dissection reduced PGE(2) to detection level and inhibited the CGRP secretion evoked by the combination of bradykinin, serotonin and histamine (all 10(-6) M). As this suppression could not be overcome by substitution of PGE(2) (10(-6) M), it is likely that exogenously applied PGE(2) differs in effect from endogenous, intracellularly synthesized prostaglandins that are accompanied by active intermediates and byproducts.

Mental maze solving.

We sought to determine how a visual maze is mentally solved. Human subjects (N = 13) viewed mazes with orthogonal, unbranched paths; each subject solved 200-600 mazes in any specific experiment below. There were four to six openings at the perimeter of the maze, of which four were labeled: one was the entry point and the remainder were potential exits marked by Arabic numerals. Starting at the entry point, in some mazes the path exited, whereas in others it terminated within the maze. Subjects were required to type the number corresponding to the true exit (if the path exited) or type zero (if the path did not exit). In all cases, the only required hand movement was a key press, and thus the hand never physically traveled through the maze. Response times (RT) were recorded and analyzed using a multiple linear regression model. RT increased as a function of key parameters of the maze, namely the length of the main path, the number of turns in the path, the direct distance from entry to termination, and the presence of an exit. The dependence of RT on the number of turns was present even when the path length was fixed in a separate experiment (N = 10 subjects). In a different experiment, subjects solved large and small mazes (N = 3 subjects). The former was the same as the latter but was scaled up by 1.77 times. Thus both kinds of mazes contained the same number of squares but each square subtended 1.77 degrees of visual angle (DVA) in the large maze, as compared to 1 DVA in the small one. We found that the average RT was practically the same in both cases. A multiple regression analysis revealed that the processing coefficients related to maze distance (i.e., path length and direct distance) were reduced by approximately one-half when solving large mazes, as compared to solving small mazes. This means that the efficiency in processing distance-related information almost doubled for scaled-up mazes. In contrast, the processing coefficients for number of turns and exit status were practically the same in the two cases. Finally, the eye movements of three subjects were recorded during maze solution. They consisted of sequences of saccades and fixations. The number of fixations in a trial increased as a linear function of the path length and number of turns. With respect to the fixations themselves, eyes tended to fixate on the main path and to follow it along its course, such that fixations occurring later in time were positioned at progressively longer distances from the entry point. Furthermore, the time the eyes spent at each fixation point increased as a linear function of the length and number of turns in the path segment between the current and the upcoming fixation points. These findings suggest that the maze segment from the current fixation spot to the next is being processed during the fixation time (FT), and that a significant aspect of this processing relates to the length and turns in that segment. We interpreted these relations to mean that the maze was mentally traversed. We then estimated the distance and endpoint of the path mentally traversed within a specific FT; we also hypothesized that the next portion of the main path would be traversed during the ensuing FT, and so on for the whole path. A prediction of this hypothesis is that the upcoming saccade would land the eyes at or near the locus on the path where the mental traversing ended, so that "the eyes would pick up where the mental traversal left off." In this way, a portion of the path would be traversed during a fixation and successive such portions would be strung together closely along the main path to complete the processing of the whole path. We tested this prediction by analyzing the relations between the path distance of mental traverse and the distance along the path between the current and the next fixation spot. (ABSTRACT TRUNCATED)