Can simultaneously acquired electrodermal activity improve accuracy of fMRI detection of deception?

Observation of changes in autonomic arousal was one of the first methodologies used to detect deception. Electrodermal activity (EDA) is a peripheral measure of autonomic arousal and one of the primary channels used in polygraph exams. In an attempt to develop a more central measure to identify lies, the use of functional magnetic resonance imaging (fMRI) to detect deception is being investigated. We wondered if adding EDA to our fMRI analysis would improve our diagnostic ability. For our approach, however, adding EDA did not improve the accuracy in a laboratory-based deception task. In testing for brain regions that replicated as correlates of EDA, we did find significant associations in right orbitofrontal and bilateral anterior cingulate regions. Further work is required to test whether EDA improves accuracy in other testing formats or with higher levels of jeopardy.     

Brain activity during a motor learning task: an fMRI and skin conductance study

Measuring electrodermal activity (EDA) during fMRI is an effective means of studying the influence of task-related arousal, inferred from autonomic nervous system activity, on brain activation patterns. The goals of this study were: (1) to measure reliable EDA from healthy individuals during fMRI involving an effortful unilateral motor task, (2) to explore how EDA recordings can be used to augment fMRI data analysis. In addition to conventional hemodynamic modeling, skin conductance time series data were used as model waveforms to generate activation images from fMRI data. Activations from the EDA model produced significantly different brain regions from those obtained with a standard hemodynamic model, primarily in the insula and cingulate cortices. Onsets of the EDA changes were synchronous with the hemodynamic model, but EDA data showed additional transient features, such as a decrease in amplitude with time, and helped to provide behavioral evidence suggesting task difficulty decreased with movement repetition. Univariate statistics also confirmed that several brain regions showed early versus late session effects. Partial least squares (PLS) multivariate analysis of EDA and fMRI data provided complimentary, additional insight on how the motor network varied over the course of a single fMRI session. Brain regions identified in this manner included the insula, cingulate gyrus, pre- and postcentral gyri, putamen and parietal cortices. These results suggest that recording EDA during motor fMRI experiments provides complementary information that can be used to improve the fMRI analysis, particularly when behavioral or task effects are difficult to model a priori.     

Development of the human lateral cuneate nucleus: a morphometric evaluation

Maturation of the brain adenylyl cyclase (AC) signalling system was investigated in the developing rat cortex, thalamus and hippocampus. Expression of AC type II, IV and VI measured by Western blot dramatically increased in all tested brain regions during the first 3 weeks after birth and these levels were maintained in adulthood. AC type I did not change during ontogenesis. In parallel, AC enzyme activities were determined in order to obtain the functional correlates to the preceding structural (immunoblot) analyses of trimeric G proteins [Ihnatovych et al., Dev. Brain Res. (2002) in press]. Surprisingly, basal, manganese-, fluoride-, forskolin- and GTP-stimulated adenylyl cyclase developed similarly. The relatively low enzyme activities, which were determined at birth, progressively increased (about four times) to a clear maximum around postnatal day PD 12. This was followed by a progressive regression to adulthood so that activity of AC at PD 90 was comparable with the low neonatal level. The peak of AC activities at PD 12 was detected in all tested brain regions. Stimulatory (isoproterenol) effect on basal AC activity as well as inhibitory (baclofen) effect on forskolin-stimulated AC activity were unchanged between PD 12 and PD 90. Thus, comparison of results of the structural and functional analyses of adenylyl cyclase signalling system revealed a clear dissociation between the increase in the amount protein of various AC isoforms and the decrease of total G-protein mediated enzyme activities between PD 12 and adulthood. As none of the complex changes in trimeric G protein levels can explain this difference, the future research has to be oriented to identification of potential negative regulators of AC in the course of brain development. Among these, the newly discovered group of GTPase activating proteins, RGS, appears to be of primary importance because these proteins represent potent negative regulators of any G protein-mediated signalling in brain.     

Task-dependent changes in brain activation following therapy for nonfluent aphasia: discussion of two individual cases.

The complex process of cortical reorganization of language-related brain regions during recovery from aphasia and the effects of therapeutic interventions on brain systems are poorly understood. We studied two patients with chronic aphasia and compared their functional neuroanatomical responses to a younger control group on two tasks, an oral-reading task involving overt speech and a "passive" audiovisual story-comprehension task. Following identical therapy, we re-examined behavioral (language) and functional neuroanatomical changes using the same functional magnetic resonance imaging (fMRI) tasks. We hypothesized that better recovery would be associated with brain activation patterns more closely resembling healthy controls, whereas positive responses to language treatment would be associated with increased activity in undamaged left perisylvian areas and/or right-hemisphere areas homologous to the damaged regions. For the participant with a frontal lesion who was most responsive to therapy, brain activation increased in the right hemisphere during oral-reading, but decreased bilaterally in most regions on story-comprehension. The other participant with a temporal-parietal lesion showed decreased activation, particularly in the right hemisphere, during oral-reading but increased activation bilaterally on story-comprehension. Results highlight individual variability following language therapy, with brain activation changes depending on lesion site and size, language skill, type of intervention, and the nature of the fMRI task.     

Measuring mania metabolites: a longitudinal proton spectroscopy study of hypomania

OBJECTIVE: Using single-voxel proton spectroscopy we aimed to investigate changes in metabolite levels in key brain regions during hypomania and euthymia in patients with bipolar disorder (BD). METHOD: Nine patients with a diagnosis of BD and nine age, sex, education, and handedness-matched comparison subjects underwent magnetic resonance proton spectroscopy (H(1)-MRS) using a 1.5 T magnet. Patients were assessed whilst hypomanic and euthymic. Metabolite (N-acetyl asparTate, NAA; myo-inositol, mI; choline, Cho) levels in the basal ganglia (BG), anterior cingulate cortex (AC), and frontal cortex (FC) were compared both between groups and within the patient group. RESULTS: Multivariate analysis revealed significant complex relationships between metabolite levels and brain regions with significant differences observed both between bipolar patients (hypomanic and euthymic) and controls, and across the two mood states. Hypomanic patients had lower mean metabolite levels when averaged across the AC and FC regions, compared with the controls. They also had a smaller difference in mean metabolite levels between the BG and FC than the control group. Euthymic patients were also found to have a smaller difference in the level of NAA between the BG and AC than the control group. CONCLUSION: This exploratory study of BD demonstrates significant differences in metabolite levels that vary both with respect to brain region and mood state. Not withstanding the confounding effects of medication and the limitation of small sample size the findings are important as they demonstrate that a longitudinal approach is a useful design especially in the context of a long-term phasic illness.     

Detection of deception using fMRI: better than chance, but well below perfection

Functional brain imaging has been considered a new and better technique for the detection of deception. The reasoning is that there is a neural locus or circuit for lying that is sensitive, specific, generalizable across individuals and measurement contexts, and robust to countermeasures. To determine the extent to which the group results predicted lying at the level of the individual, we reanalyzed data on 14 participants from a study that had previously identified regions involved in lying (thus satisfying the criterion for sensitivity). We assessed the efficacy of functionally determined brain regions based on the lie-truth contrast for N-1 participants to detect deception in the Nth individual. Results showed that no region could be used to correctly detect deception across all individuals. The best results were obtained for medial prefrontal cortex (mPFC), correctly identifying 71% of participants as lying with no false alarms. Lowering the threshold for a response increased hits and false alarms. The results suggest that although brain imaging is a more direct index of cognition than the traditional polygraph, it is subject to many of the same caveats and thus neuroimaging does not appear to reveal processes that are necessarily unique to deception.     

Deceiving others: distinct neural responses of the prefrontal cortex and amygdala in simple fabrication and deception with social interactions

Brain mechanisms for telling lies have been investigated recently using neuroimaging techniques such as functional magnetic resonance imaging and positron emission tomography. Although the advent of these techniques has gradually enabled clarification of the functional contributions of the prefrontal cortex in deception with respect to executive function, the specific roles of subregions within the prefrontal cortex and other brain regions responsible for emotional regulation or social interactions during deception are still unclear. Assuming that the processes of falsifying truthful responses and deceiving others are differentially associated with the activities of these regions, we conducted a positron emission tomography experiment with 2 (truth, lie) x 2 (honesty, dishonesty) factorial design. The main effect of falsifying the truthful responses revealed increased brain activity of the left dorsolateral and right anterior prefrontal cortices, supporting the interpretation of previous studies that executive functions are related to making untruthful responses. The main effect of deceiving the interrogator showed activations of the ventromedial prefrontal (medial orbitofrontal) cortex and amygdala, adding new evidence that the brain regions assumed to be responsible for emotional processing or social interaction are active during deceptive behavior similar to that in real-life situations. Further analysis revealed that activity of the right anterior prefrontal cortex showed both effects of deception, indicating that this region has a pivotal role in telling lies. Our results provide clear evidence of functionally dissociable roles of the prefrontal subregions and amygdala for human deception.     

Regional and subcellular distribution of Met- and Leu-enkephalin-degrading activity in rat brain

Met- and Leu-enkephalin were degraded rapidly by brain aminopeptidases with the K_m's 9.1 mM and 5.7 mM respectively; the V_max, 100 μmol/mg protein per min for Met-enkephalin and 50 μmol/mg protein per min for Leu-enkephalin. The major product for Met-enkephalin was des-Tyr-Met-enkephalin. The enkephalin-degrading activity (EDA) in the brain was 16-fold higher than in plasma and was 15% of that in the kidney. The hydrolytic activity was heterogeneous in rat brain regions. For Met-enkephalin, the activity in decreasing order was striatum, hypothalamus, hippocampus, cerebellum, cortex, mid-brain, and medulla oblongata; for Leu-enkephalin the order was hippocampus, striatum, mid-brain, cortex, hypothalamus, cerebellum, and medulla oblongata. The subcellular distribution of the EDA in the whole brain, the hippocampus, and the striatum was similar, with the soluble fraction having the highest, the synaptosomal fraction the lowest, activity. The distribution of EDA was different from the arylamidase activity with Tyr-β-naphthylamide and Leu-β-naphthylamide as substrates. Our results indicate that a group of aminopeptidases is responsible for the degradation of both enkephalins.     

Hydrocortisone induced regional cerebral activity changes in schizophrenia: a PET scan study

BACKGROUND: There is evidence that, even during remission, schizophrenia (SZ) patients are especially vulnerable to de-compensate under stress, and that they tend to have a high baseline serum cortisol levels. This study was undertaken to determine whether raising serum cortisol by the infusion of hydrocortisone, in the absence of additional psychological stress, would result in different cerebral activity changes in schizophrenic patients compared to normal controls (CON). We were especially interested in cerebral activity in regions such as the medial temporal lobe and hippocampus, since structural abnormalities in these brain regions were frequent in association with schizophrenia.METHODS: Serum cortisol levels were raised, by infusing hydrocortisone, in 8 pairwise-matched SZ patients and 8 CONs. The associated regional cerebral activity changes were analyzed using statistical parametric mapping (SPM).RESULTS: There was increased regional cerebral activity in response to elevated cortisol in the left hippocampal region in the SZ group, while the controls showed evidence of decreased regional cerebral activity in the same anatomical location. For the rest of the brain regions, cerebral activity increases and decreases, in response to raised serum cortisol, in the SZ followed the same regional pattern as in the control group, but with a smaller overall magnitude of change. The blunted response in SZ was most marked in the regions that showed greatest regional cerebral activity changes in normal subjects.CONCLUSION: Patients with schizophrenia showed an abnormal increased regional cerebral activity response to cortisol infusion in the left hippocampal region, and similar but attenuated regional cerebral activity response in other regions, when compared to matched controls.     

Effect of PUVA therapy on electrodermal activity parameters in vitiligo patients

Recent electrophysiological studies on autonomic dysfunction in vitiligo patients show an autonomic dysfunction as measured by absent sympathetic skin response (SSR). Nothing is known about the reversibility of these autonomic parameters with treatment. The present study examined how Electrodermal Activity (EDA) parameters were affected from vitiligo illness before PUVA therapy and whether any electrophysiological gains acquired from PUVA therapy would influence the progression of the condition itself. We studied in 14 healthy subjectS and 14 patients with generalized vitiligo before and after treatment. EDA was recorded with a skin conductance unit connected to a personal computer. Before treatment, skin conductance level (SCL) and habituation number (HN) was higher in vitiligo group than control groups. After treatment, SCL and HN were decreased nearly to normal value. Before and after treatment, prevalence of non-responsivity was higher in vitiligo group than controls. CONCLUSION: The sympathetic nervous system might have a particular role in the pathogenesis of vitiligo. Thus, patients with vitiligo may have changes to EDA parameters that are reversible to great extent with PUVA therapy. EDA is a useful method of studying the autonomic dysfunction in humans.     

The morphology of lipopigment in rat Purkinje neurons after chronic acetyl-L-carnitine administration: a reduction in aging-related changes.

The aging-related accumulation of neuronal lipopigment is considered to be cellular debris from processes of renewal of cellular constituents, but it can also reflect cell damage and certain diseases. Acetyl-L-carnitine (AC) has been reported to reduce some morphological and behavioral associations of brain aging and the present study investigated the effects of 37 weeks of AC administration on lipopigment in rat Purkinje neurons. Lipopigment was identified by fluorescence microscopy and the area enclosed by an outline of each discrete region of lipopigment was measured. Acetyl-L-carnitine was associated with a significant (p = 0.05) reduction in the number of discrete lipopigment regions and there was a significant (p = 0.001) association of AC administration with numbers of lipopigment regions in various size categories. As AC administration was associated with a reduction in some of the aging-related morphological changes in lipopigment, this compound is a candidate for evaluation as a long-term prophylactic agent for the adverse effects of cerebral aging.     

The effect of deception on motor cortex excitability

Although a number of recent neuroimaging studies have examined the relationship between the brain and deception, the neurological correlates of deception are still not well understood. The present study sought to assess differences in cortical excitability during the act of deception by measuring motor evoked potentials (MEPs) during transcranial magnetic stimulation (TMS). Sports fanatics and low-affiliation sports fans were presented with preferred and rival team images and were asked to deceptively or honestly identify their favored team. Hemispheric differences were found including greater excitability of the left motor cortex during the generation of deceptive responses. In contrast to current physiological measures of deception, level of arousal was not found to differentiate truthful and deceptive responses. The results are presented in terms of a complex cognitive pattern contributing to the generation of deceptive responses.     

Spatial nonuniformity of the resting CBF and BOLD responses to sevoflurane: in vivo study of normal human subjects with magnetic resonance imaging

Pulsed arterial spin labeling magnetic resonance imaging (MRI) was performed to investigate the local coupling between resting regional cerebral blood flow (rCBF) and BOLD (blood oxygen level dependent) signal changes in 22 normal human subjects during the administration of 0.25 MAC (minimum alveolar concentration) sevoflurane. Two states were compared with subjects at rest: anesthesia and no-anesthesia. Regions of both significantly increased and decreased resting-state rCBF were observed. Increases were limited primarily to subcortical structures and insula, whereas, decreases were observed primarily in neocortical regions. No significant change was found in global CBF (gCBF). By simultaneously measuring rCBF and BOLD, region-specific anesthetic effects on the coupling between rCBF and BOLD were identified. Multiple comparisons of the agent-induced rCBF and BOLD changes demonstrated significant (P < 0.05) spatial variability in rCBF-BOLD coupling. The slope of the linear regression line for AC, where rCBF was increased by sevoflurane, was markedly smaller than the slope for those ROIs where rCBF was decreased by sevoflurane, indicating a bigger change in BOLD per unit change in rCBF in regions where rCBF was increased by sevoflurane. These results suggest that it would be inaccurate to use a global quantitative model to describe coupling across all brain regions and in all anesthesia conditions. The observed spatial nonuniformity of rCBF and BOLD signal changes suggests that any interpretation of BOLD fMRI data in the presence of an anesthetic requires consideration of these insights.     

White-matter changes in early and late stages of mild cognitive impairment

Mild Cognitive Impairment (MCI) is characterized by cognitive deficits that exceed age-related decline, but not interfering with daily living activities. Amnestic type of the disorder (aMCI) is known to have a high risk to progress to Alzheimer’s Disease (AD), the most common type of dementia. Identification of very early structural changes in the brain related to the cognitive decline in MCI patients would further contribute to the understanding of the dementias. In the current study, we target to investigate whether the white-matter changes are related to structural changes, as well as the cognitive performance of MCI patients. Forty-nine MCI patients were classified as Early MCI (E-MCI, n = 24) and Late MCI (L-MCI, n = 25) due to their performance on The Free and Cued Selective Reminding Test (FCSRT). Age-Related White-Matter Changes (ARWMC) scale was used to evaluate the white-matter changes in the brain. Volumes of specific brain regions were calculated with the FreeSurfer program. Both group and correlation analyses were conducted to show if there was any association between white-matter hyperintensities (WMHs) and structural changes and cognitive performance. Our results indicate that, L-MCI patients had significantly more WMHs not in all but only in the frontal regions compared to E-MCI patients. Besides, ARWMC scores were not correlated with total hippocampal and white-matter volumes. It can be concluded that WMHs play an important role in MCI and cognitive functions are affected by white-matter changes of MCI patients, especially in the frontal regions.     

In vivo optical imaging correlates with improvement of cerebral ischemia treated by intravenous bone marrow stromal cells (BMSCs) and edaravone

Abstract

Objective:

Recent studies show that modern in vivo optical imaging can detect matrix metallopeptidase (MMP) activation in the ischemic brain. In this study, we analyze the protective effects of bone marrow stromal cells (BMSCs) and edaravone (EDA) against tissue plasminogen activator (tPA) risk in the ischemic brain with in vivo optical fluorescence MMP imaging.

Methods:

At 48 hours after 60 minutes of transient middle cerebral artery occlusion (tMCAO) with tPA, C57BL/6J mice were subjected to motor function analysis, in vivo and ex vivo optical imaging for MMP activation, gelatin zymography, and double immunofluorescent analyses with or without intravenous BMSC transplantation and the intravenous free radical scavenger EDA.

Results:

In vivo fluorescent signals for MMP were detected over the heads of living mice 48 hours after tMCAO; the strongest were in the tPA group, which were reduced by BMSC or EDA treatment. These in vivo data were confirmed by ex vivo fluorescence imaging. While massive intracerebral hemorrhages were observed in the ischemic hemispheres of the tPA group, only slight hemorrhages were found in the tPA/BMSC, tPA/EDA, and EDA groups. Gelatin zymography showed the strongest MMP-9 activation in the tPA group after tMCAO, which was reduced by BMSC or EDA treatment.

Conclusion:

The present study provides a correlation between in vivo optical imaging of MMP activation and the improvement of ischemic brain damage caused by tPA after tMCAO and treated by BMSC and EDA.     

Functional MRI of sustained attention in bipolar mania

We examined sustained attention deficits in bipolar disorder and associated changes in brain activation assessed by functional magnetic resonance imaging (fMRI). We hypothesized that relative to healthy participants, those with mania or mixed mania would (1) exhibit incremental decrements in sustained attention over time, (2) overactivate brain regions required for emotional processing and (3) progressively underactivate attentional regions of prefrontal cortex. Fifty participants with manic/mixed bipolar disorder (BP group) and 34 healthy comparison subjects (HC group) received an fMRI scan while performing a 15-min continuous performance task (CPT). The data were divided into three consecutive 5-min vigilance periods to analyze sustained attention. Composite brain activation maps indicated that both groups activated dorsal and ventral regions of an anterior-limbic network, but the BP group exhibited less activation over time relative to baseline. Consistent with hypotheses 1 and 2, the BP group showed a marginally greater behavioral CPT sustained attention decrement and more bilateral amygdala activation than the HC group, respectively. Instead of differential activation in prefrontal cortex over time, as predicted in hypothesis 3, the BP group progressively decreased activation in subcortical regions of striatum and thalamus relative to the HC group. These results suggest that regional activation decrements in dorsolateral prefrontal cortex accompany sustained attention decrements in both bipolar and healthy individuals. Stable amygdala overactivation across prolonged vigils may interfere with sustained attention and exacerbate attentional deficits in bipolar disorder. Differential striatal and thalamic deactivation in bipolar disorder is interpreted as a loss of amygdala (emotional brain) modulation by the ventrolateral prefrontal-subcortical circuit, which interferes with attentional maintenance.     

Posterior cingulum white matter disruption and its associations with verbal memory and stroke risk in mild cognitive impairment

Medial temporal lobe and temporoparietal brain regions are among the earliest neocortical sites to undergo pathophysiologic alterations in Alzheimer's disease (AD), although the underlying white matter changes in these regions is less well known. We employed diffusion tensor imaging to evaluate early alterations in regional white matter integrity in participants diagnosed with mild cognitive impairment (MCI). The following regions of interests (ROIs) were examined: 1) anterior cingulum (AC); 2) posterior cingulum (PC); 3) genu of the corpus callosum; 4) splenium of the corpus callosum; and 5) as a control site for comparison, posterior limb of the internal capsule. Forty nondemented participants were divided into demographically-similar groups based on cognitive status (MCI: n = 20; normal control: n = 20), and fractional anisotropy (FA) estimates of each ROI were obtained. MCI participants showed greater posterior white matter (i.e., PC, splenium) but not anterior white matter (i.e., AC, genu) changes, after adjusting for age, stroke risk, and whole brain volume. FA differences of the posterior white matter were best accounted for by changes in radial but not axial diffusivity. PC FA was also significantly positively correlated with hippocampal volume as well as with performance on tests of verbal memory, whereas stroke risk was significantly correlated with genu FA and was unrelated to PC FA. When investigating subtypes of our MCI population, amnestic MCI participants showed lower PC white matter integrity relative to those with non-amnestic MCI. Findings implicate involvement of posterior microstructural white matter degeneration in the development of MCI-related cognitive changes and suggest that reduced FA of the PC may be a candidate neuroimaging marker of AD risk.     

Bovine herpesvirus 5 induces an overproduction of nitric oxide in the brain of rabbits that correlates with virus dissemination and precedes the development of neurological signs

We herein report an investigation of nitric oxide (NO) levels, a candidate molecule for neuronal toxicity and dysfunction, in the brain of rabbits during experimental neurological infection by bovine herpesvirus 5 (BoHV-5). Spectrophotometry for NO products (NO₂ and NO₃) revealed that NO levels were significantly increased (F(4, 40) = 3.33; P <.02) in several regions of the brain of rabbits with neurological disease, correlating with moderate to high BoHV-5 titers. Immunohistochemistry of brain regions revealed a group of cells with neuronal and astrocyte morphology expressing the enzyme inducible NO synthase (iNOS) close to virus antigenpositive neurons. In addition, the investigation of nitric oxide levels between 2 and 6 days post infection (d.p.i.) revealed an initial increase in NO levels in the olfactory bulb and cortex (OB/OC) and anterior cortex (AC) at day 3 p.i., correlating with the initial detection of virus. As the infection proceeded, increased NO levels— and infectivity—were progressively being detected in the OB/CO and AC at day 4 p.i. (F(12, 128) = 2.82; P <.003); at day 5 p.i. in several brain regions (P <.003 in the OB/OC); and at day 6 p.i. in all regions (P <.003) but the thalamus. These results show that BoHV-5 replication in the brain of rabbits induces an overproduction of NO. The increase in NO levels in early infection correlated spatially and temporally with virus dissemination within the brain and preceded the development of neurological signs. Thus, the overproduction of NO in the brain of BoHV-5-infected rabbits may be a component of the pathogenesis of BoHV-5-induced neurological disease.     

The impact of low-grade brain tumors on verbal fluency performance

Verbal fluency has traditionally represented left hemispheric function, based on large acquired lesion studies. However, recent functional imaging studies have demonstrated bilateral hemispheric activation during phonemic and semantic word generation tasks. We examined 25 left hemisphere (LH) and 26 right hemisphere (RH) low-grade brain tumor patients on semantic and phonemic fluency. Patients were also assigned to a combined posterior (left and right) group (n = 26) or a combined posterior (left and right) group (n = 20) and compared with normal controls (NC; n = 57). We hypothesized that there would be greater left than right hemispheric phonemic and semantic fluency impairments. We also hypothesized that there would be greater anterior, specifically left anterior, than posterior impairments on phonemic fluency given their respective retrieval and initiation requirements. Finally, it was predicted that the LH patients, particularly the left posterior group, would exhibit the greatest semantic fluency impairments. Results indicated that on semantic fluency, the LH group produced significantly fewer semantic fluency responses compared to the RH group, but the expected left posterior and left frontal group differences were not found. There were no significant patient group differences associated with phonemic fluency. While we encountered semantic fluency impairments in this brain tumor population, we did not find the extensive deficits associated with the distinct or localized brain regions previously reported in the literature.     

Impact of adolescent nicotine exposure on adenylyl cyclase-mediated cell signaling: enzyme induction, neurotransmitter-specific effects, regional selectivities, and the role of withdrawal

Recent animal studies indicate that the adolescent brain is especially vulnerable to nicotine-induced alterations in synaptic function, echoing the increased susceptibility to nicotine dependence and withdrawal noted for adolescent smokers. We administered nicotine to adolescent rats via continuous minipump infusions from PN30 to PN47.5, using 6 mg/kg/day, a dose rate that replicates the plasma nicotine levels found in smokers, and examined the effects on cell signaling mediated through adenylyl cyclase (AC) and its response to catecholamines. Studies were conducted during nicotine administration (PN45) and in the posttreatment, withdrawal period (PN50, 60, 75). Adolescent nicotine augmented AC activity as evidenced by increased responsiveness to the direct AC stimulants, forskolin and Mn(2+). The effects on AC were equally noted in brain regions enriched (striatum) or sparse (cerebellum) in cholinergic projections, implying that the effects are secondary to activation/repression of neural circuits, rather than representing direct effects on AC mediated by nicotinic cholinergic receptors. AC responses to dopaminergic and noradrenergic stimulants were also enhanced by nicotine exposure. However, in contrast to earlier work with serotonin-mediated responses, the effects on catecholaminergic stimulation were smaller and did not display the sex-dependence noted for serotonin. An alternate administration paradigm that maximizes episodic withdrawal (twice-daily nicotine injections) induced AC more rapidly at lower nicotine doses. Our results indicate that adolescent nicotine exposure elicits lasting alterations in synaptic signaling that intensify and persist during withdrawal. These findings support the concept that the adolescent brain is especially susceptible to persistent nicotine-induced alterations.