Robert A. Jensen

Enhanced recognition memory following vagus nerve stimulation in human subjects.

Neuromodulators associated with arousal modulate learning and memory, but most of these substances do not freely enter the brain from the periphery. In rodents, these neuromodulators act in part by initiating neural messages that travel via the vagus nerve to the brain, and electrical stimulation of the vagus enhances memory. We now extend that finding to human verbal learning. We examined word-recognition memory in patients enrolled in a clinical study evaluating the capacity of vagus nerve stimulation to control epilepsy. Stimulation administered after learning significantly enhanced retention. These findings confirm in humans the hypothesis that vagus nerve activation modulates memory formation similarly to arousal.

Increased Extracellular Concentrations of Norepinephrine in Cortex and Hippocampus Following Vagus Nerve Stimulation in the Rat.

The vagus nerve is an important source of afferent information about visceral states and it provides input to the locus coeruleus (LC), the major source of norepinephrine (NE) in the brain. It has been suggested that the effects of electrical stimulation of the vagus nerve on learning and memory, mood, seizure suppression, and recovery of function following brain damage are mediated, in part, by the release of brain NE. The hypothesis that left vagus nerve stimulation (VNS) at the cervical level results in increased extracellular NE concentrations in the cortex and hippocampus was tested at four stimulus intensities: 0.0, 0.25, 0.5, and 1.0 mA. Stimulation at 0.0 and 0.25 mA had no effect on NE concentrations, while the 0.5 mA stimulation increased NE concentrations significantly in the hippocampus (23%), but not the cortex. However, 1.0 mA stimulation significantly increased NE concentrations in both the cortex (39%) and hippocampus (28%) bilaterally. The increases in NE were transient and confined to the stimulation periods. VNS did not alter NE concentrations in either structure during the inter-stimulation baseline periods. No differences were observed between NE levels in the initial baseline and the post-stimulation baselines. These findings support the hypothesis that VNS increases extracellular NE concentrations in both the hippocampus and cortex.

Beta-adrenergic receptor antagonist antihypertensive medications impair arousal-induced modulation of working memory in elderly humans.

It is well-established that administration of moderate doses of the adrenal catecholamines epinephrine or norepinephrine shortly after training results in the enhancement of later retention performance in laboratory animals. These substances, released endogenously as a result of arousal, are thought to modulate memory processes by stimulating peripheral receptors that send neural messages to the brain, thus altering the memory storage process. The applicability of this hypothesis to the modulation of memory processes in humans was tested in this experiment by using elderly subjects who were chronically taking beta-receptor antagonist medications to control hypertension. A moderate level of muscle-tension-induced arousal was produced by having subjects squeeze a hand dynamometer during the initial storage and recall of highlighted words in short 200-word paragraphs. Twenty young normal individuals, 22 normotensive elderly subjects, 21 elderly subjects taking either calcium-channel blockers or angiotensin-converting enzyme inhibitors to control hypertension, and 21 elderly subjects taking beta-blocker antihypertensive medications served as subjects. The young subjects, normal elderly subjects, and those taking non-beta-blocker medications all showed enhanced long-term recognition performance as a result of the arousal manipulation. However, those subjects chronically taking beta-receptor-antagonist medications showed no enhancement of memory.

EEG, physiology, and task-related mood fail to resolve across 31 days of smoking abstinence: relations to depressive traits, nicotine exposure, and dependence.

Changes in task-related mood and physiology associated with 31 days of smoking abstinence were assessed in smokers, 34 of whom were randomly assigned to a quit group and 22 to a continuing-to-smoke control group. A large financial incentive for smoking abstinence resulted in very low participant attrition. Individuals were tested during prequit baselines and at 3, 10, 17, and 31 days of abstinence. Abstinence was associated with decreases in heart rate and serum cortisol, a slowing of electroencephalogram (EEG) activity, and task-dependent and trait-depression-dependent hemispheric EEG asymmetries. Differences between the quit group and the smoking group showed no tendency to resolve across the 31 days of abstinence. Trait depression and neuroticism correlated with increases in left-relative-to-right frontal EEG slow-wave (low alpha) activity at both 3 and 31 days of abstinence. In contrast, prequit nicotine intake and Fagerström Tolerance scores correlated with alpha asymmetry and with greater EEG slowing only at Day 3. Thus, the effects of smoking abstinence appear to last for at least several months.

Effects of smoking abstinence on mood and craving in men : influences of negative-affect-related personality traits, habitual nicotine intake and repeated measurements

Abstract A two-factor model of individual differences in smoking abstinence response was assessed. The two factors were nicotine bioadaptation (nicotine exposure and self-reported tolerance/dependence) and self-medication for negative affect/psychopathology. Bioadaptation was expected to promote transient increases in smoking abstinence-related negative affect, while self-medication was expected to be related to relatively permanent increases in negative affect. Of 56 male smokers starting, 50 completed the study, 30 of whom were randomly assigned to an immediate cessation group and 20 to a continuing-to-smoke control group. Mood and craving were repeatedly measured with the Profile of Mood States (POMS) and the Shiffman Withdrawal Questionnaire, administered twice per week during a three-week pre-quit baseline period and every 48 h during the 30-day abstinence phase. POMS negative moods decreased significantly across the six pre-quit baseline days even though there was no smoking cessation-related intervention during this time, a finding with implications for the question of whether quitters return to pre-quit levels of negative affect. Support for the two-factor model was provided by three of our findings. First, POMS Depression, Tension and Anger increased in the quit group after quitting and never returned to levels corresponding to the continuingto-smoke controls even after 30 days of abstinence. Second, trait depression assessed prior to smoking abstinence correlated with abstinence-related increases in POMS state depressive affect score shortly after quitting and during the last eight days of the study. Third, pre-quit cotinine concentration correlated with increases in negative affect during the first 48 h of abstinence. The findings suggest that previous studies should be interpreted with caution because of their failure to take into account the repeated-measures effect and selective attrition.

Subjective correlates of cigarette-smoking-induced elevations of peripheral beta-endorphin and cortisol

Two experiments assessed subjective and hormonal effects of smoking cigarettes with three different nicotine deliveries. In experiment 1, 12 males smoked two cigarettes on three different occasions: (1) nicotine-free; (2) their own brand (1.0 mg FTC-estimated nicotine delivery); or (3) 2.4 mg FTC nicotine cigarettes. In experiment 2, 12 males smoked cigarettes of comparable nicotine yield using a quantified smoke delivery system (QSDS). Blood was sampled 2 min after each cigarette completion. Relative to nicotine-free smoking, plasma beta-endorphin (BE) and serum cortisol concentrations increased after quasi-ad libitum smoking of 2.4 mg, but not after 1.0 mg nicotine cigarettes. Self-reported malaise (nausea, sickness, and unpleasantness) also increased after smoking 2.4 mg nicotine cigarettes; subjective distress was correlated with changes in blood BE and cortisol, Smoking 1.0 mg cigarettes did not increase BE or cortisol, or subjective distress. QSDS smoking produced hormonal and subjective effects similar to quasi-ad libitum smoking; however, correlations between neuromodulator concentrations and mood were non-significant. These findings suggest that the elevated levels of plasma BE and cortisol reported in some smoking studies may not be characteristic effects of normal smoking.

Effects of monetary contingencies on smoking relapse: influences of trait depression, personality, and habitual nicotine intake.

Of 56 male smokers, 34 were randomly assigned (by 60% random odds) to quit smoking immediately, whereas the remaining 22 were assigned to quit after an additional 31 days. Compensation (

Arousal-induced modulation of memory storage processes in humans.

300) was contingent on abstinence for a minimum of 31 or 2 days (depending on random assignment) and completion of all experimental sessions. Contingencies for the immediate-quit group required 31 days of abstinence; those for the delayed-quit group required only 2 days of abstinence. Contingency duration (31 vs. 2 days) predicted days to relapse. All but 4 of the 31-day contingency participants maintained abstinence for at least 31 days, whereas only 3 of the 2-day contingency group abstained for 31+ days. However, 31-day contingencies did not result in longer postcontingency time to relapse. Higher trait neuroticism, depression, and psychopathic deviate scores predicted decreased time to relapse. Prequit cotinine concentrations and Fagerström Tolerance Questionnaire scores failed to predict time to relapse.

Vagus nerve stimulation potentiates hippocampal LTP in freely-moving rats

We recently demonstrated in human subjects that muscle-tension-induced arousal can enhance later retention performance and that this effect is attenuated by beta-adrenergic receptor antagonists. In that study, each subject established a baseline for muscle tension by squeezing a hand dynamometer for 30 s with maximum force. This may have served to prime subsequent arousal produced by muscle tension. Two experiments were performed to address this issue. At the beginning of each experiment, young adult subjects were asked to squeeze the hand dynamometer at maximum effort either for 30 s (Prime) or for only 1 s (No prime). Then, during the task, arousal was induced by having each subject exert a moderate amount of tension (25 to 50% of baseline maximum). In the first experiment, subjects were shown four consecutive lists of 20 highly imageable nouns, given immediate recall tests of each, and then given a comprehensive recall and recognition test at the conclusion of the experiment. Moderate arousal was induced once for each list (at encoding, consolidation, or retrieval) or not at all for one list. The sequence of arousal induction was counterbalanced. Significant enhancement of delayed recall was seen in the 30-s group for those lists in which arousal was induced during the consolidation or retrieval period with no significant effects in the 1-s group. These results demonstrate that arousal can modulate memory consolidation when induced shortly after learning and that an initial priming event may affect the response to subsequent similar arousing events. In the second experiment, subjects read paragraphs, some of which contained highlighted words (working memory task); half of the subjects were given the 30-s procedure and half the 1-s procedure. Only those subjects in the 30-s group showed significant arousal-induced enhancement of delayed recognition of the highlighted words. Again, no significant effect on retention performance was seen in the group that squeezed the hand dynamometer for only 1 s during the priming period. Pulse data suggested that there may be somewhat greater heart-rate reactivity in the 30-s group. These findings suggest that memory modulation by arousal may be primed, or enhanced, by a relevant preliminary arousal event.

Characterization of a dose—response curve for nicotine-induced conditioned taste aversion in rats: Relationship to elevation of plasma β-endorphin concentration

Previous studies have demonstrated that electrical stimulation of the vagus nerve (VNS) delivered at a moderate intensity following a learning experience enhances memory in laboratory rats and human subjects, while VNS at lower or higher intensities has little or no effect. This finding suggests that VNS may affect memory processes by modulating neural plasticity in brain structures associated with memory storage such as the hippocampus. To test this hypothesis, the present study investigated the modulatory effect of VNS on the development of long-term potentiation (LTP) in the dentate gyrus of freely-moving rats. Rats receiving 0.4 mA VNS showed enhanced potentiation of the population spike amplitude for at least 24 h after tetanus relative to the sham-stimulation group. In contrast, no such effect was observed with 0.2 mA VNS. Stimulation at 0.8 mA had a short-term effect and tended to enhance early LTP, but to a lesser extent than did 0.4 mA. The 0.4 mA stimulation was the same intensity that was previously shown to enhance retention performance in an inhibitory avoidance task. These findings suggest that the neural mechanisms underlying the mnemonic effect of VNS may involve modulating synaptic plasticity in the hippocampus. These data also suggest that neural activity in the vagus nerve, occurring as a result of changes in peripheral state, is an important mechanism by which emotional experiences and arousal can enhance the storage of memories of those experiences.