Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2020 Dec 1.
Published in final edited form as: Cogn Behav Neurol. 2019 Dec;32(4):278–283. doi: 10.1097/WNN.0000000000000208

Muscarinic and Nicotinic Modulation of Memory but not Verbal Problem-solving

Shawn F Smyth *,†, David Q Beversdorf ‡
PMCID: PMC6901099  NIHMSID: NIHMS1540472  PMID: 31800488

Abstract

Aspects of cognitive flexibility are modulated by the noradrenergic system, which is important in arousal and attention. Acetylcholine also modulates arousal and attention, as well as working memory. Effects of muscarinic and nicotinic antagonism on memory are well established. Our purpose was to test whether muscarinic and nicotinic antagonism affect aspects of cognitive flexibility, specifically verbal problem-solving, as well as memory, given acetylcholine’s role in attention and arousal. Eighteen participants attended three testing sessions. Two hours before testing, participants received either 0.6 mg scopolamine, 10 mg mecamylamine, or placebo. Then, participants were tested on three memory tasks (Buschke Selective Reminding Test [BSRT], California Verbal Learning Test [CVLT], Rey Complex Figure Test), two verbal problem-solving/cognitive flexibility tasks (Compound Remote Associates Test, a timed anagram test), and a spatial inductive reasoning task (Raven’s Progressive Matrices). Task order and drug order were counterbalanced. Memory impairment in memory was seen on one BSRT measure and multiple CVLT measures with scopolamine and with one BSRT measure with mecamylamine. There were no effects of either drug on any of the tasks involving cognitive flexibility, including verbal problem-solving. Specific memory impairments were detected using muscarinic, and to a marginal extent, nicotinic antagonists, as expected, but no effect was seen on cognitive flexibility. Therefore, although both the noradrenergic and cholinergic systems play important roles in arousal and cortical signal-to-noise processing, the cholinergic system does not appear to have the same effect as the noradrenergic system on cognitive flexibility, including verbal problem-solving.

Keywords: acetylcholine, memory, cognitive flexibility, problem-solving, semantic, creativity

Previous evidence has suggested that the noradrenergic system plays a modulatory role in the flexibility of access to lexical, semantic, and associative networks (Beversdorf et al, 1999; Campbell et al. 2008; Heilman et al, 2003). Performance on tasks targeting these networks, such as convergent tasks in verbal problem-solving (Beversdorf, 2019), is affected by the noradrenergic system and engages a range of aspects of cognition, including cognitive flexibility, which in combination are considered important aspects of creativity (Heilman et al, 2003). However, how specific this effect is to the noradrenergic system is unknown.

Previous studies have compared the effects of propranolol (beta-adrenergic antagonist), ephedrine (adrenergic agonist), and placebo on individuals performing anagram (word unscrambling) tests as a problem-solving task. After administration of propranolol, participants showed decreased solution times (ie, increased flexible access to networks) compared to after administration of ephedrine (Beversdorf et al, 1999). Another study showed that performance on verbal problem-solving after propranolol (peripheral and central beta-adrenergic antagonist) was significantly better than performance after nadolol (peripheral beta-adrenergic antagonist) in healthy individuals, suggesting that the effect of noradrenergic modulation of flexible access to networks is centrally mediated (Beversdorf et al, 2002). This effect, mediated by beta-adrenergic antagonists, does not appear to be mediated by action on alpha-2 receptors (Choi et al, 2006), dopaminergic receptors (Smyth and Beversdorf, 2007), or non-adrenergic anxiolytics (Silver et al, 2004). However, effects on verbal problem-solving have not been assessed for the cholinergic system.

Flexibility of network access may be modulated by the effect that central noradrenergic activity has on the signal-to-noise ratio within the cortex (Hasselmo et al, 1997). Central noradrenergic tone may regulate the competing needs of network flexibility (cortical “noise” or intrinsic associative processing) and action (dominant signal) (Alexander et al, 2007). Increased central noradrenergic tone may attenuate broad network searches, restricting searches only to immediate strong preferences during situations that require fast decision-making. Conversely, decreased central noradrenergic tone may facilitate broad network searches during situations when unrestricted access to the semantic network for complex problem-solving and the generation of novel solutions would be beneficial (Alexander et al, 2007). However, other pharmacological systems might be proposed to have similar effects, such as the cholinergic system.

Hasselmo and Bower (1992) demonstrated that, similar to the effects of norepinephrine on the cortical signal-to-noise ratio, the cholinergic system suppresses background intrinsic cortical activity that is involved in the interpretation and retrieval of information compared to afferent sensory fiber synapses. Acetylcholine has been proposed to modulate the general efficacy of the cortical processing of sensory or associational information (Sarter and Bruno, 1997). Cholinergic systems may be involved in the detection and selection of stimuli and associations for extended processing. These systems modulate two types of attention: sustained attention and arousal (Sarter et al, 2001).

One example of the contrasting effects of norepinephrine and acetylcholine on neural circuits comes from electrophysiological studies with administration to brain slice preparations and modeling of the results. Perfusion of norepinephrine into brain slice preparations of the rat piriform cortex suppresses the excitatory synaptic potentials in layer 1b, which contains the synapses among pyramidal cells in the cortex, while having a weaker effect on the synaptic potentials in layer 1a, containing afferent fibers (Hasselmo et al, 1997). Models based on this pattern of effects suggest a suppression of excitatory intrinsic connectivity, thereby decreasing the background activity and increasing the signal-to-noise ratio (Hasselmo et al, 1997). However, the noise may be of greater importance to access in situations where the prepotent response, and other strongly represented nodes, do not lead to the desired result (Alexander et al, 2007; Beversdorf, 2019).

Administration of cholinergic agonists into brain slice preparations of the rat piriform cortex, by comparison, results in a reduction of intrinsic fiber responses in layer 1b without causing a significant effect on the synaptic responses in layer 1a (Hasselmo and Bower, 1992), thereby resulting in a physiologically distinct pattern of effect on the signal-to-noise ratio. With this contrast in the neurophysiological effects of the two neurotransmitter systems, an assessment of whether cholinergic agents affect problem-solving in a manner previously observed with adrenergic agents (Beversdorf et al, 1999, 2002; Campbell et al, 2008) is of interest.

Furthermore, cholinergic antagonists have been shown to impair many types of working memory (spatial and nonspatial) (Ellis and Nathan, 2001). Muscarinic acetylcholine receptor antagonism has long been held as a model for memory disorders such as Alzheimer disease (Bartus et al, 1982; Drachman 1977; Drachman and Leavitt, 1974; Whitehouse et al, 1982). Specifically, the blockade of muscarinic receptors with the drug scopolamine interferes with the encoding of new verbal information with little effect on the retrieval of previously stored information (Beatty et al, 1986; Ghoneim and Mewaldt, 1975, 1977; Hasselmo, 1995, 1999; Hasselmo and Wyble, 1997; Mewaldt and Ghoneim, 1979; Tröster et al, 1989).

Dysfunction of nicotinic receptor-mediated neurotransmission has also been described in relation to aging and memory dysfunction (Little et al, 1998). Nicotinic antagonism alone has been shown to impair memory in several studies (Levin 1992; Newhouse et al, 1992, 1994). For example, Newhouse et al (1994) demonstrated increased sensitivity to nicotinic blockade in elderly individuals as opposed to younger individuals after administration of mecamylamine, a central nicotinic receptor antagonist, and Little et al (1998) demonstrated that independent administration of muscarinic and nicotinic receptor antagonists to elderly subjects impaired memory, but more profound impairment occurred when the two agents were combined.

Given the possible overlapping effects of norepinephrine and acetylcholine on the cortical signal-to-noise ratio (Hasselmo et al, 1992, 1997), together with norepinephrine’s previously described modulation of flexible access to networks, we wanted to identify whether muscarinic or nicotinic antagonism would modulate network flexibility in verbal problem-solving during convergent tasks. We also wanted to examine the cholinergic system’s effect on memory in healthy younger individuals. If a higher signal-to-noise ratio (ie, increased noradrenergic tone) results in a restriction of network flexibility, then perhaps the effects on the signal-to-noise ratio by administration of cholinergic antagonists may also improve performance on convergent tasks while also impairing performance on memory tasks. However, it is also possible that deficits in attention and working memory induced by a cholinergic antagonist will impair verbal problem-solving and other tasks involving cognitive flexibility.

METHODS

We examined the effect of cholinergic antagonists on memory and verbal problem-solving in an exploratory manner in a double-blind placebo-controlled study. The study protocol was approved by the Ohio State University Institutional Review Board, and all individuals provided informed consent before participating in the study.

Participants

We recruited 18 normal healthy individuals (9 men, 9 women) with a mean age of 24.2 years (SD = 2.1) to participate in our study, which was a sufficient sample to detect effects on verbal problem-solving with noradrenergic agents in our previous work (Beversdorf et al, 1999, 2002; Silver et al, 2004). Based on this previous work (Silver et al, 2004), the power of a sample size of 18 to detect a difference in a within-subject comparison at a significance of 0.05 is 0.92. English was the primary language of all participants. Participants with a history of any medical contraindication to anticholinergic administration or a history of psychiatric, neurologic, or developmental disorders were excluded.

Testing

Each participant attended three testing sessions, at least 4 days apart. At each testing session, participants received doses sufficient to induce mild effects on memory in healthy young adults—0.6 mg of scopolamine (Parrott, 1986), 10 mg of mecamylamine (Newhouse et al, 1992), or placebo—in a double-blind manner. Two hours later, participants were required to complete tests of memory and problem-solving/cognitive flexibility, as well as one test of spatial inductive reasoning. Test set order (versions 1, 2, and 3 of each cognitive test) and drug order were counterbalanced across an equal number of male and female participants.

The memory tasks included two tests of verbal learning—the Buschke Selective Reminding Task (BSRT; Buschke, 1973), which uses a paradigm that is believed to separate verbal memory retrieval into long-term storage and short-term recall processes, and the California Verbal Learning Test (CVLT; Delis et al, 1987) —and a test of spatial memory, the Rey Complex Figure Test (Corwin and Bylsma, 1993; Osterrieth, 1944; Rey, 1941).

The convergent verbal problem-solving cognitive flexibility tasks included two tests of verbal problem-solving: the Compound Remote Associates (CRA) Test (Bowden and Jung-Beeman, 2003) and a timed anagram test. In the CRA test, participants are expected to solve 30 different problems where three words are provided to them and a fourth word that forms a compound with the first three words needs to be generated (eg, PINE is the solution for CONE, TREE, APPLE because it forms a compound with each of the three words). A maximum of 7 seconds per question is allowed (Bowden and Jung-Beeman, 2003). In the timed anagram task, participants are expected to solve 22 scrambled letter combinations that form words when they are correctly unscrambled. A maximum of 120 seconds per item is allowed, and the natural logarithm of the total time taken is recorded, as described in previous studies (Alexander et al, 2007; Beversdorf et al, 1999, 2002; Campbell et al, 2008; Smyth and Beversdorf, 2007). These tasks are also used to assess cognitive aspects related to creativity (Beversdorf, 2019).

Lastly, we administered a test of spatial inductive reasoning, Raven’s Progressive Matrices (Raven, 1938).

Effects of test order and each individual test version’s difficulty were calculated and an adjusted score for each of the different scores from each of the cognitive tests was generated. The adjusted scores were then compared between scopolamine and placebo and between mecamylamine and placebo using within-subject t tests.

RESULTS

Memory

As expected, memory impairment was detected after administration of the muscarinic antagonist, scopolamine, but minimal impairment was observed after administration of the nicotinic antagonist, mecamylamine.

Significant impairment was seen with mecamylamine compared to placebo only on the Cued Recall scores of the BSRT (all findings uncorrected for multiple measures; mecamylamine 10.5 ± 1.0, placebo 11.0 ± 0.4, t17 = 2.41, P = 0.03). Trends were observed for several aspects of short- and long-term free and cued recall on the CVLT, including the primary verbal memory outcome of total recall on the CVLT (Total Recall Trials 1–5: mecamylamine 63.8 ± 9.0, placebo 66.2 ± 7.0, t17 = 1.97, P = 0.07). There was also a trend toward faster attempts at recall on the Rey Complex Figure on mecamylamine, but this was not associated with any improved recall, as indicated by the recall score (Table 1).

TABLE 1.

Task Performance Compared Across Each Drug Condition

Test Placebo
(95% CI)		 Scopolamine
(95% CI)		 Placebo vs Scopolamine Mecamylamine
(95% CI)		 Placebo vs Mecamylamine
Memory
 BSRT
  S1-Cued Recall 11.0 ± 0.4 10.3 ± 1.6 t17 = 1.75, P < .10† 10.5 ± 1.0 t17 = 2.41, P = .03*
  S1-30 min Delayed Recall 11.8 ± 0.6 10.5 ± 1.4 t17 = 4.23, P < .001* 11.4 ± 1.3 t17 = 1.63, P = .12
 CVLT
  Total Trials 1–5 List A 66.2 ± 7.0 59.9 ± 16.0 t17 = 2.20, P = .04* 63.8 ± 9.0 t17 = 1.97, P = .07†
  List B Recall 8.5 ± 3.0 8.5 ± 3.1 t17 = 0.04, P = .97 8.6 ± 2.7 t17 = 0.05, P = .96
  Short Free Recall 15.1 ± 1.2 13.1 ± 3.6 t17 = 2.39, P = .03* 14.6 ± 1.5 t17 = 1.76, P < .10†
  Short Cued Recall 15.4 ± 1.0 13.8 ± 3.5 t17 = 2.32, P = .03* 14.9 ± 1.3 t17 = 1.82, P = .09†
  Long Free Recall 15.3 ± 0.8 13.5 ± 3.5 t17 = 2.32, P = .03* 14.7 ± 1.4 t17 = 1.98, P = .06†
  Long Cued Recall 15.6 ± 1.0 14.1 ± 3.3 t17 = 2.13, P <.05* 15.1 ± 1.2 t17 = 1.69, P = .11
  Interference Free Recall 3.5 ± 4.3 7.4 ± 8.7 t17 = 1.76, P <.10 7.9 ± 18.0 t17 = 1.10, P = .29
  Interference Cued Recall 0.25 ± 0.60 1.3 ± 1.9 t17 = 2.25, P = .04* 0.7 ± 1.2 t17 = 1.59, P = .13
  Interference Total 3.3 ± 4.4 8.5 ± 10.3 t17 = 2.04, P = .06 7.6 ± 15.6 t17 = 1.23, P = .23
Spatial Memory
 Rey Complex Figure
  Copy Time 180.4 ± 96.4 185.7 ± 102.5 t17 = 0.33, P = .74 193.5 ± 50.7 t17 = 0.64, P = .53
  Recall Score 27.1 ± 5.2 27.2 ± 5.3 t17 = 0.06, P = .95 24.2 ± 10.7 t17 = 1.11, P = .28
  Recall Time 220.9 ± 117.6 189.4 ± 89.2 t17 = 1.28, P = .22 150.2 ± 74.5 t17 = 1.93, P = .07†
Cognitive Flexibility
 CRA
  Total Correct 6.2 ± 4.0 5.7 ± 2.9 t17 = 0.48, P = .64 5.8 ± 3.0 t17 = 0.51, P = .62
  Total Time 192.3 ± 14.1 195.6 ± 10.6 t17 = 0.85, P = .41 197.0 ± 12.4 t17 = 1.37, P = .19
 Anagram
  Anagram Time 805.7 ± 266.1 888.7 ± 387.8 t17 = 1.39, P = .18 770.3 ± 332.7 t17 = 0.54, P = .60
  Anagram In Time 56.8 ± 9.2 58.6 ± 15.3 t17 = 0.71, P = .49 56.0 ± 13.8 t17 = 0.29, P = .78
Spatial Reasoning
 Raven’s
  Ravens Correct 13.5 ± 2.2 12.9 ± 2.8 t17 = 1.28, P = .22 12.8 ± 3.1 t17 = 1.12, P = .28
  Ravens Time 545.2 ± 226.3 518.5 ± 217.8 t17 = 0.76, P = .56 552.7 ± 193.7 t17 = 0.25, P = .81
Open in a new tab

Data are presented as M ± SD and each score shown is adjusted for test order and version order.

*

Significant at P ≤ 0.05.

†

Significant at P ≤ 0.10.

BSRT = Buschke Selective Reminding Task. CRA = Compound Remote Associates Test. CVLT = California Verbal Learning Test.

Significant impairment was seen with scopolamine compared to placebo on the 30-minute Delayed Recall score on the BSRT (scopolamine 10.5 ± 1.4, placebo 11.8 ± 0.6, t17 = 4.23, P < 0.001). A significant impairment or trend with scopolamine was observed for nearly all aspects of the CVLT, including the primary verbal memory outcome of total recall on the CVLT (Total Recall Trials 1–5: scopolamine 59.9 ± 16.0, placebo 66.2 ± 7.0, t17 = 2.20, P = 0.04) (Table 1), and the later trials on List A (Figure 1). No significant effects were observed on spatial memory with the Rey Complex Figure Test accuracy of copying task (Table 1) with either drug. Analysis was not performed on the Rey Complex Figure accuracy of copying task because participants performed at ceiling in each drug condition.

Figure 1.

Figure 1.

Open in a new tab

Scores for Trials 1–5 of list A on the California Verbal Learning Test compared between scopolamine and placebo (number of words recalled out of 16 items).

*Significant at P = 0.05.

†Significant at P = 0.01.

Problem-solving and Cognitive Flexibility

No differences were observed between the placebo and either drug condition for either of the verbal problem-solving/cognitive flexibility tasks (CRA, anagrams) or for the spatial inductive reasoning task (Raven’s Progressive Matrices).

DISCUSSION

We examined the effects of muscarinic and nicotinic cholinergic antagonists on measures of verbal and spatial memory, verbal and spatial problem-solving, and cognitive flexibility. As expected, the results demonstrated that muscarinic blockade, and to some marginal extent, nicotinic blockade, impair verbal memory and learning in healthy young adults. Despite the marginally significant results for each task, verbal list learning (for example Trial 4 recall, Trial 5 recall) on the CVLT was consistently affected after administration of scopolamine taken across all measures, including the primary measure for list learning, Total Recall for Trials 1–5 for List A, was also significant. Although we detected memory impairments with scopolamine, no significant effects were found on any of the verbal problem-solving tasks (CRA, anagrams) or the spatial inductive reasoning task (Raven’s Progressive Matrices). However, this differential effect on memory and verbal problem-solving should be taken as an exploratory finding only due to the modest sample size.

Acetylcholine-related memory impairments occur to a greater degree and with use of a lower dose of the same drugs in older adults as compared to younger ones. For example, elderly individuals may have less robust cortical innervation from basal forebrain cholinergic nuclei, effectively giving them less reserve when cholinergic antagonists are given. In previous studies of younger and older patients, 10 mg of mecamylamine produced deficits in learning for the older patients, with much milder effects seen in the younger patients (Newhouse et al, 1992). It is possible that the different doses used between the two drugs used in our study may have contributed to the apparent differences between drugs in the memory effects we observed, so any interpretation of the specificity of memory effects between receptor subtypes should be made with caution, as that was not the purpose of our study.

However, although these doses did appear to be sufficient to detect memory impairments on our tasks in younger patients, they did not reveal effects on any aspect of convergent problem-solving or on spatial reasoning involving cognitive flexibility, whereas noradrenergic agents previously did reveal effects on these aspects of cognition in this population (Beversdorf et al, 1999, 2002). Thus, while both norepinephrine and acetylcholine have been implicated in altering the signal-to-noise ratio within the cortex, only norepinephrine appears to affect it in such a way that hinders flexible semantic network searches.

Previous work using functional MRI had demonstrated normalization of mesial temporal lobe activation and improved parietal deactivation (Risacher et al, 2013) as well as differential effects on the posterior cingulate (Goekoop et al, 2006), enhancement of frontal lobe activity (Saykin et al, 2004), and increased functional connectivity (Risacher et al, 2013) during memory tasks in patients with mild cognitive impairment and increased cholinergic function induced by cholinesterase inhibitors. Similarly, in healthy participants, right rostrolateral prefrontal cortex activation during incongruent hits on a sustained attention task was related to right basal forebrain threshold in the location of the cholinergic neurons, which in turn was also related to functional connectivity with the dorsal attention network (Howe et al, 2013). In contrast, functional MRI studies examining cognitive effects of adrenergic agents in patients with autism spectrum disorder revealed increased connectivity across language areas with propranolol, blocking beta-adrenergic receptors, but minimal effects on regional activation during language tasks (Narayanan et al, 2010). In the resting state, the effects of this agent on functional connectivity depend on the network assessed (Hegarty et al, 2017).

Therefore, it appears that signal-to-noise effects of the adrenergic system have preferential effects on more broadly distributed networks than on local effects, whereas the cholinergic system has both local effects and effects on the distributed networks. Problem-solving with convergent tasks, which are often used in the assessment of creativity (Bowden and Beeman, 1998), is felt to rely heavily on the interaction across distributed networks (Alexander et al, 2007; Beversdorf, 2019; Campbell et al, 2008). Thus, perhaps the selectivity of the adrenergic system’s effect on connectivity between broadly distributed components of networks explains its effect on problem-solving, whereas the cholinergic system does not have such a selective effect. However, it is also possible that impairments in working memory induced by the anticholinergic effects of the drugs studied herein may have offset any beneficial effects on the signal-to-noise ratio. Future study will be needed to disentangle these potentially counteracting effects as well as to understand how the underlying neurophysiology of the effects of norepinephrine and acetylcholine in brain circuits might be related to these findings (Hasselmo et al, 1997; Hasselmo and Bower, 1992).

As above, the flexibility of network access appears to be modulated by the effect that central noradrenergic tone has on the signal-to-noise ratio within the cortex (Hasselmo et al, 1997). Central noradrenergic tone may regulate the competing needs of network flexibility (Alexander et al, 2007). Increased central noradrenergic tone may attenuate broad network searches, restricting searches to immediate strong preferences in situations requiring fast decision-making, whereas decreased central noradrenergic tone may facilitate broad network searches where unrestricted access to the semantic network for complex problem-solving for the generation of novel solutions would be beneficial (Alexander et al, 2007).

Our previous work suggests that this effect on problem-solving is mediated by action on the beta-adrenergic receptors (Alexander et al, 2007; Campbell et al, 2008) and not by action on the alpha-2 receptors (Choi et al, 2006), dopaminergic receptors (Smyth and Beversdorf, 2007), or non-adrenergic anxiolytics (Silver et al, 2004). Our current study also suggests that this effect on problem-solving is not mediated by action at the cholinergic receptors. However, limitations do warrant some caution in this interpretation. In addition to the possibility that working memory impairments induced by the drugs may have offset any beneficial effects on verbal problem-solving, it is also possible that, despite the sample size predicted based on previous work, a larger sample is needed to demonstrate the effects on verbal problem-solving or other tasks that involve cognitive flexibility. Therefore, these findings should be considered exploratory. Additionally, there are a range of other tasks that could be explored, such as divergent tasks related to creativity (Beversdorf, 2019), that may yield different results. These issues would also need to be addressed in future studies.

ACKNOWLEDGMENTS

The authors thank the anonymous individuals who commented on an earlier version of this work.

Supported in part by a grant (K23-NS43222) from the National Institute of Neurological Disorders and Stroke to D.Q.B. and a medical student summer research scholarship from the American Academy of Neurology to S.F.S.

Glossary

BSRT

Buschke Selective Reminding Task.

CRA

Compound Remote Associates Test.

CVLT

California Verbal Learning Test

Footnotes

The authors declare no conflicts of interest.

REFERENCES

  1. Alexander JK, Hillier A, Smith RM, et al. 2007. Beta-adrenergic modulation of cognitive flexibility during stress. J Cogn Neurosci. 19:468–478. [DOI] [PubMed] [Google Scholar]
  2. Bartus R, Dean R, Beer B, et al. 1982. The cholinergic hypothesis of geriatric memory dysfunction. Science. 217:408–414. [DOI] [PubMed] [Google Scholar]
  3. Beatty WW, Butters N, Janowsky DS. 1986. Patterns of memory failure after scopolamine treatment: implications for cholinergic hypotheses of dementia. Behav Neural Biol. 45:196–211. [DOI] [PubMed] [Google Scholar]
  4. Beversdorf DQ. 2019. Neuropsychopharmacological regulation of performance on creativity-related tasks. Curr Opin Behav Sci. 27:55–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Beversdorf DQ, Hughes JD, Steinberg BA, et al. 1999. Noradrenergic modulation of cognitive flexibility in problem solving. Neuroreport. 10:2763–2767. [DOI] [PubMed] [Google Scholar]
  6. Beversdorf DQ, White DM, Chever DC, et al. 2002. Central beta-adrenergic modulation of cognitive flexibility. Neuroreport. 13:2505–2507. [DOI] [PubMed] [Google Scholar]
  7. Bowden EM, Beeman MJ. 1998. Getting the right idea: semantic activation in the right hemisphere may help solve insight problems. Psychol Sci. 9:435–440. [Google Scholar]
  8. Bowden EM, Jung-Beeman M. 2003. Normative data for 144 compound remote associate problems. Behav Res Meth Instrum Comput. 35:634–639. [DOI] [PubMed] [Google Scholar]
  9. Buschke H 1973. Selective reminding for analysis of memory and learning. J Verbal Learn Verbal Behav. 12:543–550. doi: 10.1016/S0022-5371(73)80034-9 [DOI] [Google Scholar]
  10. Campbell HL, Tivarus ME, Hillier A, et al. 2008. Increased task difficulty results in greater impact of noradrenergic modulation of cognitive flexibility. Pharmacol Biochem Behav. 88:222–229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Choi Y, Novak JC, Hillier A, et al. 2006. The effect of alpha-2 adrenergic agonists on memory and cognitive flexibility. Cogn Behav Neurol. 19:204–207. [DOI] [PubMed] [Google Scholar]
  12. Corwin J, Bylsma FW. 1993. Translations of excerpts from Andre Rey’s psychological examination of traumatic encephalopathy and P.A. Osterreith’s the Complex Figure Copy Test. Clin Neuropsychol. 7:3–15. [Google Scholar]
  13. Delis DC, Kramer JH, Kaplan E, et al. 1987. CVLT: California Verbal Learning Test: Adult Version: Manual. San Antonio, Texas: Psychological Corporation. [Google Scholar]
  14. Drachman DA. 1977. Memory and cognitive function in man: Does the cholinergic system have a specific role? Neurology. 27:783–790. [DOI] [PubMed] [Google Scholar]
  15. Drachman DA, Leavitt J. 1974. Human memory and the cholinergic system. A relationship to aging? Arch Neurol. 30:113–121. [DOI] [PubMed] [Google Scholar]
  16. Ellis KA, Nathan PJ. 2001. The pharmacology of human working memory. Int J Neuropsychopharmacol. 4:299–313. [DOI] [PubMed] [Google Scholar]
  17. Ghoneim MM, Mewaldt SP. 1975. Effects of diazepam and scopolamine on storage, retrieval, and organizational processes in memory. Psychopharmacologia. 44:257–262. [DOI] [PubMed] [Google Scholar]
  18. Ghoneim MM, Mewaldt SP. 1977. Studies on human memory: the interactions of diazepam, scopolamine, and physostigmine. Psychopharmacology (Berl). 52:1–6. [DOI] [PubMed] [Google Scholar]
  19. Goekoop R, Scheltens P, Barkhof F, et al. 2006. Cholinergic challenge in Alzheimer patients and mild cognitive impairment differentially affects hippocampal activation—a pharmacological fMRI study. Brain. 129(pt 1):141–157. [DOI] [PubMed] [Google Scholar]
  20. Hasselmo ME. 1995. Neuromodulation and cortical function: modeling the physiological basis of behavior. Behav Brain Res. 65:1–27. [DOI] [PubMed] [Google Scholar]
  21. Hasselmo ME. 1999. Neuromodulation: acetylcholine and memory consolidation. Trends Cogn Sci. 3:351–359. [DOI] [PubMed] [Google Scholar]
  22. Hasselmo ME, Bower JM. 1992. Cholinergic suppression specific to intrinsic not afferent fiber synapses in rat piriform (olfactory) cortex. J Neurophysiol. 67:1222–1229. [DOI] [PubMed] [Google Scholar]
  23. Hasslemo ME, Linster C, Patil M, et al. 1997. Noradrenergic suppression of synaptic transmission may influence cortical signal-to-noise ratio. J Neurophysiol. 77:3326–3339. [DOI] [PubMed] [Google Scholar]
  24. Hasselmo ME, Wyble BP. 1997. Free recall and recognition in a network model of the hippocampus: simulating effects of scopolamine on human memory function. Behav Brain Res. 89:1–34. [DOI] [PubMed] [Google Scholar]
  25. Hegarty JP, Ferguson BJ, Zamzow RM, et al. 2017. Beta-adrenergic antagonism modulates functional connectivity in the default mode network of individuals with and without autism spectrum disorder. Brain Imaging Behav. 11:1278–1289. [DOI] [PubMed] [Google Scholar]
  26. Heilman KM, Nadeau SE, Beversdorf DQ. 2003. Creative innovation: possible brain mechanisms. Neurocase. 9:369–379. [DOI] [PubMed] [Google Scholar]
  27. Howe WM, Berry AS, Francois J, et al. 2013. Prefrontal cholinergic mechanisms instigating shifts from monitoring for cues to cue-guided performance: converging electrochemical and fMRI evidence from rats and humans. J Neurosci. 33:8742–8752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Levin ED. 1992. Nicotinic systems and cognitive function. Psychopharmacology (Berl). 108:417–431. [DOI] [PubMed] [Google Scholar]
  29. Little JT, Johnson DN, Minichiello M, et al. 1998. Combined nicotinic and muscarinic blockade in elderly normal volunteers: cognitive, behavioral, and physiologic responses. Neuropsychopharmacology. 19:60–69. [DOI] [PubMed] [Google Scholar]
  30. Mewaldt SP, Ghoneim MM. 1979. The effects and interactions of scopolamine, physostigmine and methamphetamine on human memory. Pharmacol Biochem Behav. 10:1205–1210. [DOI] [PubMed] [Google Scholar]
  31. Narayanan A, White CA, Saklayen S, et al. 2010. Effect of propranolol on functional connectivity in autism spectrum disorder—a pilot study. Brain Imaging Behav. 4:189–197. doi: 10.1007/s11682-010-9098-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Newhouse PA, Potter A, Corwin J, et al. 1992. Acute nicotinic blockade produces cognitive impairment in normal humans. Psychopharmacol. 108:480–484. [DOI] [PubMed] [Google Scholar]
  33. Newhouse PA, Potter A, Corwin J, et al. 1994. Age-related effects of the nicotinic antagonist mecamylamine on cognition and behavior. Neuropsychopharmacology. 10:93–107. [DOI] [PubMed] [Google Scholar]
  34. Osterrieth PA. 1944. Le test de copie d’une figure complexe; contribution à l’étude de la perception et de la mémoire [Test of copying a complex figure; contribution to the study of perception and memory]. Archives de Psychologie. 30:206–356. [Google Scholar]
  35. Parrott AC. 1986. The effects of transdermal scopolamine and four doses levels of oral scopolamine (0.15, 0.3, 0.6, and 1.2 mg) upon psychological performance. Psychopharmacol (Berl). 89:347–354. [DOI] [PubMed] [Google Scholar]
  36. Raven JC. 1938. Progressive Matrices: A Perceptual Test of Intelligence. London, England: HK Lewis. [Google Scholar]
  37. Rey A 1941. L’examen psychologique dans les cas d’encéphalopathie traumatique (Les problems) [The psychological examination in cases of traumatic encepholopathy. Problems]. Archives de Psychologie. 28:215–285. [Google Scholar]
  38. Risacher SL, Wang Y, Wishart HA, et al. 2013. Cholinergic enhancement of brain activation in mild cognitive impairment during episodic memory encoding. Front Psychiatry. 4:105. doi: 10.3389/fpsyt.2013.00105 [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Sarter M, Bruno JP. 1997. Cognitive functions of cortical acetylcholine: toward a unifying hypothesis. Brain Res Brain Res Rev. 23:28–46. [DOI] [PubMed] [Google Scholar]
  40. Sarter M, Givens B, Bruno JP. 2001. The cognitive neuroscience of sustained attention: where top-down meets bottom-up. Brain Res Brain Res Rev. 35:146–160. [DOI] [PubMed] [Google Scholar]
  41. Saykin AJ, Wishart HA, Rabin LA, et al. 2004. Cholinergic enhancement of frontal lobe activity in mild cognitive impairment. Brain. 127:1574–1583. [DOI] [PubMed] [Google Scholar]
  42. Silver JA, Hughes JD, Bornstein RA, et al. 2004. Effect of anxiolytics on cognitive flexibility in problem solving. Cogn Behav Neurol. 17:93–97. [DOI] [PubMed] [Google Scholar]
  43. Smyth SF, Beversdorf DQ. 2007. Lack of dopaminergic modulation of cognitive flexibility. Cogn Behav Neurol. 20:225–229. [DOI] [PubMed] [Google Scholar]
  44. Tröster AI, Beatty WW, Staton RD, et al. 1989. Effects of scopolamine on anterograde and remote memory in humans. Psychobiol. 17:12–18. [Google Scholar]
  45. Whitehouse PJ, Price DL, Struble RG, et al. 1982. Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Science. 215:1237–1239. [DOI] [PubMed] [Google Scholar]

RESOURCES