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Associations between a neurophysiological marker of central cholinergic activity and cognitive functions in young and older adults

Associations between a neurophysiological marker of central cholinergic activity and cognitive... Background: The deterioration of the central cholinergic system in aging is hypothesized to underlie declines in several cognitive domains, including memory and executive functions. However, there is surprisingly little direct evidence regarding acetylcholine’s specific role(s) in normal human cognitive aging. Methods: We used short-latency afferent inhibition (SAI) with transcranial magnetic stimulation (TMS) as a putative marker of cholinergic activity in vivo in young (n = 24) and older adults (n = 31). Results: We found a significant age difference in SAI, concordant with other evidence of cholinergic decline in normal aging. We also found clear age differences on several of the memory and one of the executive function measures. Individual differences in SAI levels predicted memory but not executive functions. Conclusion: Individual differences in SAI levels were better predictors of memory than executive functions. We discuss cases in which the relations between SAI and cognition might be even stronger, and refer to other age- related biological changes that may interact with cholinergic activity in cognitive aging. Keywords: Acetylcholine, Aging, Cortical inhibition, Executive function, Memory, Transcranial magnetic stimulation Background in executive functions (for reviews, see [7-9]). The integrity Normal aging is associated with declines in several cognitive of cortical cholinergic inputs appears to be critical for domains, most notably episodic memory and executive modulating attention, by enhancing responsiveness to sen- functions (for reviews, see [1-4]). These cognitive deficits sory inputs to facilitate cue detection and orienting [10] (for are associated with myriad brain changes, including struc- a review, see [9]). Cholinergic neuromodulation may also tural and functional deterioration of prefrontal, basal gan- play an important role in executive functions by selectively glia, and medial temporal areas and their interconnections. enhancing task-relevant inputs via bottom-up thalamic pro- However, establishing a link between these changes and cesses, while suppressing irrelevant stimuli via top-down cognitive decline in normal aging has proven surprisingly prefrontal modulation [11] (for other perspectives, see difficult [2,5]. [12,13]). This cholinergic-dependent interaction between Alterations in two classic neurotransmitter systems bottom-up and top-down processes appears to be affected have drawn considerable attention in cognitive aging: by aging, leading to difficulty in task-switching, handling dopamine [6] and acetylcholine. For decades, acetylcholine competition among several possible responses, and suppres- (ACh) was thought of primarily as a memory-related neuro- sing unwanted responses [11]. In memory, optimal levels of transmitter, but this view has recently been revised, with ACh may facilitate encoding by increasing the influence of ACh now thought to play an equally if not more crucial role inputs into the hippocampus through enhanced potenti- ation [9,14], and/or by providing the attentional “glue” to bind together disparate elements of an episode into a uni- * Correspondence: patrick.davidson@uottawa.ca School of Psychology, University of Ottawa, 136 Jean Jacques Lussier fied memory trace [15,16]. Private, Ottawa, Ontario K1N 6N5, Canada Experimental and correlational animal studies, as well as Élisabeth Bruyère Research Institute, University of Ottawa, Ottawa, Ontario, computational modelling, have yielded much information Canada Full list of author information is available at the end of the article © 2012 Young-Bernier et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Young-Bernier et al. Behavioral and Brain Functions 2012, 8:17 Page 2 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/17 on the role of the cholinergic system in cognition. However, young and older adults and found no age differences. More the extent to which age-related changes in cholinergic neu- recently, Degardin et al. [31] performed a similar study and romodulation contribute to cognitive decline in normal reached a similar conclusion. However, as we and others human aging remains unclear. There are at least three rea- [32] have argued previously, the use of varying test inten- sons for this: First, making inferences from animal and sities to obtain a constant MEP size across participants computational models to humans has sometimes proven might have contributed to masking any age effects in the surprisingly difficult (e.g., [17,18]). Second, much of what two studies above. In line with this, we recently found a we inferabout theroleofACh in cognitiveaging comes large and selective decrease in SAI in healthy seniors when from studies in which Alzheimer’s patients are treated with we used a constant TMS test intensity approach [33]. Fur- cholinesterase inhibitors, including donepezil, galantamine, ther, we found that age-related variations in SAI explained a and rivastigmine (e.g., [19]). Unfortunately, these patients substantial proportion of the variance in timed motor tasks can be difficult to test and experience other confounding assessing processing speed. factors including significant structural and functional brain This study constitutes an extension of our previous changes. Third, manipulation of ACh via agonist and antag- findings; data were derived from thesamesampleofpartici- onist drugs (e.g., scopolamine) has produced a vast amount pants as already described [33]. In the present study, we of data, but strictly speaking this line of research tells us examined possible relationships between SAI, as a putative more about acute effects than it does about the long term marker of cholinergic-dependent cortical inhibition, and decline in cholinergic activity seen in normal aging. There is cognition in young and older healthy adults. Because mean thus a need to further examine the in vivo contribution of differences between young and older adult groups are often age-related alterations in central cholinergic function to small, especially relative to the extensive variability that can declines in human cognition. be seen among healthy older adults (e.g., some perform Recent advances in the field of non invasive brain much more poorly than young people, whereas others are stimulation have yielded new opportunities to examine indistinguishable from the young [34]), we capitalized on the neurophysiological correlates of aging using markers the individual-differences approach used by Glisky and col- of cortical excitability that can be linked with relative leagues [35,36]. This approach allows the characterization confidence to specific neurotransmitter systems [20]. of each participant’s long-term memory and executive func- One such marker involves pairing afferent nerve stimula- tions using neuropsychological testing to construct aggre- tion with transcranial magnetic stimulation (TMS) of the gate scores reflecting performance across several tasks in motor cortex to modulate motor responses evoked in each domain (for details, see Method). We hypothesized contralateral hand muscles [21]. When applied at short that age-related differences in SAI levels would be asso- intervals (e.g., 18–20 milliseconds [ms]) before TMS ciated with age-related differences in memory and executive pulses, afferent nerve stimulation typically leads to a functions. For memory, several investigators have empha- period of inhibition of the motor evoked potentials sized ACh’s putative role in binding information in memory (MEPs). This short-interval afferent inhibition (SAI) is [15], which we assessed using a canonical measure of paired mediated at the cortical level through cholinergic- associate learning (Verbal Paired Associates from the dependent GABA receptor activation [22]. The implica- Wechsler Memory Scale-III; WMS-III [37]). We also exam- tion of cholinergic action in mediating SAI is supported ined face recognition from the WMS-III because recent by in vivo observations of its reduction or even abolition studies have also described cholinergic modulation of face- by administration of a selective muscarinic cholinergic memory-related activity in the fusiform gyrus [38]. Given receptor blocker (scopolamine) in healthy participants the emphasis in the recent literature on the crucial role of [23]. Further, SAI is lower than expected in Alzheimer’s ACh in modulating executive functions [19,39,40], we also patients but restored by cholinesterase inhibitors [22]. expected correlations between SAI and our aggregate ex- SAI is also reduced in other disorders characterized by ecutive function measure. cholinergic dysfunction, including Lewy body dementia [24], multiple sclerosis [25], and Wernicke–Korsakoff Method syndrome [26], but it is normal in frontotemporal dementia, Participants a non-cholinergically mediated form of dementia [27]. To- The present data were derived from the same group of gether, these observations provide strong evidence that SAI participants previously described [33], with minor dif- is a cholinergic-dependent marker of motor intra-cortical ferences in the current sample (i.e. one young adult excitability. was excluded from the present study because of in- Given the clear decline in cholinergic modulation with complete cognitive data). We analyzed data from 24 age [28,29], one would predict that SAI would be altered young adults (age range = 18 to 30 years; M = 22.67, in healthy older adults. Yet, very few studies have examined SD = 3.49; 13 females) and 31 community-dwelling this issue. Oliviero et al. [30] compared SAI levels in healthy older adults (age range = 65 to 82 years; M = 70.29, Young-Bernier et al. Behavioral and Brain Functions 2012, 8:17 Page 3 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/17 SD = 3.81; 18 females). The two age groups were simi- delivered with a Magstim Rapid stimulator (Magstim Co. lar in education (young: M = 16.08 years, SD = 1.89; Dyfed, UK) connected to a figure-eight coil (90-mm inside older adults: M = 16.19, SD = 2.83). All participants loop diameter), held ~45° in the mid-sagittal plane. The were fluent English and/or French speakers with nor- resting motor threshold (RMT) was determined using the mal or corrected-to-normal vision (one participant was method of Mills and Nithi [45]: the RMT was defined for blind in one eye, but had no difficulty with the visual each participant as the median intensity between the tasks) and hearing, and were screened for depression upper and lower threshold values. The test TMS intensity (two participants were taking anti-depressants but their was fixed at 120% RMT for both unconditioned and condi- depression screening scores, TMS, and cognitive data tioned trials. Conditioning afferent stimulation was pro- were normal), dementia, psychiatric or neurological duced by applying 200 μs electrical pulses (S88 disorders, drug or alcohol abuse, and counter-indications to Stimulator, Grass Technologies, Astro-Med, Inc, West TMS. Participants’ medications were not altered for testing, Warwick, RI 02893 U.S.A.) on the median nerve at an with many older adults taking drugs related to vascular intensity just above the motor threshold to evoke a health (e.g., hypertension, statins cholesterol lowering minimal visible twitch of the thenar muscles [23,46]. drugs). None of the participants was taking neuroactive SAI was measured by applying afferent stimulation drugs such as neuroleptics, however one young adult and 20 ms before the TMS pulse over the motor cortex. one older adult were taking antidepressants (as mentioned Other inter-stimulus intervals (ISI; 25, 50 or 200 ms; above, their TMS data were normal). Vascular risk factors see [33]) were also investigated. Unconditioned MEP were assessed for each participant and consisted of a cumu- amplitude was first determined for each participant by lative score of 6 factors: body mass index with obesity eliciting 15 MEPs at rest (120% RMT). Following the defined as being greater than 30 kg/m , current smoking same procedure, blocks of trials were made for each status, lack of physical activity, type-2 diabetes, history of conditioned interval (order was counterbalanced across hypertension, and history of cardiac symptoms [41,42]. Vas- participants). Trials for which unwanted contractions cular risk factors for participants ranged from 0 to 3 were present were eliminated and repeated if necessary. (M = 0.44) with the maximum possible score being 6, sug- gesting generally good vascular health. All participants also Analysis of MEP data completed the Montreal Cognitive Assessment (MoCA; Mean individual values for conditioned and uncondi- [43]). Although some older adults (5/31) scored slightly tioned MEP responses were measured off-line by aver- below the recommended cutoff (i.e., >26), they were aging the amplitude (peak-to-peak) and latency of each deemed eligible for the study based on the interview and trial. SAI level was determined in each participant in their good performance on the other tasks, and on recent terms of percent of unconditioned MEP responses (i.e.% evidence that this cut-off may be too high [44]. The results MEP /MEP ). Conditioned Unconditioned of five additional participants were discarded because they did not meet inclusion criteria and thirteen more (including Memory and executive functions 6 older adults) because of incomplete testing (10 could not Participants underwent neuropsychological testing in a be reached for a second testing session resulting in missing quiet, well-lit room, in their language of choice. We cre- TMS-SAI data and 3 decided to stop before completion). ated two composite z scores for each individual, based The Research Ethics Boards of the University of Ottawa on previous factor analyses [35,36]. The first factor score and Bruyère Continuing Care approved the study procedure reflects long-term memory and is composed of five in accordance with the principles of the Declaration of Hel- scores: the Logical Memory I, Faces recognition I, and sinki. Informed consent was obtained from each participant Verbal Paired Associates I subtests of the WMS-III, Visual before the experimental session and all volunteers received Paired Associates II from the Wechsler Memory Scale– a minimal honorarium to defray expenses for participation. Revised (WMS-R; [47]), and Long Delay Cued Recall from the California Verbal Learning Test-II (CVLT-II; [48]). The TMS procedure for short-afferent inhibition second factor score, reflecting executive function, is made The TMS procedure has been reported in detail previ- up of the number of categories achieved on the computer- ously [33]. In brief, motor evoked potentials (MEP) were ized Wisconsin Card Sorting Test [49], the total number of recorded using small pairs of auto-adhesive surface elec- words produced to the cues F, A,and S on aphonemicflu- trodes (10 mm diameter, Ag-AgCl) placed over the first ency test [50], and the Backward Digit Span and Mental dorsal interosseous (FDI) muscle of the right hand. Elec- Control measures from the WMS–III. In previous studies tromyographic signals were amplified (100–500 mV/div) involving only older adults, the executive function factor and filtered (bandwidth, 10 Hz to 1 kHz) with a polygraph had also included Mental Arithmetic from the Wechsler amplifier (RMP-6004, Nihon-Kohden Corp.; BNC-2090, Adult Intelligence Scale—Revised (WAIS-R; [51]), but [35] National Instrument Corp.). Magnetic stimulation was reported that this measure did not load significantly on the Young-Bernier et al. Behavioral and Brain Functions 2012, 8:17 Page 4 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/17 executive function factor in their young adults. Therefore, Age differences in cognition we omitted this measure from the executive function z The young adults performed significantly better on sev- score in both groups to allow for direct age group eral of the memory and executive function tasks than the comparisons. older adults did (ANOVA: main effect of Age: F = 6.86, p = 0.01, significant Age X Task interaction: 1,51 F = 3.22; p = 0.003 ). At the adjusted p value, post- 7, 357 Statistical methods hoc t tests showed that the young significantly outper- Independent t-tests, with adjusted p values for multiple formed the older adults on memory for Verbal Paired comparisons (i.e. p = 0.0125), were used to examine age Associates I (t = 4.03, p = 0.0002) and Faces I (t = 3.89, 53 52 group differences on baseline measures of excitability. p = 0.0003), and number of categories on the Wisconsin Mixed analysis of variance (ANOVA) and independent Card Sorting Test (t = 4.10, p = 0.0001). Although the t-tests were used to examine differences between age two age groups could not be compared on the Visual groups. We adjusted p values to correct for multiple Paired Associates II measure using parametric methods comparisons in the between-group t-tests on the cogni- because of ceiling effects in the young adults (that is, all tive tasks (p =0.05/8, that is, p = 0.00625). We used the young adults scored 6 out of 6, whereas the older Pearson’s correlations to examine associations among adults ranged from 4 to 6), a Chi-Squared analysis sug- SAI levels and memory and executive function scores. gested a significant advantage for the young adults All statistical tests were performed using the PASW soft- 2 (χ = 9.82, p = 0.007). The factor scores, by definition, ware version 18.0 for Windows (Chicago,IL, USA).The reflected the individual test scores: The young had sig- figure was prepared with GraphPad Prism version 5.00 for nificantly higher scores than the older adults on the Windows (GraphPad Software, San Diego California USA, memory factor z score (t = 4.53, p< 0.0001), but the www.graphpad.com). groups were not significantly different from one another on the executive function factor z score (t = 1.65, p = 0.11). The mean levels of performance on the individ- Results ual cognitive tasks and the factor scores are shown in TMS and SAI Table 2. The TMS procedure was well tolerated and no participants experienced adverse effects. A thorough analysis of the Correlations between SAI and cognition physiological data has been reported previously [33] (see When we performed an analysis across all individuals Table 1 for baseline TMS measurements). Briefly, young [52,53]; but see [54,55], SAI significantly predicted the adults generally exhibited marked MEP suppression in re- memory factor score (r = −0.31, p = 0.02), whereas it did sponse to afferent conditioning leading to high levels of SAI not predict the executive function z score (r = −0.09, (18.13 ± 15.74). In contrast, seniors exhibited more variable p = 0.51; see Figure 1). The correlation between SAI and afferent-induced inhibition with a substantial proportion of memory was modest in size (r = 10%), and when we subjects (14/31) showing either low or absent inhibition (MEP ≥ 50% suppression). Accordingly, SAI levels esti- cond mated in seniors (51.36 ± 34.62) were significantly lower Table 2 Cognitive performance in the two age groups (mean ± SD) than in young adults (p< 0.001). Young Adults Older Adults (n = 24) (n = 31) Logical Memory I 30.46 ± 4.04 29.00 ± 6.77 Table 1 Hand dominance and baseline measures of Visual Paired Associates II 6.00 ± 0.00 5.50 ± 0.77 *** excitability in the two age groups (mean ± SD) Verbal Paired Associates I 26.63 ± 5.59 19.00 ± 7.84 *** Young Senior (n = 24) (n = 31) Faces I 38.71 ± 4.31 34.67 ± 3.34 *** Hand Dominance (L/R) 2/22 1/30 CVLT-II Long-Delay Cued Recall 13.67 ± 1.81 12.39 ± 2.70 Resting MT (% output) 66.00 ± 11.55 72.55 ± 12.71 Verbal Fluency (FAS) Test 40.25 ± 9.81 41.00 ± 12.20 Test MT (% output) 79.17 ± 13.82 86.97 ± 15.15 Backward Digit Span 7.67 ± 2.67 7.42 ± 2.80 Resting MEP amplitude (μV) 926.61 ± 774.34 427.22 ± 540.59* Wisconsin Card Sorting Test 4.25 ± 0.85 2.83 ± 1.51 *** Resting MEP latency (ms) 22.27 ± 1.88 24.03 ± 1.87* Mental Control 27.13 ± 4.74 26.39 ± 4.10 Intensity MNS 64.17 ± 1.80 72.87 ± 1.72 Memory factor (z score) 0.39 ± 0.39 −0.31 ± 0.68 *** Key: MEP, motor evoked potential; MNS, median nerve stimulation; MT, motor Executive function factor (z score) 0.16 ± 0.50 −0.12 ± 0.71 threshold. 1 1 Conditioning intensity for median nerve stimulation (MNS). California Verbal Learning Test-II. *Significant difference at adjusted p-values (p = 0.0125) for multiple Significant difference at adjusted p-values (p = 0.006) for multiple comparisons comparisons (see [33] for a more elaborate analysis of these age differences). *** p< 0.001. Young-Bernier et al. Behavioral and Brain Functions 2012, 8:17 Page 5 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/17 examined the correlation separately within each age significant when we examined each age group on its own group it failed to obtain significance. Although in the (r≤ |0.21|). Note that although Visual Paired Associates II is young group alone a significant correlation between SAI also a canonical measure of this ability, it was not explored levels and the executive function z score emerged in our further because of the ceiling-level scores in data, especially initial analysis (r = −0.56, p = 0.004), visual inspection for the young adults. Second, we found a significant correl- suggested that this was driven by two data points; in- ation between SAI and memory for faces (Faces I; r = −0.31, deed, if we deleted these two cases the correlation was p = 0.02), although, again, it disappeared when analyses were rendered non-significant. performed separately within each age group (r≤ |0.17|). Based on the hypotheses outlined at the end of the We also performed all analyses while excluding the five introduction, we also examined associations between SAI older adults who had MoCA scores lower than the and specific individual subtest scores. First, we found a recommended cutoff. This did not yield any changes in significant correlation between SAI and Verbal Paired the results. Associates I (r = −0.35, p = 0.008), a canonical measure of memory binding, although this correlation became non- Discussion Deficits in central cholinergic activity are thought to underlie age-related cognitive decline, but evidence regarding the specific role(s) of ACh in human cognitive aging is still scarce. We investigated the relation of SAI, a putative neurophysiological marker of cholinergic ac- tivity, to memory and executive functions in aging. Age differences in SAI Consistent with reports of impaired cortical inhibition with age [56], as a group, our senior participants exhibited reduced intra-cortical inhibition, as reflected in the overall decrease in afferent-induced inhibition. The fact that SAI has been linked with cholinergic activity in the motor cortex in pharmacological and patient studies (e.g., [22,23,57]; but see below) provides further converging in vivo evidence of a decline in central cholinergic function in normal human aging (e.g., [58]for reviews, see [28,59]). Associations between SAI and cognition The young adults outperformed their older counterparts on several measures of memory, consistent with numerous previous reports [1-4]. Although memory was clearly impaired in the older adults, executive function was not. This finding is concordant with a similar study to ours [35], which noted that others too have found this pattern. For ex- ample, Lamar and Resnick [60] reported no age differences in verbal fluency, mental control, and digit span, which were included in the present executive function factor score. SAI predicted individual performance in memory, al- though, contrary to expectations, it did not predict execu- tive functioning. These results are consistent with some studies [61], but not with others [19,39,40] and may stem from the poor vascular health of the patients included in those studies. (This issue will be discussed further below.) The association between SAI and memory is also consistent with Duzel et al. [52], who recently reported that a magnetic Figure 1 Scatter plots showing the associations between SAI levels and composite z scores of (A) memory and (B) executive resonance imaging estimate of the structural integrity of the functions. SAI levels correspond to the modulation of motor evoked basal forebrain (the major source of cholinergic input into potentials (MEP) induced by afferent conditioning at an inter-stimulus the cortex and hippocampus) predicted verbal memory in a interval (ISI) of 20 ms (% Conditioned MEP/Unconditioned MEP). mixed sample of young and older adults. Young-Bernier et al. Behavioral and Brain Functions 2012, 8:17 Page 6 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/17 In the present study, SAI levels explained approxi- better predictor of memory than executive functions, but an mately 10% of the variance in memory. Although this is even stronger indicator of motor performance and informa- comparable in size to the explanatory power of Duzel tion processing speed. et al.’s [52] measure of basal forebrain integrity, we sus- Third, recent microdialysis studies have described pect that the relation between SAI and cognition might phasic cholinergic release during attention-related tasks be even stronger under different circumstances. First, in rats [71,72]. These studies suggest that indices of rela- pharmacological studies indicate that ACh must decline tively tonic ACh levels (including SAI, positron emission past a certain threshold before changes in cognition are tomography, and magnetic resonance spectroscopy) in detectable [62-66]. Although we studied a representative the brain will need to be supplemented with methods group of older adults, only a small number of them that have higher temporal resolution when they become exhibited relatively low SAI levels. Given that cholinergic available in humans. Finally, like most studies, this one function declines with age, one future possibility would was cross-sectional. Complementary longitudinal studies be to recruit older seniors (i.e., over 80 years of age) with of within-subject changes must be completed to yield a the expectation that stronger correlations with cognition more complete understanding of the relationship be- would emerge. Also, one important putative cause of tween the onset and course of cholinergic dysfunction cholinergic decline in aging is microvascular damage to and cognitive decline in normal and pathological aging the ascending cholinergic pathways from the midbrain to (e.g., [73]cf. [74,75]). the cortex [67,68]. Our older participants were in rela- Strong evidence that SAI is a reliable marker of cholin- tively good vascular health. Were we to focus on recruit- ergic function comes from pharmacological and patient ing people in poorer vascular health, we might find studies [22,23,57], but gamma-aminobutyric acid stronger correlations between cholinergic function and (GABA), dopamine, and serotonin may also contribute cognition [39,40]. to the signal (e.g., [76,77]). For example, as we have noted previously [33], our older adults showed greater Second,itispossiblethatcholinergic modulation sup- inter-individual variability in SAI than did our young ports only relatively specific aspects of memory and execu- adults, with approximately half the seniors exhibiting tive functions and that these processes were not optimally either poor or absent intra-cortical inhibition. These assayed or taxed by the current neuropsychological battery. older adults were indistinguishable from the other A general assertion is that for ACh to be significantly impli- seniors in terms of age and vascular health, and there cated in cognitive tasks, these tasks must be difficult and re- was no evidence that these individuals were in a preclinical quire effortful attention [11,59]. The tasks in the current stage of dementia. One possibility, however, is that these study all fit this description. However, based on techniques individual differences in intra-cortical inhibition are that can target specifically the cholinergic system in animals related to variability in changes in motor cortex GABA (e.g., the immunotoxin 192 IgG-saporin), it has recently receptors in aging [78,79]. Future pharmacological and been argued that ACh is particularly important for certain neuroimaging work must verify that SAI is strongly, al- memory functions, including encoding more so than re- though perhaps not exclusively, reflective of activity in the trieval, and remembering relational and contextual informa- cholinergic system. tion in particular [15,69]. Consistent with the strong involvement of Ach in attention, studies have also suggested that the cholinergic system is more important for strategic Conclusion and effortful processing of information to be remembered We found that individual differences in episodic memory rather than when it is automatic [70]. Regarding executive could be explained in part by SAI, a putative marker of functions, cholinergic activity may be especially important central cholinergic functioning. However, cholinergic de- for task-switching, handling competition among possible cline is only one of many brain changes that occur in aging responses, and suppressing unwanted responses [11]. Al- [80-82]. The goal of future research on the biological bases though we did measure several of these putative processes of cognitive aging should be to combine multiple methods (e.g., memory binding with the visual and verbal paired to increase explanatory power, for example by combining associates subtests; switching and suppression with the multiple neuroimaging methods (e.g., [83,84]) with genetic Wisconsin Card Sorting Test), we are currently developing information (e.g., [52,85]). The short afferent inhibition a new battery to probe some of these memory and execu- marker of cholinergic integrity reported in this study is a tive sub-processes more specifically. Combined with our minimally-invasive, relatively inexpensive, significant pre- previous observation of an association between SAI and dictor of cognition. Combining it with neuroimaging, gen- complex motor tasks (i.e. Grooved Pegboard Test, complex etic, and other cognitive neuroscience methods should reaction times, go/no-go) but not with simple reaction prove useful in future studies. times in aging [33], this study suggests that SAI may be a Young-Bernier et al. Behavioral and Brain Functions 2012, 8:17 Page 7 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/17 Endnote 7. Floresco SB, Jentsch JD: Pharmacological enhancement of memory and executive functioning in laboratory animals. Neuropsychopharmacol 2011, Three older adults each did not complete one cognitive 36:227–250. measure (Faces I, Wisconsin Card Sorting Test and Visual 8. Picciotto MR, Meenakshi A, Jentsch JD: Acetylcholine. In Paired Associates II); their factor z scores were calculated Neuropsychopharmacology: The Fifth Generation of Progress. Edited by Davis KL, Charney D, Coyle JT, Nemeroff C. Philadelphia, PA: Lippincott Williams & Wilkins; by computing the mean of the remaining tests. 2002: 3–14. 9. Hasselmo ME, Sarter M: Modes and models of forebrain cholinergic Abbreviations neuromodulation of cognition. Neuropsychopharmacol 2011, 36:52–73. Ach: Acetylcholine; GABA: Gamma-aminobutyric acid; CVLT-II: California 10. Davidson MC, Marrocco RT: Local infusion of scopolamine into Verbal Learning Test - II; ISI: Inter-stimulus interval; MEP: Motor evoked intraparietal cortex slows covert orienting in rhesus monkeys. J potentials; MoCA: Montreal Cognitive Assessment; RMT: Resting motor Neurophysiol 2000, 83:1536–1549. threshold; SAI: Short-latency afferent inhibition; TMS: Transcranial magnetic 11. Sarter M, Hasselmo ME, Bruno JP, Givens B: Unraveling the attentional functions stimulation; WAIS-R: Wechsler Adult Intelligence Scale – Revised; of cortical cholinergic inputs: interactions between signal-driven and WMS-III: Wechsler Memory Scale – III; WMS-R: Wechsler Memory cognitive modulation of signal detection. Brain Res Rev 2005, 48:98–111. Scale – Revised. 12. Yu AJ, Dayan P: Acetylcholine in cortical inference. Neural Netw 2002, 15:719–730. Competing interests 13. Yu AJ, Dayan P: Uncertainty, neuromodulation, and attention. Neuron We declare no actual or potential conflicts of interest. 2005, 46:681–692. 14. Hasselmo ME, Giocomo LM: Cholinergic modulation of cortical function. J Acknowledgements Mol Neurosci 2006, 30:133–135. We thank our participants for their time and patience during testing, and 15. Botly LC, De Rosa E: A cross-species investigation of acetylcholine, Héloïse Drouin, Sabah Master, and Travis Davidson for help with data attention, and feature binding. Psychol Sci 2008, 19:1185–1193. collection and analysis. This work will serve as a partial fulfillment for a 16. Botly LC, De Rosa E: Cholinergic influences on feature binding. Behav doctoral thesis in clinical psychology by MYB. This work was supported by Neurosci 2007, 121:264–276. student awards from the Canadian Institutes of Health Research to MYB and 17. Arnsten AF, Robbins TW: Neurochemical modulation of prefrontal from the Natural Sciences and Engineering Research Council of Canada to cortical function in humans and animals. In Principles of Frontal Lobe YK, a Research Development Grant from the Faculty of Social Sciences of the Function. Edited by Stuss DT, Knight RT. New York, NY: Oxford University University of Ottawa to FT and PD, and a Discovery grant from the Natural Press; 2002: 51–84. Sciences and Engineering Research Council of Canada to PD. These funding 18. 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Neuroimage 2011, 54:1565–1577. doi:10.1186/1744-9081-8-17 Cite this article as: Young-Bernier et al.: Associations between a neurophysiological marker of central cholinergic activity and cognitive functions in young and older adults. Behavioral and Brain Functions 2012 8:17. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Behavioral and Brain Functions Springer Journals

Associations between a neurophysiological marker of central cholinergic activity and cognitive functions in young and older adults

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Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
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Abstract

Background: The deterioration of the central cholinergic system in aging is hypothesized to underlie declines in several cognitive domains, including memory and executive functions. However, there is surprisingly little direct evidence regarding acetylcholine’s specific role(s) in normal human cognitive aging. Methods: We used short-latency afferent inhibition (SAI) with transcranial magnetic stimulation (TMS) as a putative marker of cholinergic activity in vivo in young (n = 24) and older adults (n = 31). Results: We found a significant age difference in SAI, concordant with other evidence of cholinergic decline in normal aging. We also found clear age differences on several of the memory and one of the executive function measures. Individual differences in SAI levels predicted memory but not executive functions. Conclusion: Individual differences in SAI levels were better predictors of memory than executive functions. We discuss cases in which the relations between SAI and cognition might be even stronger, and refer to other age- related biological changes that may interact with cholinergic activity in cognitive aging. Keywords: Acetylcholine, Aging, Cortical inhibition, Executive function, Memory, Transcranial magnetic stimulation Background in executive functions (for reviews, see [7-9]). The integrity Normal aging is associated with declines in several cognitive of cortical cholinergic inputs appears to be critical for domains, most notably episodic memory and executive modulating attention, by enhancing responsiveness to sen- functions (for reviews, see [1-4]). These cognitive deficits sory inputs to facilitate cue detection and orienting [10] (for are associated with myriad brain changes, including struc- a review, see [9]). Cholinergic neuromodulation may also tural and functional deterioration of prefrontal, basal gan- play an important role in executive functions by selectively glia, and medial temporal areas and their interconnections. enhancing task-relevant inputs via bottom-up thalamic pro- However, establishing a link between these changes and cesses, while suppressing irrelevant stimuli via top-down cognitive decline in normal aging has proven surprisingly prefrontal modulation [11] (for other perspectives, see difficult [2,5]. [12,13]). This cholinergic-dependent interaction between Alterations in two classic neurotransmitter systems bottom-up and top-down processes appears to be affected have drawn considerable attention in cognitive aging: by aging, leading to difficulty in task-switching, handling dopamine [6] and acetylcholine. For decades, acetylcholine competition among several possible responses, and suppres- (ACh) was thought of primarily as a memory-related neuro- sing unwanted responses [11]. In memory, optimal levels of transmitter, but this view has recently been revised, with ACh may facilitate encoding by increasing the influence of ACh now thought to play an equally if not more crucial role inputs into the hippocampus through enhanced potenti- ation [9,14], and/or by providing the attentional “glue” to bind together disparate elements of an episode into a uni- * Correspondence: patrick.davidson@uottawa.ca School of Psychology, University of Ottawa, 136 Jean Jacques Lussier fied memory trace [15,16]. Private, Ottawa, Ontario K1N 6N5, Canada Experimental and correlational animal studies, as well as Élisabeth Bruyère Research Institute, University of Ottawa, Ottawa, Ontario, computational modelling, have yielded much information Canada Full list of author information is available at the end of the article © 2012 Young-Bernier et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Young-Bernier et al. Behavioral and Brain Functions 2012, 8:17 Page 2 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/17 on the role of the cholinergic system in cognition. However, young and older adults and found no age differences. More the extent to which age-related changes in cholinergic neu- recently, Degardin et al. [31] performed a similar study and romodulation contribute to cognitive decline in normal reached a similar conclusion. However, as we and others human aging remains unclear. There are at least three rea- [32] have argued previously, the use of varying test inten- sons for this: First, making inferences from animal and sities to obtain a constant MEP size across participants computational models to humans has sometimes proven might have contributed to masking any age effects in the surprisingly difficult (e.g., [17,18]). Second, much of what two studies above. In line with this, we recently found a we inferabout theroleofACh in cognitiveaging comes large and selective decrease in SAI in healthy seniors when from studies in which Alzheimer’s patients are treated with we used a constant TMS test intensity approach [33]. Fur- cholinesterase inhibitors, including donepezil, galantamine, ther, we found that age-related variations in SAI explained a and rivastigmine (e.g., [19]). Unfortunately, these patients substantial proportion of the variance in timed motor tasks can be difficult to test and experience other confounding assessing processing speed. factors including significant structural and functional brain This study constitutes an extension of our previous changes. Third, manipulation of ACh via agonist and antag- findings; data were derived from thesamesampleofpartici- onist drugs (e.g., scopolamine) has produced a vast amount pants as already described [33]. In the present study, we of data, but strictly speaking this line of research tells us examined possible relationships between SAI, as a putative more about acute effects than it does about the long term marker of cholinergic-dependent cortical inhibition, and decline in cholinergic activity seen in normal aging. There is cognition in young and older healthy adults. Because mean thus a need to further examine the in vivo contribution of differences between young and older adult groups are often age-related alterations in central cholinergic function to small, especially relative to the extensive variability that can declines in human cognition. be seen among healthy older adults (e.g., some perform Recent advances in the field of non invasive brain much more poorly than young people, whereas others are stimulation have yielded new opportunities to examine indistinguishable from the young [34]), we capitalized on the neurophysiological correlates of aging using markers the individual-differences approach used by Glisky and col- of cortical excitability that can be linked with relative leagues [35,36]. This approach allows the characterization confidence to specific neurotransmitter systems [20]. of each participant’s long-term memory and executive func- One such marker involves pairing afferent nerve stimula- tions using neuropsychological testing to construct aggre- tion with transcranial magnetic stimulation (TMS) of the gate scores reflecting performance across several tasks in motor cortex to modulate motor responses evoked in each domain (for details, see Method). We hypothesized contralateral hand muscles [21]. When applied at short that age-related differences in SAI levels would be asso- intervals (e.g., 18–20 milliseconds [ms]) before TMS ciated with age-related differences in memory and executive pulses, afferent nerve stimulation typically leads to a functions. For memory, several investigators have empha- period of inhibition of the motor evoked potentials sized ACh’s putative role in binding information in memory (MEPs). This short-interval afferent inhibition (SAI) is [15], which we assessed using a canonical measure of paired mediated at the cortical level through cholinergic- associate learning (Verbal Paired Associates from the dependent GABA receptor activation [22]. The implica- Wechsler Memory Scale-III; WMS-III [37]). We also exam- tion of cholinergic action in mediating SAI is supported ined face recognition from the WMS-III because recent by in vivo observations of its reduction or even abolition studies have also described cholinergic modulation of face- by administration of a selective muscarinic cholinergic memory-related activity in the fusiform gyrus [38]. Given receptor blocker (scopolamine) in healthy participants the emphasis in the recent literature on the crucial role of [23]. Further, SAI is lower than expected in Alzheimer’s ACh in modulating executive functions [19,39,40], we also patients but restored by cholinesterase inhibitors [22]. expected correlations between SAI and our aggregate ex- SAI is also reduced in other disorders characterized by ecutive function measure. cholinergic dysfunction, including Lewy body dementia [24], multiple sclerosis [25], and Wernicke–Korsakoff Method syndrome [26], but it is normal in frontotemporal dementia, Participants a non-cholinergically mediated form of dementia [27]. To- The present data were derived from the same group of gether, these observations provide strong evidence that SAI participants previously described [33], with minor dif- is a cholinergic-dependent marker of motor intra-cortical ferences in the current sample (i.e. one young adult excitability. was excluded from the present study because of in- Given the clear decline in cholinergic modulation with complete cognitive data). We analyzed data from 24 age [28,29], one would predict that SAI would be altered young adults (age range = 18 to 30 years; M = 22.67, in healthy older adults. Yet, very few studies have examined SD = 3.49; 13 females) and 31 community-dwelling this issue. Oliviero et al. [30] compared SAI levels in healthy older adults (age range = 65 to 82 years; M = 70.29, Young-Bernier et al. Behavioral and Brain Functions 2012, 8:17 Page 3 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/17 SD = 3.81; 18 females). The two age groups were simi- delivered with a Magstim Rapid stimulator (Magstim Co. lar in education (young: M = 16.08 years, SD = 1.89; Dyfed, UK) connected to a figure-eight coil (90-mm inside older adults: M = 16.19, SD = 2.83). All participants loop diameter), held ~45° in the mid-sagittal plane. The were fluent English and/or French speakers with nor- resting motor threshold (RMT) was determined using the mal or corrected-to-normal vision (one participant was method of Mills and Nithi [45]: the RMT was defined for blind in one eye, but had no difficulty with the visual each participant as the median intensity between the tasks) and hearing, and were screened for depression upper and lower threshold values. The test TMS intensity (two participants were taking anti-depressants but their was fixed at 120% RMT for both unconditioned and condi- depression screening scores, TMS, and cognitive data tioned trials. Conditioning afferent stimulation was pro- were normal), dementia, psychiatric or neurological duced by applying 200 μs electrical pulses (S88 disorders, drug or alcohol abuse, and counter-indications to Stimulator, Grass Technologies, Astro-Med, Inc, West TMS. Participants’ medications were not altered for testing, Warwick, RI 02893 U.S.A.) on the median nerve at an with many older adults taking drugs related to vascular intensity just above the motor threshold to evoke a health (e.g., hypertension, statins cholesterol lowering minimal visible twitch of the thenar muscles [23,46]. drugs). None of the participants was taking neuroactive SAI was measured by applying afferent stimulation drugs such as neuroleptics, however one young adult and 20 ms before the TMS pulse over the motor cortex. one older adult were taking antidepressants (as mentioned Other inter-stimulus intervals (ISI; 25, 50 or 200 ms; above, their TMS data were normal). Vascular risk factors see [33]) were also investigated. Unconditioned MEP were assessed for each participant and consisted of a cumu- amplitude was first determined for each participant by lative score of 6 factors: body mass index with obesity eliciting 15 MEPs at rest (120% RMT). Following the defined as being greater than 30 kg/m , current smoking same procedure, blocks of trials were made for each status, lack of physical activity, type-2 diabetes, history of conditioned interval (order was counterbalanced across hypertension, and history of cardiac symptoms [41,42]. Vas- participants). Trials for which unwanted contractions cular risk factors for participants ranged from 0 to 3 were present were eliminated and repeated if necessary. (M = 0.44) with the maximum possible score being 6, sug- gesting generally good vascular health. All participants also Analysis of MEP data completed the Montreal Cognitive Assessment (MoCA; Mean individual values for conditioned and uncondi- [43]). Although some older adults (5/31) scored slightly tioned MEP responses were measured off-line by aver- below the recommended cutoff (i.e., >26), they were aging the amplitude (peak-to-peak) and latency of each deemed eligible for the study based on the interview and trial. SAI level was determined in each participant in their good performance on the other tasks, and on recent terms of percent of unconditioned MEP responses (i.e.% evidence that this cut-off may be too high [44]. The results MEP /MEP ). Conditioned Unconditioned of five additional participants were discarded because they did not meet inclusion criteria and thirteen more (including Memory and executive functions 6 older adults) because of incomplete testing (10 could not Participants underwent neuropsychological testing in a be reached for a second testing session resulting in missing quiet, well-lit room, in their language of choice. We cre- TMS-SAI data and 3 decided to stop before completion). ated two composite z scores for each individual, based The Research Ethics Boards of the University of Ottawa on previous factor analyses [35,36]. The first factor score and Bruyère Continuing Care approved the study procedure reflects long-term memory and is composed of five in accordance with the principles of the Declaration of Hel- scores: the Logical Memory I, Faces recognition I, and sinki. Informed consent was obtained from each participant Verbal Paired Associates I subtests of the WMS-III, Visual before the experimental session and all volunteers received Paired Associates II from the Wechsler Memory Scale– a minimal honorarium to defray expenses for participation. Revised (WMS-R; [47]), and Long Delay Cued Recall from the California Verbal Learning Test-II (CVLT-II; [48]). The TMS procedure for short-afferent inhibition second factor score, reflecting executive function, is made The TMS procedure has been reported in detail previ- up of the number of categories achieved on the computer- ously [33]. In brief, motor evoked potentials (MEP) were ized Wisconsin Card Sorting Test [49], the total number of recorded using small pairs of auto-adhesive surface elec- words produced to the cues F, A,and S on aphonemicflu- trodes (10 mm diameter, Ag-AgCl) placed over the first ency test [50], and the Backward Digit Span and Mental dorsal interosseous (FDI) muscle of the right hand. Elec- Control measures from the WMS–III. In previous studies tromyographic signals were amplified (100–500 mV/div) involving only older adults, the executive function factor and filtered (bandwidth, 10 Hz to 1 kHz) with a polygraph had also included Mental Arithmetic from the Wechsler amplifier (RMP-6004, Nihon-Kohden Corp.; BNC-2090, Adult Intelligence Scale—Revised (WAIS-R; [51]), but [35] National Instrument Corp.). Magnetic stimulation was reported that this measure did not load significantly on the Young-Bernier et al. Behavioral and Brain Functions 2012, 8:17 Page 4 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/17 executive function factor in their young adults. Therefore, Age differences in cognition we omitted this measure from the executive function z The young adults performed significantly better on sev- score in both groups to allow for direct age group eral of the memory and executive function tasks than the comparisons. older adults did (ANOVA: main effect of Age: F = 6.86, p = 0.01, significant Age X Task interaction: 1,51 F = 3.22; p = 0.003 ). At the adjusted p value, post- 7, 357 Statistical methods hoc t tests showed that the young significantly outper- Independent t-tests, with adjusted p values for multiple formed the older adults on memory for Verbal Paired comparisons (i.e. p = 0.0125), were used to examine age Associates I (t = 4.03, p = 0.0002) and Faces I (t = 3.89, 53 52 group differences on baseline measures of excitability. p = 0.0003), and number of categories on the Wisconsin Mixed analysis of variance (ANOVA) and independent Card Sorting Test (t = 4.10, p = 0.0001). Although the t-tests were used to examine differences between age two age groups could not be compared on the Visual groups. We adjusted p values to correct for multiple Paired Associates II measure using parametric methods comparisons in the between-group t-tests on the cogni- because of ceiling effects in the young adults (that is, all tive tasks (p =0.05/8, that is, p = 0.00625). We used the young adults scored 6 out of 6, whereas the older Pearson’s correlations to examine associations among adults ranged from 4 to 6), a Chi-Squared analysis sug- SAI levels and memory and executive function scores. gested a significant advantage for the young adults All statistical tests were performed using the PASW soft- 2 (χ = 9.82, p = 0.007). The factor scores, by definition, ware version 18.0 for Windows (Chicago,IL, USA).The reflected the individual test scores: The young had sig- figure was prepared with GraphPad Prism version 5.00 for nificantly higher scores than the older adults on the Windows (GraphPad Software, San Diego California USA, memory factor z score (t = 4.53, p< 0.0001), but the www.graphpad.com). groups were not significantly different from one another on the executive function factor z score (t = 1.65, p = 0.11). The mean levels of performance on the individ- Results ual cognitive tasks and the factor scores are shown in TMS and SAI Table 2. The TMS procedure was well tolerated and no participants experienced adverse effects. A thorough analysis of the Correlations between SAI and cognition physiological data has been reported previously [33] (see When we performed an analysis across all individuals Table 1 for baseline TMS measurements). Briefly, young [52,53]; but see [54,55], SAI significantly predicted the adults generally exhibited marked MEP suppression in re- memory factor score (r = −0.31, p = 0.02), whereas it did sponse to afferent conditioning leading to high levels of SAI not predict the executive function z score (r = −0.09, (18.13 ± 15.74). In contrast, seniors exhibited more variable p = 0.51; see Figure 1). The correlation between SAI and afferent-induced inhibition with a substantial proportion of memory was modest in size (r = 10%), and when we subjects (14/31) showing either low or absent inhibition (MEP ≥ 50% suppression). Accordingly, SAI levels esti- cond mated in seniors (51.36 ± 34.62) were significantly lower Table 2 Cognitive performance in the two age groups (mean ± SD) than in young adults (p< 0.001). Young Adults Older Adults (n = 24) (n = 31) Logical Memory I 30.46 ± 4.04 29.00 ± 6.77 Table 1 Hand dominance and baseline measures of Visual Paired Associates II 6.00 ± 0.00 5.50 ± 0.77 *** excitability in the two age groups (mean ± SD) Verbal Paired Associates I 26.63 ± 5.59 19.00 ± 7.84 *** Young Senior (n = 24) (n = 31) Faces I 38.71 ± 4.31 34.67 ± 3.34 *** Hand Dominance (L/R) 2/22 1/30 CVLT-II Long-Delay Cued Recall 13.67 ± 1.81 12.39 ± 2.70 Resting MT (% output) 66.00 ± 11.55 72.55 ± 12.71 Verbal Fluency (FAS) Test 40.25 ± 9.81 41.00 ± 12.20 Test MT (% output) 79.17 ± 13.82 86.97 ± 15.15 Backward Digit Span 7.67 ± 2.67 7.42 ± 2.80 Resting MEP amplitude (μV) 926.61 ± 774.34 427.22 ± 540.59* Wisconsin Card Sorting Test 4.25 ± 0.85 2.83 ± 1.51 *** Resting MEP latency (ms) 22.27 ± 1.88 24.03 ± 1.87* Mental Control 27.13 ± 4.74 26.39 ± 4.10 Intensity MNS 64.17 ± 1.80 72.87 ± 1.72 Memory factor (z score) 0.39 ± 0.39 −0.31 ± 0.68 *** Key: MEP, motor evoked potential; MNS, median nerve stimulation; MT, motor Executive function factor (z score) 0.16 ± 0.50 −0.12 ± 0.71 threshold. 1 1 Conditioning intensity for median nerve stimulation (MNS). California Verbal Learning Test-II. *Significant difference at adjusted p-values (p = 0.0125) for multiple Significant difference at adjusted p-values (p = 0.006) for multiple comparisons comparisons (see [33] for a more elaborate analysis of these age differences). *** p< 0.001. Young-Bernier et al. Behavioral and Brain Functions 2012, 8:17 Page 5 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/17 examined the correlation separately within each age significant when we examined each age group on its own group it failed to obtain significance. Although in the (r≤ |0.21|). Note that although Visual Paired Associates II is young group alone a significant correlation between SAI also a canonical measure of this ability, it was not explored levels and the executive function z score emerged in our further because of the ceiling-level scores in data, especially initial analysis (r = −0.56, p = 0.004), visual inspection for the young adults. Second, we found a significant correl- suggested that this was driven by two data points; in- ation between SAI and memory for faces (Faces I; r = −0.31, deed, if we deleted these two cases the correlation was p = 0.02), although, again, it disappeared when analyses were rendered non-significant. performed separately within each age group (r≤ |0.17|). Based on the hypotheses outlined at the end of the We also performed all analyses while excluding the five introduction, we also examined associations between SAI older adults who had MoCA scores lower than the and specific individual subtest scores. First, we found a recommended cutoff. This did not yield any changes in significant correlation between SAI and Verbal Paired the results. Associates I (r = −0.35, p = 0.008), a canonical measure of memory binding, although this correlation became non- Discussion Deficits in central cholinergic activity are thought to underlie age-related cognitive decline, but evidence regarding the specific role(s) of ACh in human cognitive aging is still scarce. We investigated the relation of SAI, a putative neurophysiological marker of cholinergic ac- tivity, to memory and executive functions in aging. Age differences in SAI Consistent with reports of impaired cortical inhibition with age [56], as a group, our senior participants exhibited reduced intra-cortical inhibition, as reflected in the overall decrease in afferent-induced inhibition. The fact that SAI has been linked with cholinergic activity in the motor cortex in pharmacological and patient studies (e.g., [22,23,57]; but see below) provides further converging in vivo evidence of a decline in central cholinergic function in normal human aging (e.g., [58]for reviews, see [28,59]). Associations between SAI and cognition The young adults outperformed their older counterparts on several measures of memory, consistent with numerous previous reports [1-4]. Although memory was clearly impaired in the older adults, executive function was not. This finding is concordant with a similar study to ours [35], which noted that others too have found this pattern. For ex- ample, Lamar and Resnick [60] reported no age differences in verbal fluency, mental control, and digit span, which were included in the present executive function factor score. SAI predicted individual performance in memory, al- though, contrary to expectations, it did not predict execu- tive functioning. These results are consistent with some studies [61], but not with others [19,39,40] and may stem from the poor vascular health of the patients included in those studies. (This issue will be discussed further below.) The association between SAI and memory is also consistent with Duzel et al. [52], who recently reported that a magnetic Figure 1 Scatter plots showing the associations between SAI levels and composite z scores of (A) memory and (B) executive resonance imaging estimate of the structural integrity of the functions. SAI levels correspond to the modulation of motor evoked basal forebrain (the major source of cholinergic input into potentials (MEP) induced by afferent conditioning at an inter-stimulus the cortex and hippocampus) predicted verbal memory in a interval (ISI) of 20 ms (% Conditioned MEP/Unconditioned MEP). mixed sample of young and older adults. Young-Bernier et al. Behavioral and Brain Functions 2012, 8:17 Page 6 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/17 In the present study, SAI levels explained approxi- better predictor of memory than executive functions, but an mately 10% of the variance in memory. Although this is even stronger indicator of motor performance and informa- comparable in size to the explanatory power of Duzel tion processing speed. et al.’s [52] measure of basal forebrain integrity, we sus- Third, recent microdialysis studies have described pect that the relation between SAI and cognition might phasic cholinergic release during attention-related tasks be even stronger under different circumstances. First, in rats [71,72]. These studies suggest that indices of rela- pharmacological studies indicate that ACh must decline tively tonic ACh levels (including SAI, positron emission past a certain threshold before changes in cognition are tomography, and magnetic resonance spectroscopy) in detectable [62-66]. Although we studied a representative the brain will need to be supplemented with methods group of older adults, only a small number of them that have higher temporal resolution when they become exhibited relatively low SAI levels. Given that cholinergic available in humans. Finally, like most studies, this one function declines with age, one future possibility would was cross-sectional. Complementary longitudinal studies be to recruit older seniors (i.e., over 80 years of age) with of within-subject changes must be completed to yield a the expectation that stronger correlations with cognition more complete understanding of the relationship be- would emerge. Also, one important putative cause of tween the onset and course of cholinergic dysfunction cholinergic decline in aging is microvascular damage to and cognitive decline in normal and pathological aging the ascending cholinergic pathways from the midbrain to (e.g., [73]cf. [74,75]). the cortex [67,68]. Our older participants were in rela- Strong evidence that SAI is a reliable marker of cholin- tively good vascular health. Were we to focus on recruit- ergic function comes from pharmacological and patient ing people in poorer vascular health, we might find studies [22,23,57], but gamma-aminobutyric acid stronger correlations between cholinergic function and (GABA), dopamine, and serotonin may also contribute cognition [39,40]. to the signal (e.g., [76,77]). For example, as we have noted previously [33], our older adults showed greater Second,itispossiblethatcholinergic modulation sup- inter-individual variability in SAI than did our young ports only relatively specific aspects of memory and execu- adults, with approximately half the seniors exhibiting tive functions and that these processes were not optimally either poor or absent intra-cortical inhibition. These assayed or taxed by the current neuropsychological battery. older adults were indistinguishable from the other A general assertion is that for ACh to be significantly impli- seniors in terms of age and vascular health, and there cated in cognitive tasks, these tasks must be difficult and re- was no evidence that these individuals were in a preclinical quire effortful attention [11,59]. The tasks in the current stage of dementia. One possibility, however, is that these study all fit this description. However, based on techniques individual differences in intra-cortical inhibition are that can target specifically the cholinergic system in animals related to variability in changes in motor cortex GABA (e.g., the immunotoxin 192 IgG-saporin), it has recently receptors in aging [78,79]. Future pharmacological and been argued that ACh is particularly important for certain neuroimaging work must verify that SAI is strongly, al- memory functions, including encoding more so than re- though perhaps not exclusively, reflective of activity in the trieval, and remembering relational and contextual informa- cholinergic system. tion in particular [15,69]. Consistent with the strong involvement of Ach in attention, studies have also suggested that the cholinergic system is more important for strategic Conclusion and effortful processing of information to be remembered We found that individual differences in episodic memory rather than when it is automatic [70]. Regarding executive could be explained in part by SAI, a putative marker of functions, cholinergic activity may be especially important central cholinergic functioning. However, cholinergic de- for task-switching, handling competition among possible cline is only one of many brain changes that occur in aging responses, and suppressing unwanted responses [11]. Al- [80-82]. The goal of future research on the biological bases though we did measure several of these putative processes of cognitive aging should be to combine multiple methods (e.g., memory binding with the visual and verbal paired to increase explanatory power, for example by combining associates subtests; switching and suppression with the multiple neuroimaging methods (e.g., [83,84]) with genetic Wisconsin Card Sorting Test), we are currently developing information (e.g., [52,85]). The short afferent inhibition a new battery to probe some of these memory and execu- marker of cholinergic integrity reported in this study is a tive sub-processes more specifically. Combined with our minimally-invasive, relatively inexpensive, significant pre- previous observation of an association between SAI and dictor of cognition. Combining it with neuroimaging, gen- complex motor tasks (i.e. Grooved Pegboard Test, complex etic, and other cognitive neuroscience methods should reaction times, go/no-go) but not with simple reaction prove useful in future studies. times in aging [33], this study suggests that SAI may be a Young-Bernier et al. Behavioral and Brain Functions 2012, 8:17 Page 7 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/17 Endnote 7. Floresco SB, Jentsch JD: Pharmacological enhancement of memory and executive functioning in laboratory animals. Neuropsychopharmacol 2011, Three older adults each did not complete one cognitive 36:227–250. measure (Faces I, Wisconsin Card Sorting Test and Visual 8. Picciotto MR, Meenakshi A, Jentsch JD: Acetylcholine. In Paired Associates II); their factor z scores were calculated Neuropsychopharmacology: The Fifth Generation of Progress. Edited by Davis KL, Charney D, Coyle JT, Nemeroff C. Philadelphia, PA: Lippincott Williams & Wilkins; by computing the mean of the remaining tests. 2002: 3–14. 9. Hasselmo ME, Sarter M: Modes and models of forebrain cholinergic Abbreviations neuromodulation of cognition. Neuropsychopharmacol 2011, 36:52–73. Ach: Acetylcholine; GABA: Gamma-aminobutyric acid; CVLT-II: California 10. Davidson MC, Marrocco RT: Local infusion of scopolamine into Verbal Learning Test - II; ISI: Inter-stimulus interval; MEP: Motor evoked intraparietal cortex slows covert orienting in rhesus monkeys. J potentials; MoCA: Montreal Cognitive Assessment; RMT: Resting motor Neurophysiol 2000, 83:1536–1549. threshold; SAI: Short-latency afferent inhibition; TMS: Transcranial magnetic 11. Sarter M, Hasselmo ME, Bruno JP, Givens B: Unraveling the attentional functions stimulation; WAIS-R: Wechsler Adult Intelligence Scale – Revised; of cortical cholinergic inputs: interactions between signal-driven and WMS-III: Wechsler Memory Scale – III; WMS-R: Wechsler Memory cognitive modulation of signal detection. Brain Res Rev 2005, 48:98–111. Scale – Revised. 12. Yu AJ, Dayan P: Acetylcholine in cortical inference. Neural Netw 2002, 15:719–730. Competing interests 13. Yu AJ, Dayan P: Uncertainty, neuromodulation, and attention. Neuron We declare no actual or potential conflicts of interest. 2005, 46:681–692. 14. Hasselmo ME, Giocomo LM: Cholinergic modulation of cortical function. J Acknowledgements Mol Neurosci 2006, 30:133–135. We thank our participants for their time and patience during testing, and 15. Botly LC, De Rosa E: A cross-species investigation of acetylcholine, Héloïse Drouin, Sabah Master, and Travis Davidson for help with data attention, and feature binding. Psychol Sci 2008, 19:1185–1193. collection and analysis. This work will serve as a partial fulfillment for a 16. Botly LC, De Rosa E: Cholinergic influences on feature binding. Behav doctoral thesis in clinical psychology by MYB. This work was supported by Neurosci 2007, 121:264–276. student awards from the Canadian Institutes of Health Research to MYB and 17. Arnsten AF, Robbins TW: Neurochemical modulation of prefrontal from the Natural Sciences and Engineering Research Council of Canada to cortical function in humans and animals. In Principles of Frontal Lobe YK, a Research Development Grant from the Faculty of Social Sciences of the Function. Edited by Stuss DT, Knight RT. New York, NY: Oxford University University of Ottawa to FT and PD, and a Discovery grant from the Natural Press; 2002: 51–84. Sciences and Engineering Research Council of Canada to PD. These funding 18. Graef S, Schonknecht P, Sabri O, Hegerl U: Cholinergic receptor subtypes sources played no role in the design or administration of the study, the and their role in cognition, emotion, and vigilance control: an overview analysis or interpretation of the results, or the decision to submit for of preclinical and clinical findings. Psychopharmacol 2011, 215:205–229. publication. 19. Behl P, Lanctot KL, Streiner DL, Guimont I, Black SE: Cholinesterase inhibitors slow decline in executive functions, rather than memory, in Author details Alzheimer’s disease: a 1-year observational study in the Sunnybrook School of Psychology, University of Ottawa, 136 Jean Jacques Lussier Private, dementia cohort. Curr Alzheimer Res 2006, 3:147–156. Ottawa, Ontario K1N 6N5, Canada. Élisabeth Bruyère Research Institute, 20. Reis HJ, Guatimosim C, Paquet M, Santos M, Ribeiro FM, Kummer A, University of Ottawa, Ottawa, Ontario, Canada. School of Rehabilitation Schenatto G, Salgado JV, Vieira LB, Teixeira AL, Palotas A: Neuro-transmitters Sciences, University of Ottawa, Ottawa, Ontario, Canada. Heart and Stroke in the central nervous system & their implication in learning and Foundation Centre for Stroke Recovery, University of Ottawa, Ottawa, Ontario, memory processes. Curr Med Chem 2009, 16:796–840. Canada. 21. Chen R, Cros D, Curra A, Di Lazzaro V, Lefaucheur JP, Magistris MR, Mills K, Rosler KM, Triggs WJ, Ugawa Y, Ziemann U: The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee. Clin Authors’ contributions Neurophysiol 2008, 119:504–532. MYB participated in the design of the study, carried out the cognitive and 22. Di Lazzaro V, Oliviero A, Tonali PA, Marra C, Daniele A, Profice P, Saturno E, behavioural testing, performed the statistical analyses, and drafted the Pilato F, Masullo C, Rothwell JC: Noninvasive in vivo assessment of manuscript. YK participated in the cognitive testing. FT conceived of the cholinergic cortical circuits in AD using transcranial magnetic study, participated in its design, and helped with the behavioural testing. PD stimulation. Neurology 2002, 59:392–397. conceived of the study, participated in its design, helped with the statistical 23. Di Lazzaro V, Oliviero A, Profice P, Pennisi MA, Di Giovanni S, Zito G, Tonali P, analyses and drafted the manuscript. All authors read and approved the final Rothwell JC: Muscarinic receptor blockade has differential effects on the manuscript. excitability of intracortical circuits in the human motor cortex. Exp Brain Res 2000, 135:455–461. Received: 13 October 2011 Accepted: 26 April 2012 Published: 26 April 2012 24. Di Lazzaro V, Pilato F, Dileone M, Saturno E, Profice P, Marra C, Daniele A, Ranieri F, Quaranta D, Gainotti G, Tonali PA: Functional evaluation of cerebral References cortex in dementia with Lewy bodies. NeuroImage 2007, 37:422–429. 1. 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Neuroimage 2011, 54:1565–1577. doi:10.1186/1744-9081-8-17 Cite this article as: Young-Bernier et al.: Associations between a neurophysiological marker of central cholinergic activity and cognitive functions in young and older adults. Behavioral and Brain Functions 2012 8:17. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit

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Behavioral and Brain Functions – Springer Journals

Published: Apr 26, 2012

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