Age-related changes in the somatosensory processing of tactile stimulation—An fMRI study

Behavioural Brain Research 238 (2013) 259–264

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Age-related changes in the somatosensory processing of tactile stimulation—An fMRI study Stefan Brodoehl a,b,∗ , Carsten Klingner a,b , Katharina Stieglitz b , Otto W. Witte a,b a b

Hans Berger Clinic for Neurology, University of Jena, Germany Brain Imaging Center, University of Jena, Germany

h i g h l i g h t s    

We examined age-related changes in current perception thresholds (CPT) and somatosensory processing using fMRI. Activations in the contralateral SI and ipsilateral frontal cortex are increased in elderly. Activations in the bilateral SII and the cingulate cortex are decreased in elderly. The amplitude of the BOLD signal is reduced in SII but not in SI in elderly.

a r t i c l e

i n f o

Article history: Received 3 September 2012 Received in revised form 17 October 2012 Accepted 20 October 2012 Available online 30 October 2012 Keywords: Age-related Somatosensory cortex Inhibition BOLD signal Current perception threshold fMRI

a b s t r a c t Age-related changes in brain function are complex. Although ageing is associated with a reduction in cerebral blood flow and neuronal activity, task-related processing is often correlated with an enlargement of the corresponding and additionally recruited brain areas. This supplemental employment is considered an attempt to compensate for deficits in the ageing brain. Although there are contradictory reports regarding the role of the primary somatosensory cortex (SI), currently, there is little knowledge about age-related functional changes in other brain areas in the somatosensory network (secondary somatosensory cortex (SII), and insular, anterior (ACC) and posterior cingulate cortices (PCC)). We investigated 16 elderly (age range, 62–71 years) and 18 young subjects (age range, 21–28 years) by determining the current perception threshold (CPT) and applying functional magnetic resonance imaging (fMRI) using a 3.0 Tesla scanner under tactile stimulation of the right hand. CPT was positively correlated with age. fMRI analysis revealed significantly increased activation in the contralateral SI and ipsilateral motor cortex in elderly subjects. Furthermore, we demonstrated agerelated reductions in the activity in the SII, ACC, PCC, and dorsal parts of the corpus callosum. Our study revealed dramatic age-related differences in the processing of a simple tactile stimulus in the somatosensory network. Specifically, we detected enhanced activation in the contralateral SI and ipsilateral motor cortex assumingly caused by deficient inhibition and decreased activation in later stages of somatosensory processing (SII, cingulate cortex) in elderly subjects. These results indicate that, in addition to over-activation to compensate for impaired brain functions, there are complex mechanisms of modified inhibition and excitability involved in somatosensory processing in the ageing brain. © 2012 Elsevier B.V. All rights reserved.

1. Introduction Age-related changes in brain structure and function have been the motivation of previous and ongoing neuroscientific research. Physiological ageing has an immense impact on all stages of

∗ Corresponding author at: Hans Berger Clinic for Neurology, University Hospital Jena, Friedrich Schiller University, Erlanger Allee 101, D 07747 Jena, Germany. Tel.: +49 3641 9323401; fax: +49 3641 9323402. E-mail address: [email protected] (S. Brodoehl). 0166-4328/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.bbr.2012.10.038

sensorimotor processing, such as changes in peripheral neuronal structures and cortical functions. Nevertheless, there are different compensatory processes in cortical and subcortical structures that play a key role in maintaining high levels of functional performance. In addition to age-related atrophy of the brain [1,2], several studies using positron emission tomography (PET), cerebral blood flow (CBF), the cerebral metabolic rate of oxygen (CMRO2 ) or blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) [3–8] provide evidence for an overall reduction of cerebral blood flow in the ageing brain. This reduction may be caused by a decrease in overall brain activity due to a global loss of

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neurons [9,10] and a reduced vascular reactivity [11]. Furthermore, a network analysis between younger and older subjects revealed differences in networks that are related to internally driven cognitive processes (default mode network) [12] or externally driven tasks (task-positive network) [13] as well as specific deactivation patterns, even when corrected for grey matter volume changes [14–16]. There have been controversial reports regarding task-related cortex activation in ageing. Ross et al. [17] reported an age-related reduction in BOLD activation in the visual cortex after simple photic stimulation. Similar decreases in activation were reported for olfactory stimulation [18], central proprioceptive processing [19] and in the motor cortex after finger tapping [20]. On the contrary, other studies using functional imaging have revealed increased or more generalised activation patterns in elderly subjects after visual [21,22] and tactile [23] stimulation, as well as in memory [24,25] and motor tasks [26,27]. Some results are intriguing; for example, an fMRI study detected stronger activation in the primary somatosensory cortex (SI) in young adults [28], and an MEG study found increased activation in the somatosensory cortex in elderly subjects during swallowing [29]. Previous studies have described a number of cortical areas that are involved in the processing of median nerve stimulation [30,31]. Further studies have addressed age-related changes within those areas using MEG and evoked potentials (EPs) [23,32–34], demonstrating increased activation within the SI, most likely caused by altered inhibition due to ageing. Thus far, no data are available for higher regions of somatosensory processing in the ageing human brain. Consequently, this study aims to further investigate the mechanisms of age-related changes in somatosensory processing using functional magnetic resonance imaging. In this study, we hypothesised that (I) brain regions involved in somatosensory processing (SI, secondary somatosensory cortex (SII), anterior (ACC), and posterior cingulate cortices (PCC)) would reveal enlarged areas of task-related changes in BOLD activation due to disturbed intra- and inter-hemispheric inhibition, and (II) similar to the motor system, auxiliary brain regions (i.e., motor cortex, parietal cortex) would be recruited for neuronal processing. 2. Methods 2.1. Subjects We investigated 16 right-handed elderly subjects (7 females; age range, 62–71 years; mean age, 66.9 ± 5.2 years (mean ± standard deviation [SD])). The controls included 18 right-handed young subjects (10 females; age range, 21–28 years; mean age 23.0 ± 1.6 years). All subjects had no history of neurological or psychiatric diseases. All elderly subjects were examined by a neurologist, and conventional electroneurography (nerve conduction velocity measurement of the median nerve) was performed to exclude any peripheral nerve lesion or polyneuropathy. Additional exclusion criteria included diabetes mellitus, movement impairment, and a “Mini Mental State Examination” [35] score of less than 29. Investigations were performed according to the Declaration of Helsinki on biomedical studies involving human subjects. The study was approved by the local ethics committee, and all subjects provided written informed consent according to the Declaration of Helsinki. 2.2. Psychophysical testing Initially, we intended to confirm a measurable difference in the perception threshold between both groups, as described in several studies [36–39]. Therefore, we applied 40 Hz monophasic wave pulses starting at 0.5 mA to the right index finger using a clinical neurostimulator (Digitimer Constant Current Stimulator Model DS7A). Current intensity was slowly increased until each subject detected the stimulus. The procedure was repeated 20 times, and the average value was recorded as the current perception threshold (CPT). 2.3. fMRI stimulation To investigate characteristic changes in the activation pattern in response to a tactile stimulus, we used a physiological stimulus within the MRI scanner. Tactile stimuli were delivered simultaneously to fingers 1–3 of the right hand via

balloon diaphragms driven by compressed air. Each stimulus lasted for 100 ms (20 ms rise time, 30 ms plateau, and 50 ms return to baseline pressure). The tactile stimuli were presented 30 times in an event-related regime. To avoid systematic errors in haemodynamic response function estimation, the event-related interstimulus time was randomised between 8.7 and 15.8 s, and the interval between two stimuli was at least 25 s. No subject reported any painful or unpleasant sensations.

2.4. fMRI recordings All experiments were performed on a 3.0-T MR scanner (Trio, Siemens, Erlangen, Germany) to obtain echo-planar T2*-weighted image volumes (EPI) and transaxial T1-weighted structural images. Functional data were acquired in one EPI session of 703 volumes. The first three volumes were subsequently discarded due to equilibration effects. A functional-image volume comprised 20 transaxial slices including the cortex down to the SII (voxel size = 3 mm × 3 mm × 3 mm, repetition time = 2 s, echo time = 35 ms). The high-resolution T1-weighted structural images had a voxel size of 1 mm × 1 mm × 1 mm to allow for precise anatomical localisation.

2.5. Data analysis Data analysis was performed on a PC using MATLAB (Mathworks, Natick, MA) and SPM8 software (Wellcome Department of Cognitive Neurology, London, UK, http://www.fil.ion.ucl.ac.uk/spm). For each subject, all images were realigned to the first volume using six-parameter rigid-body transformations to correct for motion artefacts [40,41]. The images were co-registered with the subject’s corresponding anatomical (T1-weighted) images, re-sliced to correct for acquisition delays (referenced to the tenth slice only in the event-related design), normalised to the Montreal Neurological Institute (MNI) standard brain [42] to report MNI coordinates, and smoothed using a 6 mm full-width-at-half-maximum Gaussian kernel. Statistical analysis was performed using a general linear model to obtain statistical parametric maps by performing a multiple regression analysis. Statistical parametric maps for positive T-contrast were calculated for each condition and subject. Functional MRI signal time courses were high-pass filtered (30 s event-related design) and modelled as experimental stimulus onset functions convolved by the canonical haemodynamic response function (low-pass filter). Individual results were projected onto the co-registered individual high-resolution, T1-weighted 3-D data set. The anatomical localisations of activation were analysed by referencing the standard stereotaxic atlas and mapped by using the anatomical toolbox of the SPM software [43,44] (http://www.fz-juelich.de/ime/spm anatomy toolbox). Furthermore, all activation events were localised by visual inspection of the individual T1-weighted structural data. The individual maps were used to perform a random effect analysis to obtain consistent group activation patterns within a group (onesample t-test) and between both groups (two-sample t-test). The resulting group statistical maps were thresholded using the Bonferroni correction (FWE) within each group [45]. Because of our anatomical a priori hypothesis (deactivation was assumed to occur in the somatosensory brain areas of the contralateral SI and bilateral SII), activation T-maps were thresholded at P < 0.001 and uncorrected between groups. We were interested in whether the strength of the stimulus evoked positive BOLD responses. For this purpose, we extracted a time course of 5 points (by averaging the voxels up to a distance of 3 mm) in clusters of the highest t-values from each subject. We performed a least-squares fit of the experimental signal time courses with an inverse logit function as previously described by Lindquist and Wagner [46] as follows: L=

1 1 + e−x

(the inverse logit function)

 h(t) = ˛1 L

t − T1 D1

 + ˛3 L



t − T3 D3

 + ˛2 L



t − T2 D2

(1)



(haemodynamic response function)

 ˛3 = |˛2 | − |˛1 | and ˛2 = ˛1

L(−T3 )/D3 − L(−T1 )/D1 L(−T3 )/D3 − L(−T2 )/D2

(2)

 (constraint)

(3)

Start parameters (D1 = −1.834, D2 = −0.6314, D3 = −3.016,T1 = 4.358, T2 = 2.715, T3 = 4.516, ˛1 = 5.143) were determined by fitting the model to the SPM built-in haemodynamic response function. All individual BOLD time courses were fitted to the model. These fitted time courses were used to calculate the amplitude of the BOLD response of each subject. Values were entered into a two-sample t-test to determine (significant at P ≤ 0.001) whether the null hypothesis (absence of a significant correlation between age and the BOLD peak amplitude) could be rejected at the group level [47,48].

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3.2. fMRI experiment

Fig. 1. Age-related differences in current perception threshold (CPT). Electrical stimulation was applied to the right index finger. The thresholds of the elderly subjects (n = 16) were significantly higher than those of the young subjects (n = 18) (ANOVA, P ≤ 0.05).

3. Results 3.1. Psychophysical Psychophysical data verified that age was a significant predictor of CPT. The CPT of the right index finger was 1.79 ± 0.59 mA (mean ± standard deviation [SD]; range, 1.01–3.06 mA) in young subjects and 2.29 ± 0.66 mA (range, 1.31–3.29 mA) in elderly subjects. A repeated measures analysis of variance (ANOVA) with age as an independent factor revealed a group difference for CPT with significantly higher thresholds for elderly subjects (P = 0.030 (significant at P ≤ 0.05)). In both groups, correlation analysis revealed a positive correlation between individual CPT and age (Pearson correlation, r = 0.354, P = 0.043 (significant at P ≤ 0.05)) (Fig. 1).

Tactile stimulation of the right hand evoked highly significant activation (P < 0.005, FWE corrected) in the random effect group analysis (Fig. 2, left). In both groups, activation occurred within the left SI (Brodmann areas [BAs] 3, 1, 2), left primary and supplementary motor cortex (BAs 4, 6) as well as in the bilateral SII (BAs 13, 40, 41, 43). These activations were present in all of the individual t-maps. In the young group, there was also significant activation in the ACC (BA 24), the PCC (BA 23), and in parts of the dorsal corpus callosum (Table 1 and Fig. 2, left). At the individual level, only 3 individuals of the elderly group had significant activation in the ACC or the PCC (none in the dorsal corpus callosum), while this activation was present in all subjects of the young group. Comparing the clusters of activation between both groups, we found that in elderly subjects, the region of activation in the SI was broadly enlarged (301 voxels in elderly subjects compared to 195 voxels in young subjects), whereas in young subjects, the region of activation in the SII was enlarged (169 (right) + 164 (left) voxels in younger subjects and 30 (right) + 15 (left) in elderly subjects) (Table 1). Group comparisons revealed that activation in the bilateral SII, ACC (BA 24), PCC (BA 23), and in the dorsal part of the corpus callosum was decreased, whereas that within the right SI (BA 3) and right primary and supplementary motor cortex (BAs 4, 6) was increased in the elderly subjects (Table 1 and Fig. 2, right). For the extraction of stimulus-evoked individual BOLD responses, 5 voxels with the highest t-values from 5 clusters (by averaging the voxels up to a distance of 3 mm) of the second-level analysis were chosen based on our hypothesis that reduced inhibition leads to increased BOLD activation in elderly subjects. These voxels included 2 voxels within the left SI [MNI −42 × −28 × 61 and −48 × −25 × 49], 2 within the right [42 × −43 × 22] and left [−39 × −46 × 19] SII and 1 within the PCC [6 × −9 × 25] (derived clusters are marked in Table 1 (*)). The results indicate that whilst there was no difference in the BOLD signal intensity in the primary somatosensory cortex (SI), the BOLD signals were significantly lower in the elderly subjects than

Fig. 2. Random effect group analysis of BOLD responses to a tactile stimulus of digits 1–3 of the right hand of young (n = 18) and elderly (n = 16) subjects. Left: Second-level analysis of each group separately (one-sample t-test). Right: Second-level analysis comparing BOLD responses between both groups (two-sample t-test). Bright colours indicate high levels of significance.

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Table 1 Cortical activation in response to tactile stimulation of fingers 1–3 of the right hand. Cluster (voxels)

Young subjects (P < 0.005, FWE) 1 (195)* 2 (169) 3 (164) 4 (40) 5 (38) Elderly subjects (P < 0.005, FWE) 1 (301)* 2 (30) 3 (15) Young > elderly (P < 0.001, unc.) 1 (79)* 2 (64)* 3 (27) 4 (15) 5 (12)* Young < elderly (P < 0.001, unc.) 1 (31) 2 (11)

Brodmann area

Mean t-value ± STD (peak)

Peak at (MNI) X

Y

Z

3, 2, 1, 4, 40, 6 40, 13, 2 40, 13, 41, 2, 42, 43 24, 32 23, corp. callosum

−42 51 −51 −3 6

−28 −34 −34 17 −31

61 19 19 37 25

7.56 7.46 7.39 6.86 6.83

3, 4, 2, 1, 6, 40 2, 1, 3, 43 13, 41

−45 63 −48

−25 −19 −37

46 25 19

7.54 ± 0.82 (10.15) 7.12 ± 0.51 (8.35) 6.99 ± 0.43 (7.89)

13 23, 24, corp. callosum 13 40 13

42 6 −21 66 −39

−43 −19 −13 −40 −46

22 25 19 31 19

5.00 4.70 4.87 4.75 4.85

33 39

−10 −16

73 58

4.69 ± 0.22 (5.25) 3.59 ± 0.12 (4.80)

6, 4 3, 4

± ± ± ± ±

± ± ± ± ±

0.88 (9.74) 0.84 (10.46) 0.78 (10.09) 0.33 (7.59) 0.26 (7.47)

0.51 (6.26) 0.22 (5.70) 0.36 (5.69) 0.22 (5.97) 0.31 (5.37)

Results of the random effect group analysis of tactile stimulation of fingers 1–3 of the right hand within and between the groups of young and elderly subjects. Clusters are sorted by the amount of significant voxels. Brodmann areas (BAs) are noted in decreasing order by voxel count. BAs 3, 2, and 1 are regarded as the SI, and BAs 13, 40, 41, 42, and 43 overlap with the SII. BAs 24 and 23 correspond to the ventral anterior and posterior cortices, and BA 32 corresponds to the dorsal anterior cingulate cortex. BA 4 refers to the primary motor cortex, and BA 6 refers to the supplementary motor cortex. The MNI coordinates of the highest (peak) t-values are noted. * Clusters selected for comparison of BOLD signal change (Fig. 3).

Fig. 3. Changes of BOLD signal intensity in the contralateral SI (BAs 1 and 2), bilateral SII and PCC to tactile stimulation of the right hand in young (n = 18) and elderly (n = 16) subjects. (*) indicates a highly significant difference between the two groups (two-sample t-test, P < 0.001).

in the younger subjects (two-sample t-test, P < 0.001) in both the SII and PCC (Fig. 3). 4. Discussion We compared the current perception threshold (CPT) and differences in the event-related BOLD response to a simple tactile stimulus in young (mean age, 23 years; n = 18) and elderly (mean age, 67 years; n = 16) subjects. In line with previous studies, we found an age-related increase of the CPT [23,36–39]. In the same subjects, tactile stimulation of the right hand using a pneumatic device produced robust activation characterised by a positive BOLD response in the contralateral SI and bilateral SII, which is consistent with previous fMRI studies [48–52]. We demonstrated enlarged regional activation in the contralateral SI in response to a simple tactile stimulus in elderly subjects,

whereas the amplitude of the BOLD signal change was comparable between both groups. Moreover, in elderly subjects, decreased activation patterns in the bilateral SII, ACC, PCC, and dorsal corpus callosum were associated with a reduced task-related BOLD signal change. Further, we discovered age-related increases in cortical activity in the ipsilateral (right) SI (BA 3) and ipsilateral (right) primary and supplementary motor (BAs 4, 6) cortices. An important aspect in the present study is the application of a true physiological touch-like stimulation using a pneumatic device for task-related BOLD experiments. Previous studies applied electrical nerve stimulation, which is known to be rather unphysiological [53,54]. Furthermore, several studies described elevated somatosensory thresholds during and after electrical stimulation [52,55]. Impaired peripheral sensory function is a common feature in physiological ageing that is associated with a reduction of the number of mechanoreceptors in the skin [56] and decreases in the conduction velocity in peripheral nerves [57]. In this study, we demonstrated that although the CPT increases with age, the BOLD signal change in the SI after touch-like stimulation remains constant between young and elderly subjects. Assuming that the intensity, type, location and duration of a stimulus are mainly encoded in the SI [58,59], it appears conclusive that the overall sensory input to the SI is mostly age-independent. However, as a result of similar activation strengths, we found that the activated brain area in the SI was spatially enlarged in the elderly subjects. Similar findings of enlarged age dependent activations have also been demonstrated by other studies [23,33,34]. Because there are no indications that there are increased receptive fields in the elderly, it was suggested that this effect is caused by a change in the balance between the excitatory and inhibitory mechanisms [60,61]. The BOLD signal measured in the current study only reflects the consumption of energy, and there are many conflicting opinions regarding which aspects of information processing are the most energy consuming [62–64]. Nevertheless, it is assumed that changes in neuronal activity tightly correlate with energy demand, but this measure cannot distinguish between excitation and an energy-consuming inhibitory process [65,66]. However, recent studies using electrophysiological methods have

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demonstrated that spatially enlarged brain activations in the ageing brain are caused by a disturbed inhibition in the areas surrounding the activation (surround inhibition), which is similar to our results [60,61,67–69]. There is some experimental evidence that this age-dependent decrease in the surround inhibition is caused by a loss of inhibitory synapses rather than a loss of neurons [67,70]. A similar decrease in inhibition has been reported for the inter-hemispheric connected areas in the elderly [71,72], which might explain our findings of increased activity in the ipsilateral primary and supplementary motor cortices (BAs 4, 6) in elderly subjects. Initially, we expected increased activation in regions that are involved in higher somatosensory processing with ageing. In fact, we found significantly reduced activation within the bilateral SII, cingulate cortex, and dorsal part of the corpus callosum in elderly subjects. With respect to the available electrophysiological studies, it seems unlikely that the increased activity in the SI reflects an activation of the inhibitory neurons, which reduces the activation in the SII and cingulate cortex [60,61,67–69]. We suggest that this reduction is caused by the decreased number of synapses in the aged brain. This hypothesis also explains the previously described impaired functionality in the integration and learning performances in elderly subjects [32,34,73–76]. Therefore, it would be of great interest to determine whether more complex sensory processing, such as 2-point-spatial discrimination or surface detection, leads to similar results or whether there are compensatory strategies, such as the recruitment of additional cortical areas, that lead to increased activation patterns [77]. Nevertheless, in line with these findings, brain areas dedicated to the default mode network [12,78] such as the PCC display agerelated alterations that are linked to deficits in attention, motor control, and inhibitory modulation in cognitive processing [14,76].

5. Conclusions To our knowledge, this is the first investigation of brain ageing and cortical somatosensory processing of tactile stimuli in the primary and secondary somatosensory cortex that utilises fMRI. The results indicate that in ageing, numerous alterations such as decreased inhibition in the SI, reduced activation in the bilateral SII and a disturbance of intra- and inter-hemispheric cortical inhibition have to be considered within the somatosensory network. Whether these changes are due to altered thalamic, intra- or inter-cortical connectivity remains elusive, and further investigations are needed to examine the impact of ageing on somatosensory processing.

Authors’ contribution Stefan Brodoehl, M.D. had conceptualised the study and teamed with Katharina Stieglitz endeavouring organisation and execution, yet all the authors wrote something pertaining to this study. Carsten Klingner, M.D. had done statistical analysis and made critical analysis and review along with Otto W. Witte, M.D.

Financial disclosure There are no conflicts of interest.

Acknowledgment The authors acknowledge the MRI technicians (especially Mrs. Krumbein) who contributed to this study.

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