Elsevier

Neurobiology of Aging

Volume 65, May 2018, Pages 168-177
Neurobiology of Aging

Regular article
GABA levels and measures of intracortical and interhemispheric excitability in healthy young and older adults: an MRS-TMS study

https://doi.org/10.1016/j.neurobiolaging.2018.01.023Get rights and content

Abstract

Edited magnetic resonance spectroscopy (MRS) and transcranial magnetic stimulation (TMS) have often been used to study the integrity of the GABAergic neurotransmission system in healthy aging. To investigate whether the measurement outcomes obtained with these 2 techniques are associated with each other in older human adults, gamma-aminobutyric acid (GABA) levels in the left sensorimotor cortex were assessed with edited MRS in 28 older (63–74 years) and 28 young adults (19–34 years). TMS at rest was then used to measure intracortical inhibition (short-interval intracortical inhibition/long-interval intracortical inhibition), intracortical facilitation, interhemispheric inhibition from left to right primary motor cortex (M1) and recruitment curves of left and right M1. Our observations showed that short-interval intracortical inhibition and long-interval intracortical inhibition in the left M1 were reduced in older adults, while GABA levels did not significantly differ between age groups. Furthermore, MRS-assessed GABA within left sensorimotor cortex was not correlated with TMS-assessed cortical excitability or inhibition. These observations suggest that healthy aging gives rise to altered inhibition at the postsynaptic receptor level, which does not seem to be associated with MRS-assessed GABA+ levels.

Introduction

Healthy aging is often accompanied by various motor declines, such as impaired coordination skills (Fujiyama et al., 2012) or deterioration of fine motor functions (Opie et al., 2015). Emerging evidence indicates that this could partly be explained by a reduced ability to regulate cerebral inhibition through activation of the gamma-aminobutyric acid (GABA) neurotransmitter system (Levin et al., 2014). Nevertheless, the effect of aging on GABAergic functioning remains poorly understood. So far, inconsistent findings have been reported due to small sample sizes and methodological variations (Bhandari et al., 2016). Furthermore, it is currently unclear whether (and how) the outcome measures of the different techniques that are used to assess GABA levels and properties of the GABA neurotransmitter system relate to each other in older adults.

Quantification of in vivo GABA levels in specific brain regions is possible using edited proton magnetic resonance spectroscopy (MRS) (Puts and Edden, 2012). With the use of MRS, acquiring information about regional variation of GABA levels in the brain across the human lifespan is now possible. Previous MRS studies have detected age-related reduction of GABA levels in prefrontal and parietal regions (Gao et al., 2013, Grachev and Apkarian, 2001, Grachev et al., 2001, Porges et al., 2017) and to a lesser extent in the sensorimotor cortex (SM1) (Grachev et al., 2001), suggesting that healthy aging is associated with regional changes in GABA levels. However, the study by Grachev et al. (2001) only included middle-aged adults (40–52 years), thus data of older adults for the SM1 are lacking. It is of interest to note that variation in GABA levels within the sensorimotor cortices appears to not only be correlated with individual differences in motor performance, such as simple reaction time (Stagg et al., 2011a), but also predict neuroplasticity during motor skill acquisition (Kim et al., 2014, Stagg, 2014). Moreover, it has been observed that shifts in GABA levels, either an increase or decrease, were significantly related to motor ability in individuals with deficient neuromuscular control (Bhattacharyya et al., 2013). These observations suggest that changes in GABA levels within the primary motor cortex (M1) as a function of age may play a pivotal role in declines of motor functions.

While MRS allows in vivo quantification of GABA levels, transcranial magnetic stimulation (TMS) can be used to investigate GABA-mediated physiological inhibition. Some TMS protocols can monitor activity of postsynaptic fast acting ionotropic (GABAA) and slower acting metabotropic (GABAB) receptors, which are activated by GABA, namely short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI), respectively (Reis et al., 2008, Siebner et al., 1998, Ziemann et al., 1996). SICI involves a subthreshold conditioning stimulus (CS) that precedes a suprathreshold test stimulus (TS) by 2–4 ms (Kujirai et al., 1993, Ziemann et al., 1996), while LICI involves a suprathreshold CS that precedes a suprathreshold TS by 100–150 ms (Mcdonnell et al., 2006, Werhahn et al., 1999). The mechanisms of SICI at an interstimulus interval (ISI) of 1 ms are less known but might reflect extrasynaptic GABAergic activity (Stagg et al., 2011b). Other TMS protocols reflect the combination of GABA and glutamatergic activity including intracortical facilitation (ICF) and interhemispheric inhibition (IHI) between homologous M1s (Chen, 2004, Reis et al., 2008). More specifically, IHI allows the exploration of the activation of glutamatergic interneurons and local GABAB receptors and their interactions (Chen, 2004, Reis et al., 2008). ICF can be measured with a subthreshold CS that precedes a suprathreshold TS by 8–30 ms, whereas IHI can be explored with a suprathreshold conditioning and test stimulus and an ISI of 10–15 ms or 20–50 ms. Finally, recruitment curves allow the investigation of the net effect of excitatory and inhibitory inputs. TMS is thus a powerful tool to investigate the neurophysiological mechanisms associated with age-related changes in the regulation of GABAergic inhibitory function.

So far, TMS studies investigating age-related changes in the GABAergic receptor system within M1 under resting conditions have obtained mixed results. Some studies reported that healthy aging is generally associated with a decline in inhibition (Heise et al., 2013, Peinemann et al., 2001), whereas other studies reported no impact of aging on inhibition (Stevens-Lapsley et al., 2013, Wassermann, 2002) or even increased inhibition in older adults (Kossev et al., 2002, McGinley et al., 2010). These studies addressed either the whole lifespan (Heise et al., 2013, Wassermann, 2002) or compared young to middle-aged (Kossev et al., 2002, Peinemann et al., 2001) or older adults (McGinley et al., 2010, Stevens-Lapsley et al., 2013), which compromises comparison of their results. Discrepancies in methodological factors such as application of different TMS protocols or the use of different TMS equipment add to this difficulty. A recent meta-analysis showed a slight but no significant decline in SICI in older as compared to young adults (Bhandari et al., 2016). However, it should be noted that some studies showing a significant decrease in SICI were not included in this report (i.e., Heise et al., 2013, Peinemann et al., 2001). While a few studies have already explored the effect of healthy aging on the excitability of both GABAA and GABAB receptor systems in a single study design (Opie and Semmler, 2014, Opie and Semmler, 2016, Smith et al., 2009), it is not yet clear how changes in MRS-determined GABA levels are associated with TMS measures of excitation and inhibition in older adults.

Here, we investigated the association between sensorimotor GABA levels and TMS measures of motor cortical excitability and inhibition in young and older adults. We expected that (1) sensorimotor GABA levels decrease with age and that (2) this decrease in GABA is related to changes in motor cortical excitability and inhibition, as assessed with TMS.

Section snippets

Participants

Twenty-eight healthy young adults (mean ± standard deviation [SD]: 24.60 ± 4.16 years, age range: 19.92–34.50 years, 14 women) and 28 healthy older adults (mean ± SD: 69.07 ± 3.09 years, age range: 63.17–74.42 years, 12 women) were recruited. We chose to include older adults between 63 and 75 years because lifespan studies have shown that this age range exhibits marked differences compared to young adults (20–35 years) in functional, structural, and neurochemical brain properties, such as lower

Magnetic resonance spectroscopy

A summary of the results can be found in Table 2. With respect to the SM1 voxel, MRS data of 7 young and 6 older adults were excluded from the analysis due to the following reasons: technical problems with the scanner (young; N = 3), incorrect voxel placement (young; N = 1 and older; N = 1), and no clear GABA peak in the edited spectrum (young; N = 2 and older; N = 6). With respect to the OCC voxel, MRS data of 3 young adults were excluded from the analysis due to technical problems at the

Discussion

A first major observation of the present study was that tissue-corrected GABA+ levels in left sensorimotor and occipital regions did not change significantly as a function of age. A second major observation was that tissue-corrected GABA+ levels in the SM1 did not predict GABA-mediated cortical inhibition in either young or older adults, despite significant age-related declines for both SICI and LICI in the older as compared to young adults. Overall, these observations suggest that the decrease

Conclusion

Older as compared to young adults demonstrated significantly less resting-state inhibition as measured with the SICI and LICI TMS protocols. This is possibly mediated by changes in GABAA and GABAB receptor activity. The observed declines in TMS-assessed inhibition with age were unrelated to MRS-assessed tissue-corrected GABA+ levels within the SM1. Furthermore, we did not find any association between tissue-corrected GABA+ levels within the left SM1 and the degree of motor corticospinal

Disclosure statement

The authors disclose no conflicts of interest.

Acknowledgements

This work was supported by the KU Leuven Special Research Fund (grant C16/15/070), the Research Foundation–Flanders (FWO; G089818N), Excellence of Science grant (EOS, 30446199, MEMODYN), and the Francqui Foundation.

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