To our knowledge, this is the first TMS study investigating cortical inhibition and excitation in older adults with depression. Compared with younger healthy adults (56.1% mean cortical inhibition), we demonstrated that cortical inhibition is reduced in (i) older adults with early- or late-onset depression, (ii) older healthy adults and (iii) younger adults with depression (35.6, 39.7, and 41.7% mean inhibition, respectively). The diminished cortical inhibition observed in these three groups was specific to SICI, which reflects GABA A receptor-mediated inhibition, and not to CSP, which reflects GABA B receptor-mediated inhibition. The observed SICI reductions are congruent with earlier reports of lower SICI in adults with depression by Bajbouj et al. (left hemisphere: 35.2% inhibition, compared with 69.3% inhibition in healthy controls) [30] and Lefaucheur et al. (left hemisphere: 36% inhibition, compared with 77.4% in healthy controls) [31]. Contrary to our hypotheses, we did not discern any differences in cortical inhibition (SICI and CSP) between older adults with depression and age-matched healthy adults. However, our findings of (i) reduced GABA A receptor-mediated neurotransmission in older vs. younger adults and (ii) an association between decreasing inhibition and advancing age, are consistent with previous studies that have shown lower SICI in older, compared to younger, healthy adults [46, 47], and a similar linear relationship between SICI and age [47]. Incongruent reports of elevated SICI in older adults might be accounted for by small sample sizes in earlier reports and methodological differences between studies, including different sample demographics, CS intensities, ISIs, and locations of EMG measurement [33, 48]. Taken together, our findings suggest that GABA A receptor-mediated inhibitory neurotransmission is diminished during both aging and depression, and that the influence of aging and depressive states on TMS measures of cortical inhibition cannot be differentiated in LLD.

Various biological factors may have contributed to the observed reductions in cortical inhibition with both advancing age and depression. First, we observed a weak negative correlation between cortical inhibition (SICI) and cortical excitation (ICF) in depressed patients; it is possible that the observed inhibition deficits involve an abnormal inhibition/excitation balance in adults with depression across the lifespan. Accordingly, an abnormal GABA/glutamate signaling balance has been shown in a rodent model of depression, accompanied by a shift in the GABA/glutamate balance with antidepressant treatment [49]. Although speculative, it is possible that an abnormal balance of cortical inhibitory and excitatory neurotransmission could contribute to the observed imbalance between resting-state functional networks in depressed patients, which in turn could drive the imbalance between internal and external mental contents that is observed in depression [50]. We also found that the burden of comorbid physical illness was weakly associated with reduced GABA A receptor-mediated inhibitory neurotransmission in older adults with depression. It is important to consider the effects that systemic health in LLD may have on cortical inhibition and brain functioning in general. Depression is associated with higher rates of age-related illness [43, 44], and there is some evidence that age-related pathologies, such as hypoxia, can impair GABAergic inhibitory neurotransmission [51]. Depression has similarly been associated with accelerated biological aging [52]; aging can affect other biological processes, including muscle mass, motor units, and nerve conduction velocity [53,54,55], which may influence TMS measures of GABAergic neurotransmission in LLD. Likewise, stressful and traumatic experiences, which typically accumulate with advancing age and are risk factors for the development of depression [56], have been shown to influence GABAergic neurotransmission [57]. As such, the functional consequences of biological shifts associated with aging and depression are likely driven by the interaction of many different mechanisms, rather than GABAergic inhibition alone. Furthermore, deficits in TMS measures of cortical inhibition have been observed in a wide range of psychiatric disorders [58]. Thus, rather than being specific to depressive states, the deficits in cortical inhibition observed here in depression may be more generally associated with psychopathology across the lifespan.

In contrast to SICI, the present study did not find significant effects of age or depression on CSP duration. Changes in CSP have been reported following administration of benzodiazepines, which are positive modulators of GABA A receptors [26]. CSP may therefore reflect the tonic conductance of a subtype of GABA A receptors, in addition to GABA B receptor-mediated neurotransmission, whereas SICI more likely reflects the phasic, i.e., transient, activation of GABA A receptors at the synapse [59]. Nevertheless, abnormally short CSPs have been reported previously in older healthy adults [60] and younger patients with depression [30,31,32]. However, the mean CSP duration reported here in 30 younger healthy adults (134.2 ± 36.9 ms) appears to be considerably shorter than the mean CSP duration observed by our group previously in a sample of 25 healthy controls of similar age (158.5 ± 31.7 ms [32]). The lack of significant CSP differences between groups in the present study may be related to the shorter mean CSP in the current sample of healthy controls as compared to what was previously demonstrated. The lower healthy control CSP durations reported in the current study as compared with earlier reports could reflect the high between-subject variability of the CSP measure [61]; as such, caution should be taken when interpreting between-subject differences in CSP.

We similarly observed no significant differences in cortical excitation measures (RMT and ICF) between any groups. Our results are congruent with the majority of TMS studies assessing indices of phasic glutamatergic functioning, which have found similar cortical excitation in MDD patients and controls [30, 32, 58]. Notably, RMT is primarily dependent on ion channel conductivity, voltage-gated Na+/K+ channels [21, 62], and is unaffected by GABA [21], glutamate [63, 64], and dopamine [65]. By contrast, ICF is closely related to NMDA receptor-mediated glutamatergic function [21, 26]. NMDA receptors are a target in the treatment of depression [66], however not all patients benefit from treatment with NMDA antagonists [67]. Moreover, although some MRS studies have found abnormally low cortical concentrations of glutamate in depression [68], MRS measures of glutamate-related metabolites reflect a mix of physiological and non-physiological components of the glutamatergic system, rather than NMDA receptor-mediated cortical neurotransmission per se; as such, ICF does not correlate with MRS measures of glutamate concentrations [69]. Going forward, an investigation of the ability for cortical excitability to change, by indexing neuroplasticity using the TMS paradigm paired associative stimulation, may elicit a clearer understanding of pathophysiological mechanisms related to cortical excitation in LLD.

This work also complements the TMS literature investigating the influence of aging on various aspects of neurophysiology. We observed significant reductions in GABA A receptor-mediated neurotransmission in the motor cortex with advancing age, yet interestingly no significant differences between younger and older adults in other TMS measures of cortical inhibition and excitation (CSP, ICF, and RMT). Previous studies have similarly found no significant differences in cortical excitation with age [46,47,48], and although earlier TMS studies of cortical inhibition in older healthy adults have yielded mixed results [34], the present work involved one of the largest samples of older adults tested in a single study to date. There is evidence that other aspects of motor cortex neurophysiology are diminished in older compared with younger adults, including neuroplasticity [70, 71], interhemispheric inhibition [72, 73], and inhibitory and excitatory connectivity between ipsilateral motor regions [74]. The functional consequences of specific changes in the physiology of the motor cortex have yet to be fully characterized, yet may shed some light into age-related decline in motor control [75]. For example, contrary to the current findings, a variant of the ICF paradigm that may specifically reflect excitatory processes prior to and during particular types of grasp has been shown to be abnormal in old age and to correlate with hand dexterity [76]. Moreover, factors that can normalize impaired cortical physiology, such as an active lifestyle [73], may be useful in preventing age-related decline in functioning.

Of note, the majority of older adults with depression studied here were treatment-resistant (75%). Some studies have implicated greater GABAergic deficits in patients with treatment-resistant depression, as compared with non-treatment-resistant patients [32, 77]. However, our findings of reduced SICI in older adults with depression, as compared with younger healthy controls, were observed for subgroups of treatment-resistant and non-treatment-resistant older patients alike (see Supplementary Materials and Methods).

Some limitations of our study should be considered. First, the presented TMS findings from the motor cortex may not directly reflect brain regions involved in the pathology of depression. Future studies of LLD neuropathology should assess cortical inhibition directly in the DLPFC, using TMS combined with EEG [78]. Second, although TMS currently offers the only in vivo measures of phasic GABAergic activity in humans, TMS measures of cortical inhibition are indirect indices of GABAergic inhibitory neurotransmission. In addition, future work should include a more comprehensive clinical characterization of the control groups, such as inclusion of CIRS, MMSE, and depression scores, and further neuropsychological characterization of the LLD patients. At last, owing to our inclusion of older adults with depression that presented with cardiac or cerebrovascular risk factors, it is possible that some of the patients studied here suffered from vascular depression. Although several clinical studies show a strong correlation between LLD and cardiac risk factors, there is evidence that patients with vascular depression have different neurophysiological profiles than patients with nonvascular MDD [79]. However, the majority of the patients in the current study had recurrent MDD with onset before the age of 60, whereas vascular depression is more closely associated with late-onset MDD (onset ≥ 60 years) [80, 81].

Overall, our findings, taken together with previous reports of impaired cortical inhibition in younger adults with depression, are consistent with the age-by-disease model of LLD, which posits that age-related biological changes that contribute to the impairment of specific neuronal and glial processes promote vulnerability to the development of depressive symptoms in late-life [6, 7]. Previous literature reveals a robust and heterogeneous effect of age on numerous biological pathways that overlap with those implicated in depression pathology, including, but not limited to, glial-mediated inflammation, oxidative stress, and calcium regulation [6]. There is evidence that physiological changes in the brains of older adults and the brains of younger depressed adults are similar. Contributions of genetic, endocrine, epigenetic, and environmental factors may determine whether and when pathophysiological thresholds are reached and depressive symptoms are expressed [7].

Alternatively, the current finding that reductions in cortical inhibition are similar in depression and old age are in line with accumulating evidence that depression is a disease of accelerated biological aging [52]. Major depressive disorder is associated with higher rates of medical comorbidities, including heart disease [43], metabolic syndrome [82], and Alzheimer’s disease [83], which commonly occur in old age. Moreover, cellular biomarkers of aging and age-related disease have been observed in depression. For example, shorter telomere length, which promotes apoptosis and is typically observed in old age, has been associated with depression [84]. More specifically, an increase in the number of toxic processes, such as oxidative stress, coupled with a decline in protective factors, such as antioxidants, (i) can cause cellular damage, and (ii) have been implicated in both age-related diseases and depression [52]. Deficits in cortical inhibitory neurotransmission in depression, shown here to mimic reductions that occur in old age, therefore lend further support for the involvement of premature biological aging in depression.

In conclusion, our study is the first to examine TMS measures of cortical inhibition and excitation in LLD. We investigated a relatively large sample of older adults with early- or late-onset depression, and one of the largest samples of healthy older adults to date. Our findings indicate that cortical inhibition measures cannot differentiate between the changes associated with aging or with depression in late life. However, our findings of SICI reduction (i.e., cortical inhibition deficits), taken together with comparable previous findings of SICI deficits in younger patients with depression [30, 31], suggest that both advancing age and MDD involve reduced GABAergic inhibitory neurotransmission. These overlapping cortical inhibition reductions mirror other biological changes that occur with both age and depression, such as changes in the expression of genes coding for GABA interneuron-related peptides [85]. These observations are consistent with the conceptualization of depression as a disease of accelerated aging, and with the age-by-disease model of LLD [6, 7] and may provide targets for both the prevention and treatment of LLD. Future research should aim to clarify whether reductions in GABAergic cortical inhibition in old age, as observed here, constitute a biological risk factor for the development of depression in late-life.