Late-Life Depression [LLD]), is prevalent, disabling, and associated with high rates of
completed suicide. Among the LLD patients at the highest risk of these adverse outcomes are
those who manifest decreased processing speed and/or decreased gait speed. To develop
urgently needed novel therapeutics for LLD, a reasonable approach is to target systems
underlying the development and persistence of psychomotor slowing. One such approach has been
to augment dopaminergic signaling since post-mortem experiments and in vivo neuroimaging
studies have implicated age-related dopaminergic decline in the development of slowing.
L-DOPA is the immediate precursor of dopamine, is converted to dopamine in presynaptic
dopaminergic nerve terminals, and enhances dopaminergic transmission in multiple brain
regions. As opposed to other dopaminergic interventions (i.e., dopamine receptor agonists and
stimulants), a large literature shows beneficial effects of L-DOPA on cognitive performance
and gait in patients with Parkinson's disease, all while being a safe and well-tolerated
medication that is difficult to differentiate from placebo in terms of side effects.
A second therapeutic strategy that has been tested for LLD and is relevant to psychomotor
slowing is aerobic exercise training. A number of reports and meta-analytic reviews suggest
that exercise is an effective non-pharmacologic treatment for depression, including
depression in older adults. The largest recent study found that progressive aerobic exercise
conducted three times weekly for 30min over 24 weeks was effective for depression and was
tolerated extremely well (14.3% drop-out rate, 70% intervention adherence). Exercise training
may be effective for LLD by counteracting deleterious age-related changes related to its
development and maintenance, such as by reducing pro-inflammatory cytokines, normalizing
hypothalamic-pituitary-adrenal axis hyperactivity, and decreasing physical disability and
social isolation. Exercise also appears to facilitate adaptive neuroplastic changes in the
hippocampus, prefrontal cortex (PFC), and anterior cingulate cortex (ACC) as well as
increased white matter connectivity.
While both dopaminergic augmentation and exercise are promising interventions, neither
treatment alone may be sufficient to address the serious adverse medical and psychiatric
outcomes associated with LLD and psychomotor slowing. In our preliminary study (NYSPI IRB#
7270), L-DOPA was associated with significant improvements in gait speed, but the effect size
of this improvement was only moderate (d=0.4). L-DOPA failed to increase average gait speed
in this study above the 1m/s threshold associated with functional disability and increased
mortality risk in epidemiologic samples. While exercise has not been studied specifically in
this patient population, meta-analyses of exercise interventions in older adults suggest
overall effects on gait speed are modest (d=0.3) and perhaps not clinically significant.
Thus, one goal of this study is to combine these interventions having complementary
mechanisms of action to realize a greater therapeutic benefit.
This study includes task-based functional MRI that will allow us to probe the differential
therapeutic mechanisms of L-DOPA and exercise and further elucidate the nature of
effort-based decision making and reward deficits in LLD. Decision making about voluntary
behavior requires weighing the benefit of potential rewards against the effort cost required
to achieve them. This calculation is performed by separable populations of dopaminergic
midbrain neurons whose signals for value and effort are integrated with the ventral striatum
(VS). Anterior VS (AVS) consistently has been shown to encode subjective value, increasing
with the probability of reward and decreasing with effort discounting, while recent work
suggests dorsomedial VS (dmVS) activates during the initiation of effortful action. We
hypothesize that older adults are biased toward inactivity (and thereby at risk for
depression) on the basis of dopaminergic decline that diminishes subjective value estimates
and increases the effort cost of action (i.e., by the development of slowing). Among PD
patients, L-DOPA increases willingness to work independently of facilitating movement by
increasing subjective value estimates. By increasing fitness and helping individuals learn
about their increasing capacities, exercise may facilitate effort initiation. Below, we
evaluate whether complementary effects on effortful behavior may be achievable via L-DOPA
increasing subjective value and Exercise reducing effort cost.
