Age trajectories of functional activation under conditions of low and high processing demands: An adult lifespan fMRI study of the aging brain

Highlights

• Lifespan sample age 20–89 finds increasing activation with age on semantic judgment.

• When processing demands are increased, modulation of activation declines with age.

• Modulation decline gradient: higher to lower nigrostriatal regions as age increases.

• Modulation decline is stepwise with age: steep drops in middle- and very old ages.

Abstract

We examined functional activation across the adult lifespan in 316 healthy adults aged 20–89 years on a judgment task that, across conditions, drew upon both semantic knowledge and ability to modulate neural function in response to cognitive challenge. Activation in core regions of the canonical semantic network (e.g., left IFG) were largely age-invariant, consistent with cognitive aging studies that show verbal knowledge is preserved across the lifespan. However, we observed a steady linear increase in activation with age in regions outside the core network, possibly as compensation to maintain function. Under conditions of increased task demands, we observed a stepwise reduction across the lifespan of modulation of activation to increasing task demands in cognitive control regions (frontal, parietal, anterior cingulate), paralleling the neural equivalent of “processing resources” described by cognitive aging theories. Middle-age was characterized by decreased modulation to task-demand in subcortical regions (caudate, nucleus accumbens, thalamus), and very old individuals showed reduced modulation to task difficulty in midbrain/brainstem regions (ventral tegmental, substantia nigra). These novel findings suggest that aging of activation to demand follows a gradient along the dopaminergic/nigrostriatal system, with earliest manifestation in fronto-parietal regions, followed by deficits in subcortical nuclei in middle-age and then to midbrain/brainstem dopaminergic regions in the very old.

Introduction

Aging of the brain's structure over the course of the adult lifespan is characterized by precipitous declines in gray matter volume in association cortices, especially in the prefrontal cortex, and relative sparing of the primary sensory cortices and other regions associated with early perceptual processing (for review Rodrigue and Kennedy, 2011, Raz and Kennedy, 2009). Similarly, a broad array of cognitive functions decline with age, including speed of processing, working memory, episodic memory, and reasoning, but semantic knowledge and vocabulary tend to be preserved, or even increased with age (Ackerman and Rolfhus, 1999, Park et al., 2002, Puglisi et al., 1988). In contrast to our understanding of brain structure and cognition function, considerably less is known about the lifespan trajectory of brain function.

Typical cross-sectional comparisons pit young (usually 20–30 year olds) against old adults (usually 60–70 year olds). Such extreme group contrasts tend to find evidence for task-related BOLD “underactivation” in older adults relative to younger adults in some regions (e.g., hippocampus) and “overactivation” in many other regions, particularly frontal-parietal regions, even when task performance is roughly equivalent for old and young (for review: Cabeza, 2002, Grady, 2000, Park and Reuter-Lorenz, 2009, Reuter-Lorenz and Lustig, 2005). Thus far, we know little about brain function during critical life periods such as middle age and very old age. Hence, the focus of the present study is to characterize neural activity cross-sectionally across the adult lifespan (utilizing age as a continuous variable as well as a discrete variable with several levels: young, middle, old and very old ages) to investigate when in the lifespan and where in the brain do shifts in activation occur as we age. We investigate these questions on two tasks of theoretical importance: an easy (canonical) and a difficult (ambiguous) semantic judgment task.

The canonical (easy) task involves a semantic judgment (“living or nonliving?”) about a highly familiar concrete target such as “walrus”, “truck”, or “asphalt.” In young adults, this task broadly engages the left inferior frontal gyrus and a supporting semantic network that includes posterior inferior parietal lobe, middle temporal gyrus, fusiform and parahippocampal gyri, dorsomedial prefrontal cortex, ventromedial prefrontal cortex, and the middle cingulate gyrus (Binder et al., 2009, Spreng et al., 2010, Thompson-Schill, 2003, Wagner et al., 2001). In the aging literature, semantic judgment tasks (e.g., living/non-living judgments) have been used to study memory encoding and/or retrieval (i.e., Andrews-Hanna et al., 2007, Cabeza et al., 2004, Lustig et al., 2003, Morcom et al., 2007, Bucur et al., 2008, Grady et al., 2006, Stebbins et al., 2002) and repetition priming (e.g., Bergerbest et al., 2009, Daselaar et al., 2005, Lustig and Buckner, 2004). The majority of these studies used extreme age groups and has generally reported greater right prefrontal cortex activation in older adults compared to their younger counterparts suggesting that older adults require more neural activity to make even simple, knowledge-based judgments (Cabeza, 2002). It has been proposed that this additional activation acts as a type of scaffolding to preserve behavioral function (Park and Reuter-Lorenz, 2009). How and when in the lifespan functional activation is altered is largely unknown (although see Park et al., 2013) and thus the first focus of the present study was to examine the developmental course of brain activation across the adult lifespan in a canonical semantic judgment task condition where individuals made living/nonliving judgments about straightforward (easy) concrete nouns.

The other major focus of the present study is on the construct of mental effort or processing resources—a concept that plays a critical role in prominent theories of cognitive aging. A central theme of these theories is that aging is characterized by reduced cognitive resources available to allocate to complex mental tasks (e.g., Craik and Byrd, 1982), resulting in steeper age-related behavioral decline on difficult compared to easy tasks (McDowd and Craik, 1988). Despite a large literature on this topic in the cognitive domain (e.g., Glisky, 2007), the impact of increased processing demand on older adults has received considerably less attention in neuroimaging studies of aging, even with extreme age group designs (see Reuter-Lorenz and Cappell, 2008 for a discussion of this issue). Hence, a second goal of the present study is to investigate, across the adult life course, what regions modulate activation to increased task processing demands. To assess this, we increased task processing demands and examined individuals' ability to increase neural response when faced with a challenge. Specifically, we created a second task condition where individuals were presented with ambiguous nouns that required more deliberative processing for a response. In this condition, items were typically poor exemplars of living and nonliving categories or had multiple meanings that required more processing, e.g., “ghost”, “virus”, “coral”, “speaker”, “orange”.

There are many reports on the neural substrates associated with increased processing demands in young adults, with evidence that cognitive control regions show increased activation, including a frontal–parietal network as well as the anterior cingulate cortex (Braver et al., 2009, Braver, 2012, Brown and Braver, 2005). The broader prefrontal–striatal executive function network is dopaminergic in nature and includes regions of heteromodal association cortices involved in loops with the striatum (Alexander et al., 1986). The circuitry of this dopaminergic pathway originates in the substantia nigra and ventral tegmental area, innervates the neostriatum (caudate, putamen and nucleus accumbens), thalamus (anterior and dorsomedial nuclei), and prefrontal cortex in partially reciprocal loops (Groenewegen et al., 1990). Importantly, these are all areas known to undergo the most structural change during the course of normal aging (Raz and Kennedy, 2009, Rodrigue and Kennedy, 2011), with a precipitous decline in volume (Raz et al., 2003, Raz et al., 2010) and in neurochemical receptor structure and function (Volkow et al., 1998). Thus, we tentatively hypothesized that regions of this dopaminergic nigrostriatal system would be most likely to display age-related alterations in brain activity across the lifespan, as these regions are most sensitive to task demands and also most vulnerable to the effects of aging.

There are relatively few studies of age-related differences in neural activation to increasing task demands (see e.g., Reuter-Lorenz and Cappell, 2008 for a review). Functional imaging studies comparing younger and older adults generally find that in more demanding task conditions, younger adults can better modulate neural activity to task demands, often in prefrontal and parietal regions (Cappell et al., 2010, Davis et al., 2008, Grady, 1998, Konishi et al., 1998, Persson et al., 2004, Rypma and D'Esposito, 2000, Schneider-Garces et al., 2010; however see Nagel et al., 2009), but there is not yet information about when these shifts in modulation to processing demand occur during the lifespan, and whether this shift is incremental across the lifespan (i.e., linear) or punctuated by larger, discrete changes at certain ages (i.e., stepwise). In particular, we would expect altered modulation of activation to processing demand to be most evident in the malleable prefrontal and parietal heteromodal association cortices involved in cognitive control in middle-age as this is an important period in which structural changes to these brain structures become evident and exert cognitive consequences (Raz et al., 2005, Rodrigue and Kennedy, 2011).

With these considerations in mind, the current study investigated the following research questions: 1) How does functional brain activation to a canonical semantic judgment task differ across the adult lifespan? What regions are age-sensitive and is the relationship linear or nonlinear? Given the relative lifespan stability of semantic knowledge, we hypothesize that activation in the core brain regions of the semantic network will not differ with age, but rather activity outside this network will increase or decrease with age. 2) When processing demands are increased, how does age affect modulation of brain activity (comparing low-demand to high-demand conditions)? We hypothesize that the ability to modulate neural activation to task demands will decline with age and, given the vulnerability of the brain regions comprising the dopaminergic executive system, these age-related declines in the modulation of activation to task demand will be seen primarily in heteromodal frontal–parietal association regions. 3) When in the lifespan do these alterations to demand-modulation emerge and do different brain regions show different age-trajectories? To fully explore functional activation modulation differences in the periods of middle age and very old age, about which little is currently known, we will separately examine modulation to task demand in the following discrete age ranges: young adulthood (age 20–39), middle age (40–59), older adulthood (60–79), and very old (80–89). We hypothesize that different regions of the cognitive control system will show different age trajectories. 4) Similarly, we examine whether task-related demand modulation is altered linearly with age or whether are there greater stepwise shifts between specific age periods (e.g. between middle and old or between old vs. very old individuals)? Although there is almost no literature on functional activation in very old adults (i.e., 80 + years), we suspect that the age trajectory of altered demand modulation may be nonlinear with particularly steep drops in the ability to modulate activation to task demand in this very old population.