The Aging Brain (4): It Starts Earlier Than You think

Working Memory: There is No There There.

You wake up in the morning a day before a long trip to some distant place. There are five last minute errands that must be done today in preparation. How best to do these errands the most efficiently? To accomplish that you need to consider the five locations where these errands will occur. These locations must be mentally manipulated as to relative distances, so that you can arrive at a route plan. This plan must be retained for the duration of the five errands. After the first two errands are completed, you are diverted from the original plan because of a minor emergency. It takes you two hours to deal with that, before you can return to the planned errands. As it happens, the minor emergency required some travel, such that the original planned route for the three remaining errands is no longer efficient. In fact, now, it would be best to do them in reverse order. You improvise, revise the plan for the remaining three stops, and return home all five errands completed.

The foregoing is an example of working memory. We can define working memory as the maintenance and manipulation of information over short time periods to guide goal-oriented behavior. In the above example, the goal-oriented behavior is executing the five errands. Mental manipulations of the five errands are necessary to devise the initial planned route. This information must be maintained for constant reference, until all five errands are successfully accomplished. The interruption and diversion from the initial planned route, requires further mental manipulations of the remaining three errands and a new plan. A prerequisite for these later mental manipulations, is that the memory—delayed recall-- of the remaining three errands is maintained in a consciously accessible way.

There are distinctive features of Working Memory relative to other types of memory. First, it is short term: minutes to days. In the above example, the only event that might be consolidated into a long-term memory, is the emergency. All else will fade when you board your plane. Second, the devising and successful execution of the plan, demands selective attention to the task, by filtering of stimuli extraneous to the task, both internal and external. In a word, focus.

The Aging Brain and Working Memory

Working memory is one of the executive functions most sensitive to aging. Working memory decay contributes to the age-related declines in fluid intelligence, the ability to solve novel problems (10.1037//0278-7393.15.3.507).

The neural substrates for working memory—and other executive functions-- were long thought to reside primarily or exclusively in the prefrontal cortex (10.3758/cabn.4.4.528). The maintenance of working memory despite interruption was thought to depend on the continuous activity of local circuits in the prefrontal cortex. The age-related shrinkage of the prefrontal cortex lends credence to this view.

Recent research, however, indicates that working memory depends on more distributed brain activities, throughout the cortex and well beyond, to parts of the brain not normally associated with cognition. This reorientation puts more explanatory weight on how different brain areas are connected in healthy individuals, how these neural networks vary among healthy individuals, and how these neural networks change during both healthy and pathological aging.

The fundamental units of the nervous system are neurons (https://staff.itee.uq.edu.au/janetw/cmc/chapters/Introduction/slides/slide1.html). A neuron consists of a cell body, called the soma, as do all other cells in your body. But unlike those other cells, neurons have two unique kinds of projections, called dendrites and axons. Dendrites make short distance contact with many other neurons; axons make long distance contact with a few other neurons. The cerebral cortex, the outermost layers of the brain, is comprised of neuronal cell bodies and dendrites, collectively known as gray matter. Beneath the gray matter are the bundles of axons, called the white matter. The white matter is not a part of the cerebral cortex; it is considered subcortical.

On the localist view of brain functions, the gray matter is emphasized: neuronal cell bodies and short-range dendritic connections. This is the only way to make sense of the claim “the prefrontal cortex is the seat of the highest cognitive functions”. On this view axons have a limited role in working memory. Axons convey basic raw inputs to the prefrontal cortex from elsewhere in the brain. The inputs are then processed in an “executive way”, in this case to construct a plan of action. The results of the prefrontal processing are conveyed by axons to relevant brain areas where they are realized in the appropriate behavior, in this case completing the errands.

From a connectivist perspective, in contrast, the executive functions—such as working memory—are distributed throughout much of the brain. Axons therefore figure more prominently, as the long-range connectors between distant brain bits. On this view, the network of neural pathways is the relevant unit for a function like working memory. Hubs, such as particular neuronal groups in the prefrontal cortex are necessary but not sufficient to support working memory of the sort described in the opening paragraph. The correlation between age related declines in working memory and age-related shrinkage of the prefrontal cortex may have a deeper common cause.

The first attempts to explore neural substrates for working memory and other executive functions outside of the prefrontal cortex, sought connections with nearby cortical regions, particularly the parietal cortex. A prefrontal-parietal circuit was identified in which there is reciprocity of influence (PMC5729190). Other circuits were identified that connected all major areas of the cerebral cortex (PMC8871396, 34366794).

The hippocampus, which lies just below the cerebral cortex was long treated as the “subcortical” structure of most relevance for executive functions like working memory. In recent years, however, the neural networks thought to support working memory have expanded to subcortical regions between the cerebrum and the spinal cord. Foremost among these is the cerebellum. The cerebellum is connected—through axons-- to every part of the cerebral cortex (34321336). When axonal pathways between the cerebellum and the cortex are compromised, so too is working memory along with other cognitive functions (PMC3815977).

Between the cerebellum and the cerebrum is another brain region, called the thalamus. Long thought to function primarily as a waystation in the transmission of visual and auditory stimuli, from eyes and ears to the cerebral cortex, the thalamus is now recognized as another important computational center supporting working memory (PMC6650151). Disruption of thalamic inputs to the cerebral cortex compromise working memory (PMC6431254).

Perhaps the most surprising of the subcortical regions relevant to working memory is the rearmost part of the brain, called the brainstem, which terminates in the spinal cord. Of the major brain regions, traumatic injuries to the brainstem are among the most catastrophic. That’s because the brainstem supports vital physiological functions, such as breathing, heart contractions, blood chemistry, blood pressure, body temperature and a host of others. Only recently has it occurred to some, that the brainstem might support cognitive activities as well.

In one recent brainstem study, infarcts--local disruptions of the blood supply—were shown to affect several cognitive functions, including working memory. It is noteworthy that the areas impacted by the infarcts consisted solely of axons (10.1017/S1355617703000146). That suggests an important role for the brainstem in cognitive connectomes. But most surprising to me are recent studies on another area of the brainstem that has axonol projections pretty much throughout the brain that decay with age (34139886). Some of these projections participate in neural networks that support working memory and other executive functions. In fact, in one recent review, the source of these projections in the brainstem are claimed to be integral to fluid intelligence, more integral than the prefrontal cortex (34764223).

I think it’s a mistake to identify another brain area to replace the prefrontal cortex as the source of any executive function. The point of the connectionist critique of the overemphasis on the prefrontal cortex is that ultimately, there is no there (10.1017/S0140525X15000631). Like all brain processes, those that support working memory can only be identified by means of their coordinate activities.

But at minimum these brainstem studies demonstrate that to increase our understanding of aging executive functions, we need to not only move beyond the prefrontal cortex, but beyond the cerebral cortex altogether (10.1016/j.tics.2009.04.008), to widely distributed subcortical areas, and their functional connections. There is now abundant evidence that parts of the connectome that support working memory deteriorate with age. It may well be that the aging of neural hubs in these networks is secondary to the aging of their connections. For example, age-related shrinkage of the prefrontal cortex may result from reduced inputs from the cerebellum and the brainstem.

The connectionist perspective requires a reorientation as to how best to slow or reverse age-related cognitive declines. And how best to treat neurodegenerative diseases.