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One of the most interesting research efforts of the past few years seems to have taken a page from the preoccupations of the self-help magazine world: the cognitive decline of the brains of aging baby boomers and the obese nature of their grandchildren. These topics have been united by the well-established finding that restricting caloric intake leads to an increased life span in almost every animal tested. Because eating habits are formed early in life, the prediction is that a sensible diet will increase a person’s life span.

Is that true? The link between caloric restriction and life span is certainly solid, although the jury is still out on many of the claims made in the general media. Serious scientists have been studying the molecular biology behind this link for a number of years. One particular group of sequences seems to stand in the gap between aging and food, that of the sirtuin family of genes (also called silent information regulator [SIR] genes). One member of the family, the SIR2 gene, has been studied in particular detail. This article discusses age-related cognitive decline, caloric intake restriction, and the role SIR2 plays in the process.

As the brain ages

It is the canonical experience of people older than 40 that senior moments become an increasingly familiar part of one’s thinking life. We forget names, we forget places, we forget where we put our car keys, and we wonder when—and why—our retrieval systems began to abandon us. Higher-order processing begins to change as well as memory, perhaps not as obviously, but apparently in a far more dramatic way. Although the types of cognitive decline clearly vary from one person to the next, no one escapes these behavioral changes completely or, perhaps, the panic that ensues for some individuals when they compare their previous talent with current abilities.

It is axiomatic that cognitive decline occurs because of physical changes that human brains undergo as they age. Yet demonstrating the specifics of the relationship has not always been easy. With the advent of more sophisticated technologies (and improvements in older technologies), that has begun to change. We now know that changes in the regulation of global gene expression patterns—mostly down-shifting—are observed in a broad swath of the CNS during aging. Gene products specifically involved in the physiological processing of inhibitory signals mediated by γ-aminobutyric acid) have shown particular vulnerability. These neuron-related changes are disproportionately large when compared with changes in other tissues (eg, kidney and muscle tissues show age-related up-regulation).

Alterations in gross neuroanatomical structure have also been observed for many years. Some of the most dramatic involve disruptions of the myelinated fibers that yoke disparate brain regions together to provide specific functions—particularly in the prefrontal cortex (PFC). The changes are generally not due to neuronal loss in the PFC, which is actually quite minimal in most aging brains, but to loss of functional connectivity. The accompanying disruptions of neural integration in these regions of the aging brain result in less organized activity than is found in the brains of youthful controls. Such alterations are thought to be associated with a measurable behavioral change in aging populations: disruption of executive function (a task involved in everything from impulse control to planning for the future). This is part of a general age-related decline in the brain’s higher-order functional abilities.

One of the challenges of studying cognitive decline in elderly populations is separating normal changes in cognition from abnormal pathological changes. Although these are not always easy to distinguish, examination of the aging hippocampus has provided valuable insights. The normal aging pattern of the hippocampus involves an inhibition of metabolic activities of the dentate gyrus and subiculum. That is not what you see in patients who have Alzheimer disease. At least initially, the inhibition primarily targets the entorhinal cortex. Neuronal death in these tissues, with a general volumetric shrinkage of the medial temporal lobe, has been shown to distinguish the disease state from typical aging processes.

It is also a matter of calories

Many of the data presented above appear to describe natural, typical processes. But are they inevitable? One of the first questions many people ask after going a few rounds with their senior moment brains is: can the decline be reversed? These are often the questions asked by people who want to increase their life span. The surprising answer to both questions, in a few cases described below, is yes.

One of the most remarkable discoveries in the field of life span alteration occurred in the past century and has to do with caloric restriction. (This does not mean caloric starvation; malnutrition does not provide the benefit and is a completely different issue.) A controlled decrease in the amount of calories consumed has changed the life span of a surprising variety of animals, including mammals. It truly does mean that if you eat less, you will live longer.

The benefits of caloric restriction have been shown to have brain-specific effects as well. Caloric restriction can alter the regulatory genetic down-shifting phenomenon discussed earlier. It has also been shown to change the age-related neuronal degradation in nonhuman primates. Most relevant to our story, caloric restriction can affect human cognitive functioning. In one remarkable study, a caloric restriction protocol that lasted 90 days dramatically improved the verbal memories of a healthy geriatric cohort. Caloric restriction has even been shown to inhibit amyloid-related plaque formation in transgenic mice models of Alzheimer disease.

A matter of genes

Such robust findings work like scaffolding for researchers interested in the molecular biology behind the aging process and have certainly piqued the interest of people wanting to extend their life spans. What is the molecular mechanism behind the life span–extending properties of feeling hungry all the time? One of the earliest fruits of these research efforts was the isolation and characterization of the SIR genes.

The SIR genes were first isolated and characterized in yeast. They are a highly conserved family of sequences found in animals as diverse as roundworms and humans. One intensely studied member of this family is the SIR2 gene (Figure).

The SIR2 gene product functions as an NAD+-dependent deacetylase. In the presence of NAD+, SIR2 removes acetyl groups from proteins. Histone proteins are a favorite target of SIR2. As you may recall from your undergraduate days, histones are groups of proteins around which DNA molecules wrap themselves, somewhat like popcorn wrapped around string. Histones are deeply involved in regulating gene expression. Adding or subtracting subgroups to histones can profoundly influence the expression patterns of the genes in contact with the molecules.

How does SIR2 fit into the caloric restriction story? It was shown years ago that if you introduce SIR2 into yeast in such a fashion that you overdrive its expression, you can increase the yeast’s life span (measured as the number of times a cell completes a round of replication). If you severely restrict the caloric intake of an unmanipulated yeast, you can do the same thing. If you look for levels of SIR2 protein, you find that starvation has elevated its activity. The association appears to be strong, both by correlation and by direct intervention. The link between SIR2 protein and caloric restriction was first found in insects and then in mammals.

Subsequent research has muddied the waters of this otherwise seemingly tight story, however. Other researchers failed to replicate the results of the initial findings. Questions about various technical aspects that provided the original findings have been raised as well. There appear to be differences between genetic backgrounds in the primary test vehicles, from yeast to mice. These issues have yet to be fully resolved.

Such controversies are the nature of a good research project that, while hardly finished, has reached a certain maturity. These controversies are not deal killers regarding the association between the aging process and what goes in your mouth. The devil, as they say, is in the details. The fact that these issues can be raised at all demonstrates the enormous strides that researchers are making regarding the association between aging and eating—two of the most socially important issues of our time. That the arguments can revolve around deciding how the subtraction of acetyl groups changes the cell cycle simply shows how intimate, and how sophisticated, the progress has become.

This article originally appeared in Psychiatric Times.

I seldom address the notion of consciousness—let alone motivations—in this column for a very good reason. Nobody really knows what they are or even if there is a “they.” The literature is confusing, but it hasn’t stopped researchers from speculating on possible neuroanatomical and biochemical substrates that undergird the phenomena. Without a broad consensus about what is being studied, there can be no neurons, let alone molecules, for active experimental consideration. After all these years, researchers have yet to isolate an area of the brain solely devoted to the experience of consciousness. There may be none.

Given the importance of these issues to the mental health professions, I revisit the concept of motivations from time to time—but only when the data are conservatively presented, with sober, modest conclusions. The findings described here originate from experiments that have attempted to determine how we voluntarily choose to perform a motor task (action planning). This work requires reviewing background information on association cortices and the neural substrates behind a decision to initiate voluntary action.

Association cortices

Functionally, the cortical regions of the brain and their myriad interlocking circuits can be divided into 3 modules. These consist of front-, back-, and middle-end domains.

• Front-end functional domains are sensory information processing centers. The brain receives input from the eyes, ears, and other sensory systems. It sends the input off to various places for further processing.

• Back-end functional domains involve motor control systems. These systems essentially respond to whatever command the sensory cortices give to it (eg, execute a decision to move).

• The middle-end suite involves nearly everything other than front-end and back-end functional domains. These association cortices generally entail higher processing features and are some of the least understood and the most mysterious parts of the brain.

One such cortex, located in the inferior posterior parietal cortex, is a sensorimotor association region that links sensory stimuli to motor movement. It may even be involved in sensory prediction, which calculates the consequences of a given action through the simultaneous evaluation of input from both sensory (front-end) and motor (back-end) functional domains.

Volitional motor movement

Many of the actions humans initiate on a day-to-day basis seem to depend on a kind of internal free will. This sequence of events (also known as volitional motor movement) gives humans a sense of control: we act because we want to act. That is why researchers use volitional motor movements in their research designs. Researchers interested in volitional behavior study neural prime movers behind decision making.

Exactly what does it mean to want to do something? We do not really know. The events that initiate movement occur in a fairly straightforward sequence (although it depends on the source of the signal). For example, a central processing area with directives for voluntary motor movements pass through a final staging area before the execution of an action. This region is the primary motor cortex.

Research on laboratory animals demonstrates that this cortex decides on a course of action that depends on the source of signals it receives before the execution of that action. One source originates in the premotor cortex. Signals in this area initiate movements in response to a specific external trigger, such as a visual cue.

The second source arises in the presupplementary motor area, which is stimulated when laboratory animals make the same movements mentioned above, but they do not originate from responses to an external source. The movement instead arises spontaneously; a thought is internally generated through intentional actions. There is an observed rapid rise in electrical signals that build up just before the brain executes these actions. This has led to the notion that the presupplementary motor area harbors some kind of readiness potential, a useful function in generating movement (Figure).

In terms of human behavior, complex human brains have many more research issues to solve than standard laboratory animal research can address. One potential confounder is conceptual. With research of this type, scientists often tell subjects to choose (or not to choose) from a variety of options. Is that voluntary? Hardly. This is like saying, “Okay, it’s time to have some voluntary volitional behavior now,” or like runners at a race who respond to the starting gun. Do volitional actions disappear in these experiments with human subjects? Are these subjects simply reacting to commands to respond, not to respond, or to respond however they want? To test volition, researchers should not control the input. Nevertheless the experimenter must, almost by definition.

Wilder Penfield revisited

Another complexity involves engineering. How does conscious intent to move an arm relate to the actual movement of the arm? This could be partially resolved with electrical stimulation mapping in which surgeons create a map of the brain on conscious patients to understand what tissues need to be avoided during certain manipulations (such as resection). No pain neurons exist in the brain. The patient, immobilized in a stereotactic frame, can be consciously interrogated while the surgery takes place. The surgeon applies a gentle electrical current to the open tissue, talks to the patient about what he or she is experiencing, and makes a map that discerns what areas to avoid during cutting. Working primarily with epileptic patients, the legendary Canadian physician Wilder Penfield first performed these techniques.¹

This technique has proved to be of great value in understanding volitional components of motor movement. It was discovered almost 2 decades ago that if one stimulates a specific area of the human presupplemental area, the patient will experience a conscious urge to move.² This gets around the runner’s starting gun problem mentioned previously. An external electrical stimulator supplies a specific quantity of electricity—and a desire to do something is suddenly generated!

As important and well-characterized as these data are, they hardly explain what causes the presupplemental area to generate the signal in subjects not undergoing surgery. Some research findings answer this question and have led to some intriguing results.^3,4

When the inferior posterior parietal cortex was stimulated, the patient experienced an urge to move specific body parts. Stimulating one area caused patients to want to move their arms. Another region, the lips. Another region, the chest. This is similar to what one observes in frontal lobes, except that you are nowhere near the frontal lobes. Recall that this is the associative cortex region (a sensorimotor associative area at that), quite distinct from anything observed in the well-characterized general motor areas of the frontal lobes. Was this simply a remote stimulation?

This result showed that the answer would be no. The parietal cortex urges were qualitatively different from those obtained by stimulating parts of the presupplementary cortex. It is well known that if the presupplementary cortex is stimulated at a low current, the urge to act is acquired. However, if the same region is stimulated at high current, actual movement occurs. That’s not what happened in the parietal cortex. The urge was stimulated at low intensities, but movement was never generated at higher ones. Instead, subjects felt that they had already performed some movement.

This is important. The desire to move did not result from subtle motor contractions that may have been generated by motor regions (an alternative idea that has been put forth as a rational explanation for the results in previous experiments). Parietal stimulation never produces muscle activity, regardless of the intensity. The stimulation of the premotor cortex itself produces large-limb movements in subjects, but never the desire to move the limbs. They usually remain unaware that movement has occurred when these regions are stimulated.

These results suggest the presence of 2 specific aspects of conscious intention (however one defines it). One might be the conscious correlation of preparatory motor commands in the presupplemental cortex region, as is clearly observed in laboratory studies of animals. The other might involve sensory prediction of the consequences of those commands, under the domain of the association cortex region. A portion of conscious intent seems to be a specific class of experiences housed within the parietal lobe.

Conclusions

It appears that the parietal lobe contributes to the conscious experience of intention, at least in regard to motor movement. These results cement 1 more brick onto the great construction project that seeks to define intention. But they hardly hint at the overall building.

Pushing the edge of our understanding into the murky world of association cortex only means that future experiments will be trickier to interpret. Electrical stimulation mapping, as good as it is, is necessarily a blunt instrument that stimulates thousands of neurons simultaneously. Not isolated modules, these regions connect to each other in complex, little-understood ways. That the regions produce different behaviors is an important finding but not a defining one.

How do the frontal and motor aspects of volitional experience differ from the parietal, sensory versions? What factors stimulate the parietal lobes in the first place? What about remote effects?

Questions such as these remain to be answered and are just a few of the many that researchers will face as they attempt to define intentional and conscious experiences.

This article originally appeared in the Psychiatric Times.