FROM GLUCOSE TO GRAY MATTER: HOW DIABETES ALTERS THE BRAIN

Diabetes is a chronic condition that primarily affects the heart, kidneys, and eyes, but it also has a profound impact on the brain. The vascular damage, oxidative stress, and insulin resistance associated with diabetes can lead to memory loss, attention deficits, and executive dysfunction (high-level cognitive processes that enable an individual to plan, organize, make decisions, solve problems, control impulses, and complete tasks). From neuropsychiatric dysfunctions to structural changes, diabetes affects the brain in multiple ways.

As of 2021, 11.6% of the U.S. population, or 38.4 million people, had diabetes, with Type 2 diabetes being the most prevalent form. This number continues to rise, largely due to the increasing rates of obesity, poor dietary practices , and sedentary lifestyles. While much attention is given to the impact of diabetes on the cardiovascular and renal systems, its effects on the brain are gaining more attention.

Since glucose is the brain's primary energy source, fluctuations in blood sugar can directly impact it. Both hyperglycemia and hypoglycemia can disrupt the brain’s integrity and performance, as well as insulin resistance associated with diabetes.

Chronic hyperglycemia damages blood vessels throughout the body, including those in the brain. High blood sugar levels can lead to thickening of the blood vessels and atherosclerosis (narrowing of the arteries). This can reduce cerebral blood flow, depriving the brain of oxygen and nutrients. Over time, this may result in neurocognitive decline, affecting memory, attention, and executive function. Reduced blood flow also increases the risk of strokes and other vascular events which can further damage brain tissue. Hyperglycemia is also known to increase the production of reactive oxygen species (ROS), molecules that damage tissues, including neurons. This accelerates brain aging and is linked to neurodegenerative diseases, particularly in brain regions crucial for memory, like the hippocampus. The hippocampus is vital for converting short-term memories into long-term memories. When impaired, it can lead to memory loss, difficulty learning new information, and overall neurocognitive decline.

Hypoglycemia can also have significant effects on the brain. When blood sugar levels drop significantly, the brain may not have enough fuel to function properly, leading to various neurocognitive and physical symptoms. The severity of these effects can range from mild confusion to life-threatening situations, if blood sugar levels fall too drastically. Hypoglycemia can cause confusion, poor judgment, difficulty processing information, and memory lapses. Severe episodes of hypoglycemia can even lead to loss of consciousness, seizures, or comas.

Further, insulin resistance in the brain impairs the activity of several important neurotransmitters, including dopamine, serotonin, and acetylcholine. These neurotransmitters are involved in mood regulation, memory, and learning. Disruptions in their signaling can cause neurocognitive problems, i.e. memory loss and difficulty concentrating, and could lead to mood disorders like depression and anxiety.

In addition to functional neurocognitive issues, long-term diabetes, especially when poorly managed, can lead to physical changes in brain structure. MRI studies show that people with diabetes often have smaller brain volumes, particularly in areas related to memory and learning. This shrinkage is thought to be related to the accumulation of advanced glycation end-products (AGEs), which form when high blood sugar interacts with proteins, causing tissue damage and stiffening.

Managing diabetes can be stressful, and for many, this stress contributes to mental health challenges, such as depression and anxiety. The stress of maintaining blood sugar levels, adhering to dietary restrictions, and coping with potential complications can exacerbate neurocognitive problems. In fact, people with both diabetes and depression are at a much higher risk of experiencing memory issues, attention deficits, and executive dysfunction. Depression in individuals with diabetes is linked to biological factors, i.e. inflammation and insulin resistance, and behavioral factors, i.e. poor diet and lack of exercise, creating a vicious cycle that further impacts neurocognitive health.

The good news is that proactive management of diabetes can reduce the risk of neurocognitive decline and support long-term brain health. Keeping blood sugar levels stable through diet, exercise, and medication is the foundation for preventing both short-term neurocognitive issues and long-term brain damage. Physical exercise improves insulin sensitivity, promotes the growth of new brain cells, and supports overall brain health. A balanced, nutrient-dense diet, rich in vegetables, fruits, whole grains, and lean proteins helps stabilize blood sugar and supports neurocognitive function. Engaging in activities that challenge the brain, such as puzzles, reading, or learning new skills helps keep neurocognitive abilities sharp. Managing stress through relaxation techniques, hobbies, and proper sleep hygiene can also improve brain health. By taking proactive steps, individuals with diabetes can protect both their physical and neurocognitive health for years to come.

FEAR ON THE BRAIN

We often think of fear as a temporary state. It is an emotional and physiological reaction to an external stimulus that usually subsides once the stimulus ends. However, certain types of fear, namely prolonged or life-threatening, can cause permanent changes in our brains. This is why Post Traumatic Stress Disorder can be such a difficult disorder to treat.

The fear response starts in a region of the brain called the amygdala. When triggered, other areas of the brain are activated in order to prepare us for fight or flight, i.e. Motor functions. It also triggers the release of stress hormones and our sympathetic nervous system. Ultimately, making us more efficient at times of danger: muscles grow due to increased heart rate and breathing and gastrointestinal system slows down.

However, a different part of the brain called the hippocampus, which is closely connected to the amygdala along with the prefrontal cortex mitigate the fear by interpreting the threat in its context. For example, if you encountered a shark in open waters vs. a shark in an aquarium, your experience of fear would vary significantly given the context. This is because the hippocampus and the prefrontal cortex judge the context and then dampen the amygdala’s fear response. Generally speaking, this neurophysiological process is rather straightforward when we are talking about isolated and mild to moderate fear events. When we are discussing prolonged or life-threatening events, that is altogether a different story.

Researchers from the Tulane University School of Science and Engineering and Tufts University School of Medicine found that the stress neurotransmitter norepinephrine, also known as noradrenaline, facilitates fear processing in the brain by stimulating inhibitory neurons in the amygdala to generate a repetitive bursting pattern of electrical discharges. This is particularly the case when there is persisting fear, or an extreme amount of fear being triggered. This bursting pattern of electrical activity changes the frequency of brain wave oscillation in the amygdala from a resting state to an aroused state that promotes the formation of fear memories.

This changes the electrical discharge pattern in the amygdala, which transitions the brain to a state of heightened arousal that facilitates memory formation and fear memory. Because of the neurophysiological alterations, patients with PTSD often struggle with re-experiencing of traumatic events and hyper-vigilance.

Disorders of anxiety and fear include phobias, social phobia, generalized anxiety disorder, separation anxiety, PTSD and obsessive-compulsive disorder without appropriate treatment can become chronic and debilitating. Without understanding the neurophysiological basis of fear, it’s difficult to appreciate how to really help individuals that are often paralyzed by their fears. Treating anxiety disorders such as PTSD is not as simple as enlisting them in talk therapy. Rather, it is considering how best to rewire their brains from the heightened state due to the electrical discharges and the neurophysiological changes. The best form of treatment is conjunctive therapy with behavioral, cognitive and neurochemical (medications) approaches. Combined, these could help the individual normalize the brain function.

In my practice, I encounter patients regularly that have been involved in catastrophic injuries, varying from construction site accidents to transit accidents. What I often see is along with their head injuries, patients are often dealing with the residual effects from the fear/anxiety related to the accident itself. Thus, it is important that we take note of the effects of fear on the brain as these can often cause insidious problems that compound patient recovery.

BASELINE BRAIN FUNCTION: TESTING FOR PREMORBID FUNCTIONING

With the increasing accessibility of information these days, individuals are becoming more aware of the fragility of the brain. From an athlete’s risk of concussions during a football game to the possibility of a brain contusion from a car accident, there is more concern around brain injuries than ever before.

As a result of this increased awareness, the demands on the field of neurology and its subspecialties have grown. This growth has also raised more questions. One common recurring question is, how do doctors determine the chronicity and severity of a neurological injury.

Doctors often rely on brain imaging to determine diagnosis, treatment and prognosis. MRIs are the most accurate type of brain scan science has to offer (at the moment) and they are effective in identifying hematomas, hemorrhages, and cerebral edemas, but not so effective at identifying other types of brain injuries. For example, MRIs usually cannot detect any abnormalities in a patient with traumatic brain injury. It isn’t until much later that an MRI or a CT scan is able to detect brain atrophy from a TBI (results when dead or injured brain tissue is reabsorbed following the injury). At that time, it is much too late to implement any reversable treatments. Since brain scans are often unremarkable in these cases, we must rely on other clinical tools to properly diagnose and treat these injuries.

Since microscopic injuries to the brain cause long term problems, it is key to detect them early in order to adequately treat them. One of the methods employed to do so is through baseline cognitive testing. Baseline cognitive tests are measures that neuropsychologists administer to assess brain function during a healthy state. Following a concussion, neuropsychologists can use a post-injury test (and compare against your baseline cognitive test) to help determine the severity of the injury and the treatment you’ll need.

In my practice, I work a lot with professional athletes and especially football players. Since concussion protocols have been put into place, the National Football League has implemented a baseline cognitive test for all incoming athletes called the ImPact. This allows team doctors to re-examine the athlete when a head injury occurs and compare test results at the time of injury to their baseline. From the results, the doctors are able to identify a) if an injury occurred, b) the severity of the injury, and c) the treatment required.

But what happens when there’s been a neurological insult, and we have no baseline tests? What then can we compare the post-injury test to in order to determine if there has been an injury?  And its level of chronicity and severity? This is where the importance of premorbid testing comes in!

A test of premorbid functioning estimates an individual's pre-morbid (pre-injury) cognitive functioning. Similar to that of baseline testing, a pre-morbid test allows us to determine a) if an injury occurred, b) the severity of the injury, and c) the treatment that is needed. The difference is that in this case, the test takes place after the injury, and we are estimating the pre-morbid level of functioning using empirically based measures and collateral information.

Empirically based measures are standardized assessment procedures that assess for crystallized intelligence. Crystallized intelligence is information that relies on accumulated knowledge, such as vocabulary and reading. Generally speaking, these are not vulnerable to brain damage, with the exception of patients with aphasias (communication disorders) due to damage to the Wernicke’s or Broca’s areas in the brain. In patients with aphasia, the LOFT (Lexical-Orthographic Familiarity Test) can be used. This is a forced-choice recognition task based on lexical familiarity judgments. In studies on aphasic patients, it was found that when compared to non-brain damaged individuals, their scores on the LOFT were statistically insignificant, meaning aphasic patients were not affected in their ability to perform on this test.

Combining the results from empirically based measures with clinical impressions derived from socioeconomic variables such as the patient's level of academic, occupational, social and interpersonal relation areas, neuropsychologists can confidently generate a premorbid estimate of cognitive functioning. This is particularly important in the medical-legal field when doctors are asked to consider pre-existing conditions and apportion when there are pre-existing factors.

More often than not, we do not have a brain MRI or CT scan from before a neurological insult. Individuals typically are not getting a brain scan when they are healthy. Similarly, individuals are not getting a neurocognitive evaluation or baseline cognitive test when they are healthy. This means doctors are typically not provided baseline studies. It is therefore important that we always include premorbid testing to help us determine the individual’s premorbid level of cognitive functioning. This is the only way in which we can effectively determine whether there was truly an injury and the chronicity and the severity of the injury.

Without understanding what the starting point is, doctors cannot truly appreciate what, if any, change has occurred.