Can ADHD be identified in blood?

Posted by on May 31st, 2007 | Comments off

Researchers Sharon A. Murphy, MD, and Douglas Woodruff, MD, psychiatrists in private practice in Baltimore, Maryland presented their findings at the 160th annual meeting of the American Psychiatric Association (APA). Their work is based a particular technique called cell membrane potential. They propose that use of this technique may help medical professionals clearly identify attention deficit hyperactivity disorder (ADHD), bipolar disorder, and possibly major depressive disorder.

According to investigators, this physiologic property of cells differs among these disorders and is also differentiated from that seen in healthy controls. This is an interesting theory which has some credibility from years of previous research on manic and depressed persons. To extrapolate this theory to ADHD persons is intriguing.

The theory is a little complex, so I’ll attempt to simplify it. Cells contain energy. In that regard, they are like little batteries. If you attach a voltmeter to two terminals of a battery, a voltage difference will be measured across the two terminals. If you have a battery tester that lights up, you’re actually testing the voltage difference between the positive and negative ends of the battery. Since a cell is like a battery, if you attach a voltmeter to measure voltage across the cell membrane (outside of a cell) you’ll find that the inside of the cell has a negative voltage (measured in millivolts; mV) with respect to the outside of the cell (which is referenced as 0 mV).

If the cell is at rest, it is termed the resting membrane potential. By convention, the potential outside the cell is arbitrarily defined as zero. There exists an excess of negative charges inside the membrane because it is filled with many potassium (K+) and organic ions. Thus, the potential difference across the membrane is expressed as a negative value. The resting membrane potential is disrupted when net flux of ions (charged particles) moves into or out of the cell. Ions flow through various channels constructed of proteins to traverse the cell membrane. These are called, ion channels. Sodium and potassium are known as electrolytes – substances that conduct electrical activity that play a vital role in the normal functioning of the nervous system. There is a higher concentration of sodium outside the nerve cell and a higher concentration of potassium inside. The sodium pump is a process that maintains the normal distribution of sodium and potassium.

The researchers maintain that when cells are placed in a potassium-free buffer, the assay used in their test, cells are stressed. Abnormal regulation of ion distribution and variability in the functioning of the sodium-potassium pump within cells is known to be associated with bipolar I disorder and may also be a hallmark of ADHD, according to Drs. Murphy and Woodruff. I had heard of malfunctioning neuronal sodium-potassium pumps being associated with bipolar I disorder or ADHD, but not blood cells, so this intrigued me.

“While using the membrane potential assay to identify bipolar I disorder, we were intrigued by data that suggested this membrane potential test is also sensitive to presumed malfunctioning of the sodium-potassium pump in ADHD,” the authors reported.

Here’s the theory upon which the researchers are presumably basing their work: Any factor that alters the sodium or potassium pump in a neuron likely alters the neuron’s capacity to respond to stimuli basically affecting the functioning of the neurons. This may then affect the central nervous system and human behavior. Various studies over many years have demonstrated that depressed and manic patients may exhibit disturbances in the distribution of sodium and potassium (pump problems). Some research indicates patients with psychotic depression and mania had higher levels of intracellular sodium. The hypothesis is that manic and depressed people may have a highly excitable (hyperexcitable) central nervous system due to the excess sodium levels. They are treated successfully with lithium salts which greatly reduce intracellular sodium and so may reduce central nervous system hyperexcitability.

Murphy and Woodruff recruited 273 subjects, of whom 123 were controls. Within that group, 55 were identified by the blood work assay as having bipolar I disorder, and 95 were identified as having ADHD. The assay consists of fluorescence intensity of the membrane potential dye in patients’ blood cells. I would truly enjoy seeing fluorescence intensity of membrane potential dye. Fluorescence intensity is widely used in the manner in which the researchers used it. However, fluorescence intensity is a relative measurement which depends on instrument characteristics. This means that different fluorescence measuring instruments or even the same fluorescence instrument produce different data at different times. Additionally, turbidity (similar to muddy water) or the presence of colored compounds in the sample further complicate the interpretation of the measurements.

After all was said and done, the researchers used clinical response to medication to see if their diagnoses were correct. If the patients responded well, then the researchers concluded they were right! I’ve seen many medical practitioners perform this reverse diagnosis; concluding a child has ADHD if he responds well to ADHD medication.

Seems rather ridiculous. Both their methodology and their conclusions seem quite a stretch given the technology they’re working with.

Murphy and Woodruff claim that their test gives “a very clear and distinct difference among the controls, people with ADHD, and people with bipolar I disorder.” The average membrane potential ratio was 0.8, and the average ratio for ADHD was 1.1; the mean ratio in controls was 0.9

Essentially, I have five primary arguments against this type of test presenting any conclusive evidence:

  • It is curious that the researchers used blood cells rather than neurons as previous research upon which their theory is based was produced from neural cell examination.
  • Fluorescence is a relative measurement that varies with each measuring instrument and is highly susceptible to the most minor variations in the substance being measured.
  • Using a reverse diagnosis to verify one’s test data is suspect.
  • Their data don’t seem statistically significant, but since they didn’t provide their standard deviation, one cannot determine significance.
  • Extrapolation to ADHD from bipolar I is quite a stretch.

Again, the Holy Grail of ADHD is to find that true biological marker that absolutely defines the disorder. We haven’t been able to find it for mania, depression, etc. for the past 50 years. I doubt we’ll find one for ADHD for a variety of reasons, but that’s another chapter unto itself.

ADHD and Impulse Control

Posted by on May 29th, 2007 | Comments off

STOP/GO NEURONS PROVIDE IMPULSE CONTROL

The April issue of Psychological Review published a study based on a theoretical model proposed by neuroscientist Gordon Logan and physicist William Cowan. Vanderbilt University psychologists, Jeff Schall and Leanne Boucher co-author this study. Their data attempt to provide insight into the relationship between the brains physical movement control systems and its relationship to ‘mind.’

The theoretical model developed by Cowan and Logan posited that physical impulse control involved two independent processes: one telling stop and the other telling us to go – similar to a racing scenario.

According to co-author, Jeff Schall, the research “…helps explain the impulsivity of people with attention deficit and hyperactivity disorder.”

The researchers used physiological data collected from monkeys that were taught to look at a visual target unless a stop signal activated. With the stop signal activated, the monkeys ceased looking at the target. These stop/go tasks produced quantified data correlating to the monkeys’ abilities to stop a planned action.

The researchers found that while go processes and stop processes are independent processes, they are actually carried out on complex network of interacting neurons, which is rather paradoxical.

“For most of the race, ’stop’ and ‘go’ act independently.’Stop’ interacts with ‘go’ very briefly–it basically has one chance to knock ‘go’ out of the race. It needs to react strongly and rapidly after the stop signal is given,” Schall said. “If it is successful, the subject stops his or her planned movement. If it is unsuccessful, the subject goes ahead. In individuals with impulse control problems, ’stop’ more often loses the race.”

In relation to ADHD, Login cites, “Applying the model to children’s behavior revealed that stop signal task times are significantly longer in children with attention deficit and hyperactivity disorders than in other children. We think of people who are impulsive as acting too quickly. Kids with ADHD are actually slower on the ‘go’ task than the control kids. It’s not that they go too quickly; they stop too slowly.”

In a stretch, the researchers imply that their data are some of the first to bridge cognitive research and neurophysiology–making the connection between the mind and the brain.

“For years, one group of researchers was looking at what neurons are doing, and a different group of researchers was looking at what people are doing,” said Palmeri, associate professor of psychology. “Now there is a point of contact between decades of important research in neurophysiology and decades of important research in cognitive modeling. Research that has very different histories and approaches is really starting to come together.”

To be realistic, I suppose that research, insight, and information, must advance in stages. However, applying this model doesn’t seem as progressive as the authors imply. It doesn’t advance our knowledge on a practical level as we’ve known for years about the stop/go processes and impulse control of ADHD. “The ‘stop’ too slowly” comment by Login is nothing new; it’s been stated for years. Their model simply confirms what developmental psychologists and occupational therapists have been proposing for years based on field observations. The researchers’ correlations to neuronal activity aren’t especially new either.

Perhaps a better holistic model may be obtained from Marvin Minsky’s book (1988), The Society of Mind which offers a better model consisting of what Minsky calls agents. Minsky theorizes that human intelligence is the result of interactions of simple parts called agents. These agents are themselves mindless. The interactions between the simple agents constitute the “Society of Mind.” It definitely encompasses the ‘stop/go’ model espoused by the Vanderbilt scientists and predates it by almost ten years.