Diagnosing Depression Through Blood

Major depressive disorder (MDD) is estimated to affect 6.7% of the adult population in the United States every year (Lepine & Briley, 2011). The number of people who suffer from major depressive disorder is expected to increase as our youth continues to age (Hidaka, 2011). According to the World Health Organization, depressive disorders have been identified as the number one cause of disability in the world (Ferrari et al., 2013). This further supports the responsibility throughout the medical community to diagnose depression accurately and provide appropriate interventions quickly.

As with other psychiatric diseases, we do not yet fully understand the neurobiological mechanisms of major depressive disorder. Perhaps the most well known theory for the neurobiological underpinnings of depression is the monoamine hypothesis. This hypothesis holds that serotonin and norepinephrine, or the lack there of, can explain the pathophysiology of major depressive disorder. The most widely used antidepressants target this deficiency. Despite such medications causing immediate increases in monoamines in neuronal synapses, it often takes ten to fourteen days before mood is therapeutically affected (Hindmarch, 2001). Similarly, studies have complicated this theory by demonstrating that differences in monoamine levels cannot effectively distinguish patients with major depressive disorder and healthy controls (Higgins & George, 2013). As such, we know that the mechanisms underlying depression are more complicated than any one group of neurotransmitters can explain.

Just as our understanding of the neurobiological mechanisms of major depressive disorder is not complete, the etiology of MDD remains complicated and relatively unclear. The interplay of an individual’s genetic makeup and the experiences he or she encounters is often the culprit for the later development of mental illness. This also holds true for depression. However, the exact genes that are responsible for major depressive disorder have eluded discovery for quite some time.

In September, researchers at Northwestern University published their research claiming to have identified a blood test that could be used to diagnose MDD based on components of an individual’s genetic material. Currently, a major depressive disorder diagnosis is based on a clinical interview. In this interview, a patient’s presentation is dissected based on symptoms and whether certain diagnostic criteria are met according to the DSM. Understandably, there is some degree of subjectivity in this process. A serum blood test would provide medical professionals with the ability to make this diagnosis objectively.

The objective diagnosis of MDD is based on the identification of specific serum transcriptomic biomarkers in patients suffering from major depressive disorder. The blood test distinguishes depression based on the levels of nine RNA markers – ADCY3, DGKA, FAM461, IGSF4A/CADM1, KIAA1539, MARCKS, PSME1, RAPH1, and TLR7.

RNA, or ribonucleic acid, is a macromolecule that serves many functions for the cell. Perhaps most notably, it copies and transfers the genetic code needed for the synthesis of proteins. These proteins, in turn, are responsible for various catalytic and structural processes that every cell depends on (Clancy, 2008). For this reason, proteins are often recognized as “the workhorses” of the cell (e.g., Lodish et al., 2000). However, it is our genetic code that determines which and how many proteins are produced.

The researchers at Northwestern were also able to utilize the RNA markers of MDD patients as a means to measure the efficacy of cognitive behavioral therapy (CBT). In the study, the researchers measured the levels of the RNA markers after 18 weeks of CBT. Using certain markers, they were able to distinguish patients for whom therapy was effective (i.e. patients that were no longer depressed) from those whose depression persisted despite cognitive behavioral therapy. Patients with depression that remitted at the conclusion of CBT displayed differences in the levels of ASAH1, ATP11C, and KIAA1539 as compared to those patients whose depression did not remit. Thus, the levels of certain RNA markers could provide objective evidence for the efficacy of this intervention. That is, levels of these markers should change if patients with MDD respond to CBT therapeutically.

Beyond following the trends of certain markers to determine if CBT is effective, specific baseline characteristics of several markers could be used to predict who would have therapeutic responses to cognitive behavioral therapy in the first place. The researchers found that the co-expression patterns of certain transcripts differed significantly at baseline between patients who were no longer depressed and patients who were still depressed following CBT. In utilizing these markers, medical professionals could identify appropriate treatment regimens for each individual and anticipate whether such interventions would be effective.

Despite certain RNA markers changing in response to CBT, some transcript level differences persisted between patients with MDD and controls irrespective of whether patients with MDD were currently depressed or not. These differences were found in the levels of RAPH1, KIAA1539, and DGKA. As such, these RNA markers were both highly specific and sensitive for patients with MDD and those who never had MDD. It would be these markers, presumably, that could be objectively relied on to aid medical professionals in their capacity to diagnose.

Because of how distressing and disabling life with MDD can be, it is vitally important for the medical community to arrive at such a diagnosis with accuracy and confidence. The researchers at Northwestern may have found a method that ensures exactly that. According to Eva Redei, the leading author on the paper, “this clearly indicates that you can have a blood-based laboratory test for depression, providing a scientific diagnosis in the same way someone is diagnosed with high blood pressure or high cholesterol” (Paul, 2014). As our ability to diagnose depression increases, our understanding of its etiology and neurobiological mechanisms will plausibly expand. Likewise, as the diagnosing of mental illness becomes more “scientific,” we can hope, from a global perspective, that it might help to combat the long-standing stigma that often surrounds it.

References

Clancy, S. (2008). RNA functions. Nature Education, 1(1): 102. Retrieved from http://www.nature.com/scitable/topicpage/rna-functions-352

Ferrari, A.J., Charlson, F.J., Norman, R.E., Patten, S.B., Freedman, G., Murray, C.J., Vos, T., & Whiteford, H.A. (2013). Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLoS Medicine, 10(11). doi: 10.1371/journal.pmed.1001547

Hidaka, B.H. (2012). Depression as a disease of modernity: explanations for increasing prevalence. Journal of Affective Disorders, 140(3), 205-214. doi: http://dx.doi.org/10.1016/j.jad.2011.12.036

Higgins, E.S. & Georfe, M.S. (2013). The neuroscience of clinical psychiatry: The pathophysiology of behavior and mental illness. Philadelphia, PA: Lippincott Williams & Wilkins.

Hindmarch, I. (2001). Expanding the horizons of depression: beyond the monoamine hypothesis. Human Psychopharmacology: Clinical and Experimental, 16(3), 203-218. doi: 10.1002/hup.288

Lepine, J.P., & Briley, M. (2011). The increasing burden of depression. Neuropsychiatric Disease and Treatment, 7, 3-7. doi: 10.2147/NDT.S19617

Lodish, H., Berk, A., Zipursky, S.L., Matsudaira, P., Baltimore, D., & Darnell, J. (2000). Molecular cell biology. New York: W.H. Freeman.

Paul, M. (2014, September 16). First blood test to diagnose depression in adults. Retrieved from http://www.northwestern.edu/newscenter/stories/2014/09/first-blood-test-to-diagnose-depression-in-adults.html

Redei, E.E., Andrus, B.M., Kwasny, M.J., Seok, J., Cai, X., Ho, J., & Mohr, D.C. (2014). Blood transcriptomic biomarkers in adult primary care patients with major depressive disorder undergoing cognitive behavioral therapy. Translational Psychiatry, 4, doi: 10.1038/tp.2014.66

Sleepwalking

Sleepwalking is mysterious, fascinating and sometimes lethal.

Dr. Matthew J. Wolf-Meyer published an article, on December 13, 2012, entitled, Sleepwalking Killers-And What They Tell Us About Sleep. The article discusses a few cases of homicidal sleepwalking, but most notably, the case of Kenneth Parks. In the 1980’s a man named Kenneth Parks killed his mother-in-law, while sleepwalking. Parks had a history of sleepwalking and other parasomnias, including nocturnal enuresis and night tremors. Parks was recently fired from his job, under extreme stress, had a history of depression and was sleep deprived. While sleepwalking, Parks drove about 15 miles to his mother-in-laws’ home, where he entered, fumbled around and then proceeded to stab her to death. While driving home, he woke up, yet, was unable to recall the events of what just occurred. He did, however, realize something was gruesomely awry, as he was covered with blood. He then turned himself into the police.  Unintentional homicide with the defense of sleepwalking may have been hard for Park to prove, however, during his episode, Park obliviously and severely cut both of his own hands. This accidental self-mutilation, inevitably helped prove his case of being unaware of his actions, while sleepwalking (Wolfe-Meyer, 2012).

What is Sleepwalking?

First, let’s define normal sleep. Sleep can be most simply divided between two phases: non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep.  NREM sleep can further be divided into four stages, where stages three and four (S3, S4) are the deepest stages of sleep, called slow wave sleep (SWS). During REM sleep, dreams are vivid and muscles are paralyzed so the “acting out” of dreams is usually suppressed. With NREM sleep however, muscles are not paralyzed, but sleeping persons usually don’t move during this phase (Higgins & George, 2013). But what happens when they do?

▶ How Does Sleepwalking Work? – YouTube.

Sleepwalking, or somnambulism, is the incomplete transition from S3, S4 deep, SWS to wakefulness (Reading, 2014). Thus sleepwalking, along with similar NREM parasomnias, such as, confusional arousal and night terrors, which commonly co-exist (Sehgal, 2011), are called arousal disorders. Sleepwalkers are oxymoronic, because they are technically asleep, yet they are also partially awake, which enhances the  mysterious allure of this parasomnia. In a recent 2013 study, researchers capture brain imaging via single-photon emission computerized tomography (SPECT) scans. Surprisingly, the SPECT scans revealed deactivation of frontoparietal associative cortices, with simultaneous activation of the posterior cingulated and anterior cerebellum networks. Additionally, no deactivation of the thalamus was detected (Zadra, 2013). Since the thalamus plays a large role in wakefulness, it’s fascinating that this portion of the brain remains activate during sleepwalking. Aside from vascillating between states of consciousness, generally sleepwalkers do not have significant incidences of psychopathology (Banerjee, 2011).

Sleepwalking is not a dream, although for some, it may be a walk in the park. Sleepwalking activities range from simple to complex, with varied intensity. Some sleepwalkers merely sit up in bed, while others, as in the case of Mr. Parks, have committed murder. Children may experience the spectrum of mild confusion arousals with limited sleepwalking to frightening night terrors accompanied with sleep running and screaming (Banerjee, 2011). Adults typically exhibit various automatic behaviors, including: getting dressed, cooking, eating, driving, sexual activity (sexomnia, more prevalent with men) and violence (Montplaisir, 2013). In general, men are more likely to  experience sleepwalking than females (AASM, 2014).

Since sleepwalking occurs while in the deepest phase of sleep, it is often very difficult to awaken a sleepwalker. Sleepwalkers may become combative or excessively violent when touched in this state (Guilleminault, 1999). If it becomes necessary to awaken a sleepwalker for safety purposes, it’s best to gently guide the person back to bed and try a calm approach. Most sleepwalkers report no recollection of their episodes. However, in some studies, those who did have recall, reported themes of unpleasant visual imagery, feelings of impending doom (Reading, 2014), misfortune and apprehension (Banerjee, 2011).

What’s the likelihood of becoming a Sleepwalker?

Unless you were apart of the roughly 40% of childhood sleepwalkers (Higgins & George, 2013) the chances of you joining the up to 4% of adult sleepwalkers (AASM, 2014) is pretty slim.  A Finnish study showed monozygotic twins where five times more likely to both have adulthood sleepwalking continue from childhood than dizygotic twins. This study further reinforces the fact that sleepwalking is typically genetic, with 80% of sleepwalkers having at least one immediate family member previously affected from childhood (Zadra, 2013). While there is still much theory about  sleepwalking and it’s origins, one research study states that sleepwalking is inherited as an autosomal dominant disorder, and has pinpointed the exact genetic locus for this parasomnia at chromosome 20q12-q13.12 (Banerjee, 2011).

Triggers and Treatment

Both newly onset and exacerbated continuing cases of adult sleepwalking can be triggered by situational stress (Pressman, 2011), sleep deprivation, noisy environments, alcohol, and short-acting hypnotics, such as Zolpidem (Reading, 2014).

When seeking treatment, sleepwalkers should be sure to rule out the most common differential diagnosis – nocturnal frontal lobe epilepsy (NFLE). Table 2, from the American Academy of Sleep Medicine, shows the clinical features of both sleepwalking and NFLE.

Avoidance of the aforementioned triggers, proves excellent treatment for sleepwalking. Children usually outgrow of this disorder and do not need medical intervention. Parents can help children reduce the episodes of sleepwalking, with scheduled awakening several hours after bedtime and just before their usual sleepwalking time (Banerjee, 2011). Adult treatment may include: scheduled awakening, hypnotherapy and benzodiazepines (Zadra, 2013). Clonazepam is the most commonly distributed benzodiazepine for sleepwalking. Benzodiazepines sensitize GABA  receptors, which increase GABA activity in neurons. This increased GABA activity promotes higher inhibition of the central nervous system, which helps control sleepwalking (Higgins & George, 2013).

All things considered in this post, think back to the opening case of Kenneth Parks. Based on the evidence based research presented, do you think he stands a good chance in court with his sleepwalking defense and why?

 

References

American Academy of Sleep Medicine (AASM). (2014). Sleepwalking and sleep talking.Retrieved on Nov 15th, 2014 from:http://www.aasmnet.org/Resources/FactSheets/SleepwalkingTalking.pdf

Banerjee, D., & Nisbet, A. (2011). Sleepwalking. Sleep Medicine Clinics, 6(4), 401-416.doi:10.1016/j.jsmc.2011.07.001.

Higgins, E., & George, M. (2013).  Anxiety. In The Neuroscience of Clinical Psychiatry:The Pathophysiology of Behavior and Mental Illness (2nd ed).(pp.174-188).Philadelphia:  Lippincott Williams & Wilkins.

Montplaisir, J. Zadra, A., Desautels, & A., Petit, D. (2013). Somnambulism: Clinical aspects and pathophysiological hypotheses. The Lancet Neurology, 12(3), 285-294. Retrieved from SCOPUS database.

Pressman, M. R. (2011). Common misconceptions about sleepwalking and other parasomnias. Sleep Medicine Clinics, 6, xiii-xvii. doi:http://dx.doi.org/10.1016/j.jsmc.2011.08.008

Ohayon, M. M., Guilleminault, C., & Priest, R. G. (1999). Night terrors, sleepwalking, and confusional arousals in the general population: Their frequency and relationship to other sleep and mental disorders. Journal of Clinical Psychiatry, 60(4), 268-276. Retrieved from SCOPUS database.

Reading, P. (2014). Things that go bump in the night: Diagnosing sleep-related movement disorders without a sleep laboratory. Journal of the Royal College of Physicians of Edinburgh, 44(1), 57-63. Retrieved from SCOPUS database.

Sehgal, A., & Mignot, E. (2011). Genetics of sleep and sleep disorders. Cell, 146(2), 194-207. doi:http://dx.doi.org/10.1016/j.cell.2011.07.004

Wolfe-Meyer, M. (2012). Sleepwalking killers – And what they tell us about sleep. Day In, Day Out. Retrieved on November 15, 2014 from: http://www.psychologytoday.com/blog/day-in-day-out/201212/sleepwalking-killers-and-what-they-tell-us-about-sleep

Zadra, A., & Pilon, M.Chapter. (2011) 52 – NREM parasomnias. Handbook of clinical neurology (pp. 851-868) Elsevier. doi:http://dx.doi.org/10.1016/B978-0-444-52007-4.00011-4

The Truth About Lucid Dreaming

“I was standing in a field in an open area when my wife pointed in the direction of the sunset. I looked at it and thought, ‘How odd; I’ve never seen colors like that before.’ Then it dawned on me: ‘I must be dreaming!’ Never had I experienced such clarity and perception— the colors were so beautiful and the sense of freedom so exhilarating that I started racing through this beautiful golden wheat field waving my hands in the air and yelling at the top of my voice, ‘I’m dreaming! I’m dreaming!’ Suddenly, I started to lose the dream; it must have been the excitement, I instantly woke up. As it dawned on me what had just happened, I woke my wife and said, ‘I did it, I did it!’ I was conscious within the dream state and I’ll never be the same. Funny, isn’t it? How a taste of it can affect one like that. It’s the freedom, I guess; we see that we truly are in control of our own universe.” (Self report of a lucid dream experience from LaBerge, 1991, p. 5)

Most of us perceive a fairly clear distinction between being asleep and being awake, that distinction being marked by the presence or lack of consciousness.  Lucid dreaming, however, turns this notion on its head.  Lucid dreaming has attracted attention from scientists for its unique combination of characteristics inherent to both dreaming and wakefulness.  In a lucid dream, the dreamer is aware that he is dreaming and often has control over his participation in the dream environment (LaBerge, 2014).  This state of adaptable sub-consciousness has proven desirable to many people (imagine being able to fly at will!), but its value to researchers lies in its applicability to establishing a neurological basis for consciousness and applicable treatment modalities.

Sleep is divided into five distinct categories, one of which is rapid eye movement (REM) sleep (Higgins & George, 2013).  Previously, it was believed that dreaming was limited to REM sleep; recent studies, however, have proven that dreams occur in all stages of sleep.  While dreams in non-REM sleep are characterized by thoughts, REM dreams are typically “illogical, bizarre, and even hallucinatory” (p. 179).  It is no surprise then that most lucid dreams take place during this hallucinatory period (Bootzen, 1990). Ogilvie (1983) reported that 86% of cases of lucid dreaming occurred during REM sleep and similar studies have provided analogous findings.

Another way to distinguish the stages of consciousness is through their characteristic electroencephalographic (EEG) rhythms.  Theta activity, for example, is predominant in stage 1 sleep while delta activity is indicative of stage 4, the deepest sleep stage (Faust, 2005).  One notable frequency is gamma waves, which range from 40 Hz to 100 Hz and have been linked to consciousness while awake (“Mental Health Daily,” 2014).  Gamma waves are crucial for higher cognitive functions, such as information processing, learning, and memory.  Remarkably, in one study, applying 40 Hz of current to the frontal lobe of a sleeping brain induced lucid dreaming in 77% of participants (Hughes, 2014).  This data only strengthens the link between lucid dreaming and consciousness.  While dreaming is a state of primary consciousness and wakefulness a state of secondary consciousness, lucid dreaming appears to be a unique hybrid of the two (Hobson, 2010).

Though the timing in the sleep cycle and EEG rhythm of lucid dreams has been identified, the brain structures involved with this phenomenon are slightly more difficult to pinpoint.  One theory suggests that the activation of the dorsolateral prefrontal cortex (DLPFC) is required (Stumbrys, 2013).  It is believed that activation of this area, which is normally deactivated during REM sleep, allows the dreamer to become aware that he is dreaming (Muzur, 2002).  In his study, Stumbrys attempted to manipulate activation of the DLPFC by providing transcranial direct current stimulation (tDCS) to the area.  Over the course of this three-night analysis, 19 participants received either 10 minutes of tDCS or mock stimulation during each REM period.  Stumbrys and his colleagues found that the group receiving actual tDCS reported increased lucidity in their dreams.  Though further research is indicated, this study provides support for the involvement of the DLPFC in lucid dreaming.

The ultimate hope of any researcher is that his findings can be applied practically to benefit patients.  While lucid dreaming has historically been of interest in the psychological community, it is more recently becoming relevant as a potential treatment.  A pilot study in the Netherlands evaluated the effects of lucid dreaming treatment (LDT), a cognitive restructuring technique, on chronic nightmares in patients with post-traumatic stress disorder (Spoormaker, 2006). Patients in the treatment group were taught to trigger lucidity with certain exercises.  These exercises included intending to be in the recurrent situation prior to sleeping, consciously imagining the recurrent situation while conceiving that they were dreaming, and constructing a ‘triumphant ending’ to the nightmare (p. 391).  Participants who received even a single 2-hour session of LPT reported a significant decrease in nightmares.  Overall sleep quality and PTSD symptom levels, unfortunately, remained stable for all groups.  Nevertheless, nightmares can be a cause of considerable distress for patients.  The utility of lucid dreaming in decreasing the incidence of recurring nightmares in patients with PTSD is suggestive of further research.

The benefits of lucid dreaming to the general population have also been well documented.  Similar to meditation, lucid dreaming is thought to make the individual more aware and more “present” (Brogaard, 2012).  It has been reported to increase spirituality, enhance self-realization, and even cure writer’s block! Beverly D’Urso, an avid lucid dreamer, reports that it was not until she overcame in-dream paralysis and reached her computer that she was able to complete her Ph.D. dissertation in reality.  The potential for problem solving and self improvement through lucid dreaming are some of the potentially endless possibilities.

Due to its reliance on patient self-report, lucid dreaming was once thought to be somewhat of a myth.  Though the exact level of consciousness experienced while lucid dreaming is debatable, its potential as a basis for treatment is undeniable.  At the very least, lucid dreaming is a thought-provoking phenomenon that warrants further studies.

 

References

Bootzen, R.R., Kihlstrom, J.F. & Schacter, D.L., (1990). Sleep and Cognition. Washington, D.C.: American Psychological Association (pp. 109-126).

Brogaard, B. (2012). Lucid Dreaming and Self-Realization. Psychology Today.

Faust, O., Kannathal, N., Chua, T., & Laxminarayan, S. (2005). Non-linear analysis of EEG signals at various sleep stages. Computer Methods and Programs in Biomedicine, 80(1), 37-45.

Higgins, E., George, M., (2013). The Neuroscience of Clinical Psychiatry (2nd ed.). Philadelphia, PA. Lippincott Williams & Wilkins. p. 174-187.

Hobson,  (2010). Lucid dreaming and the bimodality of consciousness. Advances in Consciousness Research, p. 155-165.

Hobson,  (2009). The neurobiology of consciousness: Lucid dreaming wakes up.. International journal of dream research, 2(2), p. 41-44.

Hughes, V. (2014, May 11). Seeking Roots of Consciousness, Scientists Make Dreamers Self-Aware. National Geographic.

LaBerge, S. (1991). Exploring the World of Lucid Dreaming. New York, NY: Ballantine Books.

LaBerge, S. (2014). Lucid dreaming: Paradoxes of dreaming consciousness.. Varieties of anomalous experience: Examining the scientific evidence (2nd ed.). (pp. 145-173).

Mental Health Daily (2014). 5 Types Of Brain Waves Frequencies: Gamma, Beta, Alpha, Theta, Delta. http://mentalhealthdaily.com/2014/04/15/5-types-of-brain-waves-frequencies-gamma-beta-alpha-theta-delta/

Muzur A, Pace-Schott,  E. F.; Allan Hobson (2002). “The prefrontal cortex in sleep”. Trends Cogn Sci. 1;2(11) (11): p. 475–481.

Ogilvie, R., Hunt, H., Kushniruk, A. & Newman, J. (1983). Lucid dreams and the arousal continuum. Sleep Research, 12, 182.

Spoormaker, V., I, van den Bout J. (2006). Lucid Dreaming Treatment for Nightmares: A Pilot Study. Psychotherapy and Psychosomatics; 75: p. 389-394.

Stumbrys, T. (2013-12). Testing the involvement of the prefrontal cortex in lucid dreaming: A tDCS study. Consciousness and cognition, 22(4), 1214-1222.doi:10.1016/j.concog.2013.08.005

 

 

Club Drugs off the Dance Floor: MDMA-Induced Psychotherapy for Posttraumatic Stress Disorder

Since the early 1980s, 3,4-methylenedioxymethamphetamine (MDMA), otherwise known as ecstasy and amongst recreational users as “molly”, short for “molecular”, has been increasingly associated with rave culture and is one of the most commonly used drugs worldwide. MDMA is an amphetamine and a potent psychostimulant that was first synthesized in the early 1900s by the pharmaceutical company Merck. It was rediscovered in the 1970s and was briefly used in controlled psychotherapy sessions, prior to 1985, when the Food and Drug Administration scheduled MDMA as a drug of abuse making it illegal to possess the drug in the United States. Typical effects of consuming MDMA are increased empathy and affiliation, increased intimacy, decreased anxiety, euphoria, and generally a positive cognitive state.  Many of these subjective effects are due to the rapid release of the neurotransmitter, serotonin, and activation of serotonin receptors (Oehan, Traber, Widmer, & Schnyder, 2013).

Open-label clinical trials of MDMA-augmented psychotherapy, in other words taking MDMA prior to beginning a therapy session, are being explored for the treatment of Posttraumatic Stress Disorder (PTSD), an anxiety disorder characterized by re-experiencing trauma while simultaneously avoiding triggers and excessive arousal related to the trauma. PTSD is a common problem in medical and psychiatric practice in the United States, with roughly 8% of Americans in the general population presenting with symptomology, and a prevalent and costly public health issue worldwide (Oehan et al., 2013). In specific populations, like soldiers returning from combat or those who are victims of rape, the prevalence rate is much higher. Unfortunately, PTSD is an anxiety disorder that oftentimes can be treatment resistant. The current thinking about the psychopathology of PTSD is that there are exaggerated and uncontrolled responses by the amygdala, an area of the brain associated with emotional processing and reactions, to trauma-specific cues or triggers. At the same time there is an inhibition of the amygdala by the ventromedial prefrontal cortex, a part of the brain’s frontal cortex thought to be responsible for the processing of risk and fear, inhibiting emotional responses, and decision-making, the orbitofrontal cortex, another part of the frontal cortex involved in decision-making, and the hippocampus, part of the brain associated with consolidation of information into memories (Oehan et al., 2013).  Thus, MDMA-assisted psychotherapy is a novel approach that employs the drug as a catalyst for the psychotherapy itself in order to reduce some of these neurobiological effects of re-experiencing adverse events.

Before proceeding further, it is important to note here the difference between controlled, clinical use of MDMA and illicit use of MDMA or ecstasy, oftentimes with unknown purity and dosage.  In a clinical setting the drug is not laced with any other substance, in essence it is pure, and the dosage is precise. A typical clinical dose of MDMA is 1.25mg and the effects last, on average, three to six hours (Johansen & Krebs, 2009). When MDMA is used clinically, patients are monitored by trained clinicians in a safe, therapeutic environment while the drug is measurable in their system.  Another important thing to note is that MDMA is often inaccurately lumped together with psychedelic drugs like lysergic acid diethylamide (LSD) or psilocybin, but MDMA has a different mechanism of action and doesn’t cause users to hallucinate (Kupferschmidt, 2014). As previously mentioned, MDMA activates brain receptors for serotonin, along with dopamine, and norepinephrine, while also inducing release of serotonin from nerve endings. Rather than hallucinating, MDMA causes widespread physiological and psychological euphoria (Kupferschmidt, 2014).

The positive cognitive state produced by MDMA in turn reduces reported levels of fear. In relating this to PTSD, MDMA could possibly facilitate the processing of trauma in the amygdala and subsequently better encode information in the hippocampus as positive emotional experiences, rather than the negative ones often associated with PTSD (Oehan et. al, 2013). MDMA also robustly increases oxytocin release. Oxytocin is a hormone produced by the hypothalamus and stored and released by the posterior pituitary gland. This increased hormonal release yields remarkable prosocial behavior or actions that benefit others, like empathy (Dumont, Sweep, van der Steen, Hermsen, Donders, Touw, van Gerven, Buitelaar, & Verkes, 2009). Oxytocin has also been shown to assist in encoding positive social memories by the hippocampus. Thus, the MDMA-induced release of oxytocin during controlled psychotherapy sessions could strengthen the relationship between the therapist and the patient. It also may strengthen feelings of trust between patient and provider in their therapeutic alliance with one another. These feelings of empathy and trust can help facilitate beneficial exposure of past traumatic events by the patient to their provider (Johansen et al., 2009). This is important for people with PTSD, for often they may feel quite vulnerable and may be unwilling to open up to their providers about their trauma experiences and the anxieties associated with these memories.

A study published in 2014 in the journal of Biological Psychiatry, looked via magnetic functional imaging (fMRI) at the brains of 25 healthy volunteers — once after taking MDMA and once after taking a placebo. While inside of the MRI scanner, the study participants were asked to recall a good and bad memory from their lives. The participants typically rated their favorite memories as more vivid, emotionally intense, and positive after taking the MDMA compared with the placebo. Important to note was that they also rated their bad memories less negatively after taking the MDMA. The subjective findings were correlated objectively with a decrease in activity, shown by the fMRI scans, in the limbic system, which includes the amygdala. The connection between the medial prefrontal cortex and the amygdala was reduced under the influence of MDMA. This reduced communication and the decrease in activity is a positive finding, for it is the opposite of what is seen in patients who suffer from anxiety disorders, like PTSD, as mentioned previously.  It seems that controlled amounts of MDMA decrease the potential detrimental impacts that painful memories can invoke. This supports the aforementioned idea that MDMA could help patients with PTSD revisit their trauma in therapy without the overwhelming cascade of negative emotions and arousal. The limitation of this study, of course, was that it was conducted in healthy individuals and with these positive significant results, there needs to be future studies done looking at the brain images of people with PTSD under the influence of controlled- MDMA administration (Carhart-Harris, Murphy, Leech, Erritzoe, Wall, Ferguson, Williams, Roseman, Brugger, Meer, Tanner, Tyacke, Wolff, Sethi, Bloomfield, Williams, Bolstridge, Stewart, Morgan, Newbould, Feilding, Curran, & Nutt, 2014).

For all anxiety disorders, including PTSD, it is important in treatment to reduce the avoidance of negative emotions associated with anxiety triggers. In a therapeutic setting, MDMA has the potential to activate emotions associated with anxiety and/or trauma, while still allowing the patient to feel safe and in control. According to Mithoefer, Wagner, Mitoefer, Jerome, & Doblin (2011), their study looking at MDMA-induced psychotherapy with female sexual assault victims showed that after two months, 10 out of 12 of the women who had received MDMA along with psychotherapy no longer met the diagnostic criteria for PTSD, compared with two out of eight patients who had received placebo and psychotherapy. The Clinician Administered PTSD Scale (CAPS) measured the subjects’ symptoms (Bright & Doblin, 2011). An important thing to note was that there were no serious adverse events associated with this study, which is a criticism studies involving MDMA often receive. While there have been many adverse effects of recreational use of MDMA reported in the media recently, the controlled use of MDMA in a clinical setting offers great potential in treating people with PTSD by offering them a safe environment to be exposed to their past traumatic experiences while nurturing a trusting and empathic bond with their care provider in therapy.  In order to assess whether the benefits of controlled treatment with MDMA outweigh the risks and before truly calling this type of psychopathological and therapeutic research controversial, future studies need to be done in order to more widely explore the effects that MDMA can have in psychotherapy sessions for those with anxiety disorders.

 

References

Bright, S. J. & Doblin, R. (2011). From disco-biscuit to prescription medicine in just 10 years? MDMA-assisted psychotherapy for post-traumatic stress disorder (PTSD). Australasian Professional Society on Alcohol and other Drugs Conference, 30(S1), 15.

Carhart-Harris, R. L., Murphy, K., Leech, R., Erritzoe, D., Wall, M. B., Ferguson, B., . . . Nutt, D. J. The Effects of Acutely Administered 3,4-Methylenedioxymethamphetamine on Spontaneous Brain Function in Healthy Volunteers Measured with Arterial Spin Labeling and Blood Oxygen Level–Dependent Resting State Functional Connectivity. Biological Psychiatry(0). doi: http://dx.doi.org/10.1016/j.biopsych.2013.12.015

Dumont, G. J., Sweep, F. C., van der Steen, R., Hermsen, R., Donders, A. R., Touw, D. J., . . . Verkes, R. J. (2009). Increased oxytocin concentrations and prosocial feelings in humans after ecstasy (3,4-methylenedioxymethamphetamine) administration. Social Neuroscience, 4(4), 359-366. doi: 10.1080/17470910802649470

Johansen, P. O. & Krebs, T.S. (2013). How could MDMS (ecstasy) help anxiety disorders? A neurobiological rationale. Journal of Psychopharmacology, 23(4), 389-391. doi: 10.1177/0269881109102787

Kupferschmidt, K. (2014). Can ecstast treat the agony of PTSD? Science, 345(6192), 22-23. doi: 10.1126/science.345.6192.22

Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T., Jerome, L., & Doblin, R. (2011). The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Journal of Psychopharmacology, 25(4), 439-452. doi: 10.1177/0269881110378371

Oehen, P., Traber, R., Widmer, V., & Schnyder, U. (2012). A randomized, controlled pilot study of MDMA (±3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD). Journal of Psychopharmacology, 27(40), 40-52. doi: 10.1177/0269881112464827

Obsessive Compulsive: A Disorder of Movement?

Obsessive Compulsive: A Disorder of Movement?

Obsessive Compulsive Disorder (OCD) has long been conceptualized as an anxiety disorder and accordingly, was classified as one in the DSM IV.  Recent neuropsychiatric research has increasingly separated the disorder from other anxiety disorders such as Generalized Anxiety Disorder (GAD), Separation Anxiety Disorder (SAD), Panic Disorder, (PD), and Post-Traumatic Street Disorder (PTSD) in terms of pathophysiology.  This new understanding of OCD is especially apparent in the DSM V as the disorder is now listed with a group of related disorders and points to more of an “OCD spectrum” (Pallanti, S., Grassi, G. & Cantisani, A., 2014).  The increased biological differentiation may have implications with regard to treatment at both behavioral and psychopharmacological levels. This post aims to examine the pathophysiology of anxiety, of OCD, and of the relationship OCD may have to disorders outside of the anxiety realm.

Literature has long indicated that the amygdala plays a role in the fear response, memory of the fear, and in turn, in the development of anxiety (Davis, M., 1992).  More recent findings suggest that a larger circuit is involved in learned fear and includes the ventromedial prefrontal cortex, hippocampus, thalamus, and the amygdala (Cha, J., Greenberg, T., Carlson, J., DeDora, D., Hajcak, G., 2014).  It is thought to be the impairment of this circuit that results in the elevated fear associated with an anxiety disorder (Cha, J. et al, 2014).

In addition to brain structures, the altered transmission of specific neurotransmitters are involved in the development of an anxiety disorder.  Specifically, an acute decrease in GABA , the majority inhibitory neurotransmitter of the brain, results in acute anxiety symptoms while a defect in the GABA system leads to ongoing fear and anxiety (Charney, D., Buxbaum, J., Sklar, P., & Nestler, E. 2013).  This is widely received as alcohol, benzodiazepines, and barbituates all bind to the receptor and are known to have a calming effect (Higgins, E., & George, M. 2013).  While giving a benzodiazepine to someone with acute anxiety is known to be effective, it anecdotally seems unlikely that giving one to someone with OCD would be of much use.  With regard to neurotransmitters, OCD is understood to result from a problem with serotonin and dopamine (Vliet, I., Well, E., Bruggeman, R., Campo, J.,Hijman, R., 2013).

So why has OCD been classified as an anxiety disorder? The understanding is that the compulsions aim to relieve the anxiety caused by the obsessions (Vliet, I. et al, 2013).  However, there appears to be a link between OCD and many non-anxiety disorders including movement disorders such as Parkinson’s disease and tic Disorders as well as links with epilepsy and streptococcal infections.

While the literature on the coexistence of Parkinson’s Disease and either Obsessive Compulsive Disorder or Obsessive Compulsive Personality Disorder is varied, it has been a topic of research interest for good reason.  Parkinson’s Disease involves impairment of the fronto-basal ganglia circuitry; the same circuit now believed to be involved in the pathophysiology of OCD (Nicoletti. A., Luca, A., Raciti, L., Contrafatto, D., Bruno, E., 2013).  This link between OCD and altered movement is also seen with childhood tic disorders; comorbidities of childhood tic disorders include obsessive-compulsive symptoms in as many as 30-50 percent of tic patients (Martino, D. & Mink J., 2013).  There do appear to be differences in treatment responsiveness when comparing tic OCD and non-tic OCD with the non-tic type responding more to SSRI’s and the tic-related type responding better to antipsychotic medications (Martino, D. & Mink J., 2013).  This might suggest a relationship between the antipsychotic antagonization of dopamine and the role of dopamine in movement disorders.

Literature also points to a correlation between OCD and epilepsy, especially of the temporal lobe (Kaplan, P., 2011) with almost a quarter of patients with temporal lobe epilepsy displaying symptoms of OCD (Kaplan, P., 2011).  It is thought to stem from impairment of the frontal-thalamic-pallidal-striatal-anterior cingulate-frontal circuits (Kaplan, P., 2011).  Further connecting OCD with movement disorders is its possible link with Group A Beta Hemolytic Streptococcal (GABHS) infection.  The term PANDAS, or Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infection, refers to the abrupt onset of symptoms consistent with OCD, Tourette’s Syndrome, or a Tic Disorder following a streptococcal infection (Leslie, D., Kozma, L., Martin, A., Landeros, A., Katsovich, L., 2008).  Whether this is secondary to an immune response or to more generalized stress, remains unknown (Leslie, D. et al, 2008).  Whatever the pathophysiological cause may be, it appears to exacerbate symptoms of several movement disorders and among them, OCD.

This shift away from conceptualizing OCD as primarily a disorder of anxiety has treatment implications ranging from therapy and medication to psychosurgery.  Neurosurgery (anterior capsulotomy) has decreased symptoms in patients with treatment resistant OCD; however, the invasive and irreversible nature of the procedure limits it use (Abelson, J., Curtis, G., Sagher, O., Albucher, R., Harrigan, M., 2005) and I would imagine, ethically, also has ramifications.  Accordingly, an alternative procedure is being explored and has been deemed effective by multiple studies.

Currently the evidence-based treatment for OCD is cognitive behavioral therapy, pharmacology or both (Ooms, P. Mantione, M., Figee, M., Schuurman, R., Munckhof, P., 2013). Approximately 10% of patients having received these treatments are considered treatment resistant and for these individuals deep brain stimulation (the implantation of electrodes in specific brain areas) is recognized as an option (Ooms, P. et al, 2013).  In a study examining quality of life following DBS for treatment-refractory OCD, quality of life improved across physical, psychological, and environmental spears. However there was no significant improvement in perceived social function (Ooms, P. et al, 2013).  In a study of DBS using hardware initially developed for movement disorders, leads were bilaterally implanted in four patients and two patients showed significant symptom improvement (Abelson, J. et al, 2005).   In a different study of four patients having received DBS, one of four showed significant improvement with two others showing mild improvement (Vliet, I. et al, 2013).

DBS targets the nucleus accumbens, an area helpful in the relay of information between the amygdala, basal ganglia, mesolymbic dopaminergic areas, mediodorsal thalamus, and prefrontal cortex (Sturm, V., Koulousakis, A., Herholz, T., Klein, J. & Klosterkotter. J., 2003).  Blocking information flow within the nucleus accumbens via deep brain stimulation showed symptom improvement in both patients with OCD as well as other anxiety disorders (Sturm, V. et al, 2003).

While based on the aforementioned pathophysiology of anxiety disorders, it seems likely that blocking information to the amygdala would decrease anxiety, it is notable that by blocking the nucleus accumbens, information to the basal ganglia is also affected.  The basal ganglia is an area affected in movement disorders (Higgins, E., & George, M., 2013) and further investigation is warranted with regard to its role in OCD symptom improvement.

 References

Abelson, J., Curtis, G., Sagher, O., Albucher, R., Harrigan, M., Taylor, S., Martis, B. & Giordani, B. (2005).  Deep Brain Stimulation for Refractory Obsessive-Compulsive Disorder.  Biol Psychiatry, 57, 510-516.  Retrieved from www.elsevier.com/locate.biopsych

Cha, J., Greenberg, T., Carlson, J., DeDora, D., Hajcak, G., & Mujica-Parodi, L. (2014).  Circuit-Wide Structural and Functional Measures Predict Ventromedial Prefrontal Coretx Fear Generalization:  Implications for Generalized Anxiety Disorder.  The Journal of Neuroscience.  34(11):4043-4053.

Charney, D., Buxbaum, J., Sklar, P., & Nestler, E. (2013).    Differential Roles of GABA Receptors in Anxiety.  In Neurobiology of Mental Illness (4th ed.). (pp567-579. New York, NY:  Oxford Press; US.

Davis, M. (1992).  The Role of the Amygdala in Fear and Anxiety.  Annual Review Neuroscience.  15:353-75.  Doi:0147-006X/92/0301-0353.

Kaplan, P. (2011). Epilepsy & Behavior.  Epilepsy & Behavior.  22(3):428-32.

Higgins, E., & George, M. (2013).  Anxiety. In The Neuroscience of Clinical Psychiatry:  The Pathophysiology of Behavior and Mental Illness (2nd ed).(pp.263-274).  Philadelphia:  Lippincott Williams & Wilkins.

Leslie, D., Kozma, L., Martin, A., Landeros, A., Katsovich, L., King, R.& Leckman, J. (2008).  Neuropsychiatric Disorders Associated with Streptococcal Infection:  A Case-Control Study Among Privately Insured Children.  J Am Child Adolesc Psychiatry. 47(10):1166-1172.  doi: 10.1097/CHI.0b013e3181825a3d.

Martino, D. & Mink J. (2013).  Tic Disorders.  Continuum Journal/American Academy of Neurology 19(5):1287-1311. doi: 10.1212/01.CON.0000436157.31662.af.  Retrieved from www.continuumjournal.com

Nicoletti. A., Luca, A., Raciti, L., Contrafatto, D., Bruno, E., Diblio, V., Sciacca, G., Mostile, G., Petralia, A., & Zappia, M. (2013).  PLOS One. 8(1): e54822, doi: 10.1371/journal.pone.0054822.

Ooms, P. Mantione, M., Figee, M., Schuurman, R., Munckhof, P. & Denys. D. (2013).  Deep Brain Stimulation for Obsessive-Compulsive Disorders:  Long-Term Analysis of Quality of Life.  J. Neurol Neurosurg Psychiatry.  Published Online First:  05/25/2013; 0:1-6. Doi: 10.1136/jnnp-2012-302550.

Pallanti, S., Grassi, G. & Cantisani, A. (2014).  Emerging Drugs to Treat Obsessive Compulsive Disorder.  Expert Opinion on Emerging Drugs. 19(1):67-77. doi: 10.1517/14728214.2014.875157.

Sturm, V., Koulousakis, A., Herholz, T., Klein, J. & Klosterkotter. J. (2003).  The Nucleus Accumbens:  A Target for Deep-Brain Stimulation in Obsessive-Compulsive and Anxiety Disorders.  J Cem Neuroanat. 26(4):293-9.

Vliet, I., Well, E., Bruggeman, R., Campo, J.,Hijman, R., Megan H., Balkom, A., & Rijen, P. (2013).  An Evaluation of Irreversible Psychosurgical Treatment of Patients with Obsessive-Compulsive Disorder in the Netherlands, 2001-2008.  Journal of Nervous & Mental Disease.  2013(3):226-228. Doi: 10.1097/NMD.0b013e3182848b15.

Chocolate and Memory

 

 

Go Ahead. Grab that third…fourth…fifth piece of Halloween chocolate.

It’s good for your memory!

chocoFor years, people have been trying to find ways to improve their memory power, whether it be through brain games, aerobic exercise,, or consuming certain natural supplements. Well, what if one of the most delicious, decadent sweets out there could actually heighten the power of our memory as we age? According to a recent experimental study conducted at Columbia University (Brickman et al.,2014), chocolate, specifically dark cocoa, can improve the functioning of one’s memory by sharpening specific brain regions responsible for memory that tend to weaken as we age. The research was led by Dr. Small, Professor of Neurology and Director of the Alzheimer’s Disease Research Center at the CUMC Taub Institute, who has long been studying the effects of various compounds in foods and exercise on memory (Belluck, 2014). In this current study, “Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults,” Small was able to support a strong connection between high levels of flavanols, an antioxidant found in high concentrations in cacao, and higher levels of memory performance (Brickman et al., 2014). The flavanol of specific interest is epicatechin.

The study looked at 50-69 year old subjects who presented with no signs of cognitive disease. Subjects were split into two groups, the high flavanol group and the low flavanol group. The high flavanol group consumed 900 mg of flavanols with at least 138mg of that being epicatechin, which again is found in high concentration in dark cacao. The low flavanol group could not consume more than 10mg of flavanols with less than 2mg of epicatechin. Memory tests and brain imaging were done at baseline and at the completion of the three month trial (Brickman et al., ). At the end of the experiment, the high flavanol group had a 25% memory performance increase from their baseline tests, compared to the low flavanol group, whose scores stayed the same (Eck, 2014). “If a participant had the memory of a typical 60-year-old at the beginning of the study, after three months that person on average had the memory of a typical 30- or 40-year-old,” said Dr. Small (Columbia University Medical Center, 2014).

The high flavanol group also showed an increase in blood volume circulation, in the dentate gyrus of the hippocampus. However, there was no difference from baseline in the activation of the entorhinal cortex of the hippocampus. Now, what exactly are these brain structures, and what does it mean that one had increased blood volume and the other did not after the three month period of high flavanol intake? Well, simply put, it means that the flavanol epicatechin may halt age related loss of recognition memory (the type of memory associated with the dentate gyrus), but will not prevent Alzheimer’s related memory loss (the type of memory associated with impairments of the entorhinal cortex) (Eck, 2014).

Before we go any further, let’s address some of the science and anatomy behind all of this. The entorhinal cortex and the dentate gyrus are two anatomical components of the hippocampus, the brain’s center for memory. The entorhinal cortex serves as the major interface between the hippocampus and the neocortex (area that controls higher functions), as it has several projection areas such as the parietal, temporal, and prefrontal cortex (Witter, 2011). The entorhinal cortex serves as the major substrate controlling various declarative memories. Even those memories that come racing in when one sees or smells something; that is the entorhinal cortex at work too (projections to the occipital and olfactory cortices). The entorhinal cortex is directly linked to Alzheimer’s disease and other cognitive impairments. Decreased volume of the entorhinal cortex is considered a reliable factor to identify those at risk for Alzheimer’s (Witter, 2011). Even mild atrophy of the entorhinal cortex will produce memory loss. An ill working entorhinal cortex means an ill working hippocampus.

The dentate gyrus also has a significant role in memory, especially in episodic memories and spatial memories. Its role in memory is thought to be directly linked to its ability for neurogenesis (creation of new neurons) (Aimone, 2007); it is one of the few places where neurogenesis occurs in the adult human brain. This is one of the primary reasons that the dentate gyrus plays a large role in the formation of these new memories, especially spatial ones. In one rat study, 90% of their dentate gyrus was destroyed, and the rats were no longer able to maneuver a maze to which they were previously exposed (Aimone, 2007). Additionally, the dentate gyrus serves as the pre-processing unit between the entorhinal cortex and the hippocampus (Amaral, Scharfman, Lavenex, 2007). It receives information from the entorhinal cortex, organizes the information into distinct categories, and then sends it off for proper storage in the hippocampus. The dentate gyrus is one of the last stops for the entorhinal cortex, and it is this endpoint that suggests the dentate gyrus is the first step in retrieval of those memories.

So, what about those flavanoids? Flavanoids, which have been shown to have direct effects on the hippocampus, are secondary metabolites of various plants. There are several types of them, with epicatechin being of greatest focus in this experimental design since its effects are most specific to the dentate gyrus.  Flavanoids work in the brain by increasing blood flow to the hippocampus, and wherever there are areas of increased blood volume, new cells can easily proliferate-neurogenesis!(Spencer, 2008). Flavanoids also work in the hippocampus by increasing the density of the dendritic spines of the axons, which increases the strength between synapses and produces the best conditions for learning and memory.

Epicatechin specifically works in the dentate gyrus by increasing blood circulation (Belluck, 2014), increasing neuronal spine density, increasing the rate of neurogenesis, and increasing the up-regulation of genes associated with learning, and as result, increasing retention of relational/spatial memories (Spencer, 2008).  Lastly, flavanoids serve as a protective factor to hippocampus neurons, as they may shield neurons from oxidative damage and neuroinflammation. Spencer (2008) discussed an earlier study that also looked at the effects of epicatechin on cognitive performance. They studied 1,640 subjects, over the age of 65, who were free from dementia over the course of ten years. Researchers found that high levels of epicatechin were associated with significantly better cognitive performance with a better evolution of performance over time (analyzed their performance four times over the ten years).

Now, it is safe to say most of us consume flavanoids almost every day! They are found in many foods like grapes, tea, blueberries, raspberries, onions, parsley, broccoli, leeks, citrus, beans, apples, wine, and spices, with tea and apples having very high epicatechin levels (Spencer 2008). Additionally, there are many other foods out there that have claimed to improve memory. Blackberries and cherries are  high in anthocyannis, which can enhance memory function (Moore 2013). Omega-3 fatty acids and DHA improve memory health as well, and these are found in seafood, algae, and fatty fish. Walnuts have also been correlated with improvement in working memory. Taking this information and thinking back to the study, one would wonder if the subjects consumed any of these foods at a high intake that could have potentially improved their memory, in addition to the high epicatechin cacao shakes.

Ultimately, the data out there, including the results from the study, “Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults,” (Brickman et al., 2014) are pretty intriguing… but how does this translate to the common man? In order to consume the same amount of epicatechin as the high flavanol group, one would need to eat 300g of dark chocolate per day or 100g of baking chocolate or unsweetened cocoa per day (Belluck, 2014). So, scientists say the key problem here is that in order to ingest sufficient epicatechin that would lead to an increase in blood circulation, dendritic spine densities, neurogenesis, and synaptic communication all in the dentate gyrus to a level that would lead to improved memory function, one would need to eat about seven average-sized candy bars daily (Belluck, 2014, Eck, 2014, Brickman et al., 2014)… Problem? Hey, I see the glass half-full. Now, where is that Snicker’s bar…

References

Aimone, J.B. (2007). Adult neurogenosis. Scholarpedia, 2, 2100.      doi:10.4249/scholarpedia.2100

Amaral, D.G., Scharfman, H.E., & Lavenex, P. (2007). The dentate gyrus: Fundamental  neuroanatomical  organization (dentate gyrus for dummies). Department of Psychiatry    and Behavioral Science, 163, 3-22. doi: 10.1016/S0079-6123(07)63001-5

Belluck, P. (2014). To improve a memory, consider chocolate. NY Times. Retrieved from   http://www.nytimes.com/2014/10/27/us/a-bite-to-remember-chocolate-is-shown-to-aid       memory.html?partner=rss&emc=rss

Brickman, A.M., Khan, U.A., Provenzano, F.A., Yeung, L.K., Suzuki, W., Schreoter, H., …  Small, S.A. (2014). Enhancing dentate gyrus function with dietary flavanols improves  cognition in older adults. Nature Neuroscience. doi: 10.1038/nn.3850

Columbia University Medical Center. (2014). Dietary cocoa flavanols reverse age-related  memory decline in healthy older adults. ScienceDaily. Retrieved from  www.sciencedaily.com/releases/2014/10/141026195046.htm

Eck, A. (2014). Dark chocolate could improve memory by 25%, but you’d have to eat  seven bars a day. PBS Online. Retrieved from  http://www.pbs.org/wgbh/nova/next/body/seven-bars-dark-chocolate-improve-memory-  25/

Moore, M. (2013). Memory boosting foods. Academy of Nutrition and Dietetics. Retrieved  from http://www.eatright.org/Public/content.aspx?id=6442477741

Spencer, J.P. (2008). Food for thought: The role of dietary flavonoids in enhancing human  memory, learning, and neuro-cognitive performance. Proceedings of the Nutrition  Society, 67, 238-252. doi: 10.1017/S0029665108007088

Witter, M. (2011). Entorhinal cortex. Scholarpedia, 6,:4380. doi:  10.4249/scholarpedia.4380

HIV-Associated Cognitive Impairment

HIV-associated cognitive impairment

The human immunodeficiency virus (HIV) has long been known to cause significant neuropsychiatric symptoms as it progressively infects the central nervous system (CNS). Indeed, in 10-20% of patients,  neurologic disorders are the first manifestation of symptomatic disease (McGuire, 2003). As antiretroviral therapies have developed, and dramatically improved the management of HIV, the incidence of the more severe classes of HIV-associated cognitive impairment have declined (Daugherty-Brownrigg, 2013). However, few individuals infected with HIV are able to escape at least some degree of impairment (Valcour, Esmaeli & Wendelken, 2014). Research continues into the underlying pathophysiology of this process, and possible treatments to halt its progression.

Cognitive impairment resulting from HIV is divided into three main categories, ordered by increasing severity: asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD) (Valcour et.al., 2014). I will use the shorthand of HAD throughout this summary to reference the range of cognitive impairments attributable to HIV.

Because degree of cognitive impairment correlates with CD4+ count and viral load, measures of HIV infection in the body, the advent of more effective therapies have nearly eliminated the incidence of HAD (Childs, Selnes, Chen, Miller, Cohen & McArthur, 1999). Currently, only 2-3% of patients in developed countries experience this severe level of impairment (Valcour et.al., 2014). Unlike Alzheimer’s dementia, HIV-associated dementia is not generally progressive, but rather, waxes and wanes (Valcour et.al., 2014). Additionally, it can be mitigated with adjustments in pharmacological treatment.

Neurobiology

As is the case with many neurocognitive disorders, the underlying mechanisms of HAD are still largely unknown. There is a consensus, however, that the pathways can be largely traced to the action of macrophages, microglia, and astrocytes (Kaul, Garden & Lipton, 2001). HIV is believed to enter the brain in the early stages of infection, often before any obvious symptoms are observed (McArthur, Brew & Nath, 2005). This is because HIV specifically targets the nervous and lymphatic systems, which have cells expressing the CD4 receptor which HIV binds to (Kaul et.al, 2001).

Once contracted, the course of the HIV infection is insidious. Kaul, et.al, (2001) describe how the virus enters the brain stealthily, utilizing a “Trojan Horse” strategy, then initiates a devastating cascade of events that facilitates a cycle of further infiltration and deterioration. HIV is able to cross the blood-brain barrier (BBB) while inside of a monocyte it has infected (Kaul et.al, 2001). Crossing of the BBB by monocytes and macrophages is highly regulated (Kaul et.al, 2001).. However, once the infection is inside, all of this changes.

The BBB is maintained by the tight junction proteins which connect astrocytes and endothelial cells; this is what maintains the integrity of the barrier (Kaul et.al, 2001). While the barrier’s primary function is to protect the brain from intruders, it is also highly sensitive to intrusion and takes drastic measures to ensure its safety (Minagar, Shapshak, Fujimura, Ownby, Heyes, & Eisdorfer, 2002). Once the barrier has been breached, it allows more and more surveillance cells from the immune system to enter to fight whatever unwelcome visitors have entered.

HIV takes advantage of this mechanism. By causing parenchymal inflammation, including the accumulation of cytokines such as tumor necrosis factor (TNF), interleukin 1, and interleukin 6, HIV signals more leukocytes to its location (Minagar et.al., 2002). The permeability of the BBB is increased to allow the influx of immune system cells. This resulting flood enhances the inflammatory effect, contributing to neurotoxicity (Kaul et.al, 2001).

As the BBB naively invites immune system cells to cross its membrane, cells infected with HIV enter freely. The virus localizes in macrophages, microglia and astrocytes (Minagar et.al, 2002). Astroctyes, which are critical to maintaining the integrity of the BBB, are thus recruited to even further damage the brain’s protective barrier (Kaul et.al, 2001). By infecting the very cells that are rushing to aid the brain, HIV gains a foothold in the CNS.

HAD: Presentation

To understand how HAD presents, it is important to understand what regions of the brain are affected by HIV.  HIV infection of the brain is focused within the basal ganglia, deep white matter, and brainstem (McArthur et.al, 2005). Though HIV does not directly infect neurons, the sequence of inflammatory events that compromises the brain’s essential structure results in a marked loss of density of white matter, neuronal loss, and dendritic simplification (McArthur et.al, 2002).

As Higgins and George (2013) explain, the formation of dendritic spines, number of neurons and neuronal density are critical to memory formation. With HAD, there can be a decrease in brain density of up to 40% in frontal and temporal regions, and up to a startling 50-90% in the hippocampus, the critical center of memory encoding and consolidation (McArthur et.al, 2002). This is the underlying pathology of HIV-associated dementia.

Because of the regions affected, HAD manifests on three levels: motor, cognitive, and behavioral. Motor dysfunction can present as issues with gait, tremors, and loss of fine motor function. Cognitive impairments include mental slowing, forgetfulness, and impaired concentration. Finally, behavioral dysregulation includes depression, mania, emotional lability, withdrawal, avolition and personality changes. Control of speech, movement and memory are affected by the inflammatory damage to the basal ganglia and hippocampus (McArthur et.al, 2002).

Diagnosis and Treatment

Diagnosing HIV-related dementia can prove a difficult task. Since HAD is generally seen with advanced HIV disease, there are many other factors that may be the underlying cause of the cognitive symptoms. They may be side effects of medications, other psychiatric issues, or secondary cognitive impairments, related to opportunistic infections that strike the brain when CD4 counts are low (below 200 cells/mm3) (AIDS.gov, 2010).

Further complicating this task is the fact that many patients who are clearly showing signs of dementia often have no detectable virus in the CSF (McGuire, 2003). This does not, however, preclude a high viral load within the brain itself (McGuire, 2003). Rather, it demonstrates the ineffectiveness of CSF as a measure. However, there are few other ways to try to gain a picture of how the infection is progressing.

Though antiretroviral agents (ARV) remain the mainstay of treatment, there are limited in their efficacy to fight CNS infection as they are unable to cross the BBB (McGuire, 2003). However, as Dawn McGuire, MD, (2003) explains, ARVs do appear to attenuate the neurotoxicity of circulating monocytes and macrophages that are infected. While they would normally cause major neuronal death, with ARV treatment, they appear to “cripple” neurons rather than kill them outright (McGuire, 2003). Thus, antiretroviral treatment has slowed the progression of HAD compared to the devastating, rapid disease frequently seen in the early years of the HIV epidemic (McGuire, 2003).

Despite these advances, there is still major work to be done. Though much of the neuropsychiatric suffering caused by HIV in earlier years has been mitigated in developed countries, the vast majority of those infected with HIV are concentrated in regions where access to these drugs is still sporadic at best. Globally, only 23% of children in need of antiretroviral treatment are receiving it, and 37% of adults (WHO, 2014). Though increased research into the underlying pathophysiology of HAD is important, the higher priority should be increasing access to ARVs for all patients in need (WHO, 2014).

References

AIDS.gov. (2010). AIDS/HIV basics: Dementia. Retrieved 11/1, 2014, from http://www.aids.gov/hiv-aids-basics/staying-healthy-with-hiv-aids/potential-related-health-problems/dementia/

Childs, E. A., Lyles, R. H., Selnes, O. A., Chen, B., Miller, E. N., Cohen, B. A., … & McArthur, J. C. (1999). Plasma viral load and CD4 lymphocytes predict HIV-associated dementia and sensory neuropathy. Neurology52(3), 607-607.

Daugherty-Brownrigg, B. (2013). HIV-Associated Dementia. In Mental Health Practitioner’s Guide to HIV/AIDS (pp. 245-246). Springer New York.

Higgins, E. S., George, M. S., (2013). The Neuroscience of Clinical Psychiatry (2nd ed.). Philadelphia, PA. Lippincott Williams & Wilkins.

Hult, B., Chana, G., Masliah, E., & Everall, I. (2008). Neurobiology of HIV. International Review of Psychiatry20(1), 3-13.

Kaul, M., Garden, G. A., & Lipton, S. A. (2001). Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature410(6831), 988-994.

McArthur, J. C., Brew, B. J., & Nath, A. (2005). Neurological complications of HIV infection. The Lancet Neurology4(9), 543-555.

McGuire, D. (2003). Neurologic manifestations of HIV. Retrieved 11/01, 2014, from http://hivinsite.ucsf.edu/InSite?page=kb-00&doc=kb-04-01-02

Minagar, A., Shapshak, P., Fujimura, R., Ownby, R., Heyes, M., & Eisdorfer, C. (2002). The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis. Journal of the neurological sciences202(1), 13-23.

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