For the Love of Curves: Depression, Suicidality, and (micro)Architecture

Competence in the field of psychiatry requires, at the very least, accepting the idea that understanding neural architecture plays a critical role in how providers interpret symptoms and, more importantly, how prescribers treat those symptoms. Unlike the field of architecture, however, with all of its applicable mathematical algorithms, psychiatry (despite extensive progress in the field) continues to be in a stage of psychopharmacological trial and error. In patients with depression, there have been many studies showing a decreased volumetric capacity in several regions of the brain. Of note, the hippocampus, pre-frontal cortex, cingulate gyrus, and cerebellum have all been found to be reduced in volume (Bijanki et al., 2014; van Tol, 2010). Additionally, post-mortem microscopic examinations show decreases in total cortical thickness as well as diminished size of individual neurons (Higgins & George, 2013). Several theories attempt to address and explain the pathology behind these neural changes, some more promising than others, while simultaneously providing novel ways in which providers can treat the observable signs and symptoms.

In order to understand and implement possible treatments, however, it is important to question what exactly happens at the cellular level. Researches have attempted to explain, with convincing data, the decreases in hippocampal volume in relation to the overactivity of the HPA axis. More specifically, elevated levels of cortisol have been implicated in the variations seen in hippocampal morphology (Wiedenmayer et al., 2006). One possible explanation seems to be that elevated levels of cortisol and an overactive HPA axis can be directly toxic to the brain, so much so that it can potentially disrupt normal neuronal growth, resulting in neurologic and psychiatric diseases (Schiavone et al., 2013).

While the hippocampus and the ventricles of the brain have historically been implicated in depression, a recent study investigated the implications that the changes in cortical structures would have on overall neural anatomy. Maller et al. (2014) investigated the prevalence of occipital lobe asymmetry within psychiatric populations: those with depression in comparison to healthy controls.. More specifically, the researchers wanted to investigate if the enlarged lateral ventricles seen in those with depression would result in a pattern of curvature, wherein one occipital lobe would wrap around the other, something the researchers termed “occipital bending” (Maller et al., 2014). Maller et al. (2014) suggest that “incomplete neural pruning may lead to the cranial space available for brain growth being restricted, or ventricular enlargement may exacerbate the natural occipital curvature patterns, subsequently causing the brain to become squashed and forced to ‘wrap’ around the other occipital lobe” . As is the case with any new study, the clinical implications remain unclear, but the data do provide a new way of looking at anatomical variation in those with major depressive disorder: the effects are not simply localized or seen on a cellular level, but can be observed at a macroscopic level.

At a microscopic level, the effects, or lack thereof, of oxygen have recently been implicated in the signs and symptoms of depression. More specifically, researchers are beginning to look deeply into the effects that hypoxia can have on the synthesis of serotonin. Katz (1982) was one of the first researchers to propose the possibility that hypoxia and symptoms of depression could be interrelated. He proposed that a decrease in biogenic amine synthesis, in other words the synthesis of serotonin, due to low oxygen levels could result in decreased appetite, libido, motivation, and changes in sleep patterns (Katz, 1982). Similarly, various researchers have implicated levels of oxygen and its relation to the suicide rates seen with COPD, asthma, and smokers (Goodwin, 2011; Goodwin et al., 2012; Li et al., 2012). Interestingly, researchers have also shown that the human body doesn’t simply use oxygen for energy, but that many enzymatic pathways in the brain require oxygen and those same pathways can be affected even by mild hypoxia (Vanderkooi et al., 1991). Based on research into suicide rates among those living in high altitudes (Kim et al., 2011; Haws et al., 2009), Young (2014) proposes the idea that because serotonin synthesis, when measured appropriately, is low in individuals with suicidal ideation as well as in those with previous suicide attempts and that because low serotonin levels are associated with lowered mood, impulsivity, and aggression, that perhaps we should be looking at the association between high altitudes (where oxygen levels are low) and depression/suicide rates. Similarly, a recent study by the University of Utah proposed that “a potential cause for depression at [high] altitude might be found in low levels of serotonin [because] hypoxia impairs an enzyme involved in synthesis of serotonin, likely resulting in lower levels of serotonin that could lead to depression” (Study Links Thin Air, Higher Altitudes to Depression in Female Rats, 2015). More importantly, if the decrease in brain serotonin synthesis associated with hypoxia does lead to depression in subsequent suicide and suicidal attempts, a clinically relevant issue that inevitably surfaces is treatment.

Symptoms of major depression, including suicidal behavior and suicidal attempts, are associated with impaired neuronal plasticity. Treatment options for depression have historically relied on the ability of antidepressants to promote neurogenesis, synaptogenesis, neuronal maturation, as well as increases in brain derived neurotrophic factor (BDNF). “BDNF belongs to the family of neurotrophins that are characterized by their ability to regulate diverse neuronal responses, including the type and number of afferent synapses” (Müller et al., 2000). Some studies have found that patients with major depressive disorder (MDD) who had attempted suicide had lower levels of serum BDNF while other studies have shown that plasma BDNF was significantly lower in suicidal compared to nonsuicidal MDD patients (Deveci et al., 2007; Kim et al., 2007). Several classes of antidepressants, MAOIs, SSRIs, TCAs, and SNRIs modulate the expression of BDNF by upregulating gene expression; the implication being that it may be the upregulation of BDNF that plays a critical role in the actions of antidepressant treatment (Duman & Monteggia, 2006). “BDNF levels can therefore be useful markers for clinical response or improvement of depressive symptoms, but they are not diagnostic markers of major depression” (Lee & Kim, 2010).

A relatively recent and important clinical finding has been the effectiveness of ketamine and its potential for treating depression and suicidal behavior. Historically, ketamine, a noncompetitive NMDA receptor antagonist that blocks glutamate, has been used for the induction and maintenance of general anesthesia. Recently, however, many studies have shown promising results in the treatment of depression and acute suicidality. In some patients with treatment-resistant major depressive disorder, ketamine was shown to rapidly reduce suicidal thinking (Price et al., 2014). After infusion of ketamine, suicidal ideation scores decreased significantly, as measured through various suicide subscales and rating instruments, within 40 minutes of administration; the decreases remained significant through four hours post-infusion (Diaz Granados et al., 2010). The implication here is that ketamine may be an antidepressant treatment option in emergency clinical settings, with special implications in acute situations of suicide.

Despite the promise that ketamine may have as an option for depressed patients at imminent risk of suicide, providers need to remain vigilant of its potential consequences. As with many treatments for depression, practitioners in the field of psychiatry are still not sure how those treatments work exactly or what consequences they may have in the future. Whatever the cause of depression or suicidal ideation may be and while these treatments may be restoring functional cognitive capacity, resolving conflict in micro-architecture, and restoring the appropriate curvature of the brain, the question always remains: what are the unintended consequences of implementing treatment longterm?

References

Bijanki, K. R., Hodis, B., Brumm, M. C., Harlynn, E. L., & McCormick, L. M. (2014). Hippocampal and Left Subcallosal Anterior Cingulate Atrophy in Psychotic Depression. PLoS ONE,9(10), e110770. doi: 10.1371/journal.pone.0110770

Diaz Granados, N., Ibrahim, L., Brutsche, N., Ameli, R., Henter, I. D., Luckenbaugh, D. A., …Zarate, C. A. (2010). Rapid Resolution of Suicidal Ideation after a Single Infusion of an NMDA Antagonist in Patients with Treatment-Resistant Major Depressive Disorder. The Journal of Clinical Psychiatry, 71(12), 1605–1611. doi: 10.4088/JCP.09m05327blu

Deveci, A., Aydemir, O., Taskin, O., Taneli, F., Esen-Danaci, A. (2007). Serum BDNF levels in suicide attempters related to psychosocial stressors: a comparative study with depression. Neuropsychobiology, 56, 93-97.

Duman, R. S., & Monteggia, L. M. (2006). A neurotrophic model for stress-related mood disorders. Biological Psychiatry, 59(12), 1116-1127. doi: 10.1016/j.biopsych.2006.02.013

Goodwin, R. D. (2011). Is COPD associated with suicide behavior? J Psychiatr Res, 45, 1269-71.

Goodwin, R. D., Demmer, R. T., Galea, S., et al. (2012). Asthma and suicide behaviors: results from the Third National Health and Nutrition Examination Survey (NHANES III). J Psychiatr Res, 46, 1002-7.

Haws, C. A., Gray, D. D., Yurgelun-Todd, D. A., et al. (2009). The possible effect of altitude on regional variation in suicide rates. Med Hypotheses, 73, 587-90.

Higgins, E., & George, M. (2013). The neuroscience of clinical psychiatry: The pathophysiology of behavior and mental illness (2nd ed.). Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins.

Katz, I. R. (1982). Is there a hypoxic affective syndrome? Psychosomatics, 23, 846-853.

Lee, B. H. & Kim, Y. K. (2010). The roles of BDNF in the pathophysiology of major depression and in antidepressant treatment. Psychiatry Investig, 7, 231-235. doi: 10.4306/pi.2010.7.4.231

Kim N, Mickelson JB, Brenner BE, et al. (2011). Altitude, gun ownership, rural areas, and suicide. Am J Psychiatry, 168, 49-54.

Kim, Y. K., Lee, H., P., Won, S. D., Park, E. Y., Lee, H. Y., Lee, B. H., et al. (2007). Low plasma BDNF is associated with suicidal behavior in depression. Prog Neuropsychopharmacol Biol Psychiatry, 31, 78-85.

Li D, Yang X, Ge Z, et al. (2012). Cigarette smoking and risk of completed suicide: a meta-analysis of prospective cohort studies. J Psychiatr Res, 46, 1257-1266.

Maller, J. J., Thomson, R. H. S., Rosenfeld, J. V., Anderson, R., Daskalakis, Z. J., Fitzgerald, P. B. (2014). Occipital bending in depression. Brain: A Journal of Neurology. 137(6), 1830-1837. doi: 10.1093/brain/awu072

Müller, M. B., Toschi, N., Kresse, A. E., Post, A., Keck, M. E. (2000) Long-term repetitive transcranial magnetic stimulation increases the expression of brainderived neurotrophic factor and cholecystokinin mRNA, but not neuropeptide tyrosine mRNA in specific areas of rat brain. Neuropsychopharmacology, 23, 205-215.

Price, R. B., Iosifescu, D. V., Murrough, J. W., Chang, L. C., Al Jurdi, R. K., Iqbal, S. Z., . . Mathew, S. J. (2014). Effects of ketamine on explicit and implicit suicidal cognition: A randomized controlled trial in treatment-resistant depression. Depression and Anxiety, 31(4), 335-343. doi:10.1002/da.22253

Schiavone, S., Jaquet, V., Trabace, L., & Krause, K.-H. (2013). Severe Life Stress and Oxidative Stress in the Brain: From Animal Models to Human Pathology. Antioxidants & Redox Signaling,18(12), 1475–1490. doi:10.1089/ars.2012.4720

Study Links Thin Air, Higher Altitudes to Depression in Female Rats. (2015). Retrieved October 30, 2015, from http://healthcare.utah.edu/publicaffairs/news/2015/03/03-25-15_KankekarRats.php

Wiedenmayer, C. P., Bansal, R., Anderson, G. M., Zhu, H., Amat, J., Whiteman, R., & Peterson, B. S. (2006). Cortisol Levels and Hippocampus Volumes in Healthy Preadolescent Children. Biological Psychiatry, 60(8), 856–861. doi: 10.1016/j.biopsych.2006.02.011

Van Tol, M. (2010). Regional brain volume in depression and anxiety disorders. Archives of General Psychiatry, 67(10), 1002-1011. doi:10.1001/archgenpsychiatry.2010.121

Vanderkooi JM, Erecinska M, Silver IA. (1991). Oxygen in mammalian tissue: methods of measurement and affinities of various reactions. Am J Physiol, 260, C1131-50.

Young, S. (2013). Elevated incidence of suicide in people living at altitude, smokers and patients with chronic obstructive pulmonary disease and asthma: Possible role of hypoxia causing decreased serotonin synthesis. Journal of Psychiatry & Neuroscience, 38(6), 423-426. doi: 10.1503/jpn.130002

Understanding the Anxious Mind: Neurotransmitters, Hormones, and Nutrition

Anxiety has been my companion for as long as I can remember. The outline of most of my milestones, a spectator at every exam, and a recipient of my awards. As most people become excited about the unexpected, I am unable to breathe. I find myself paralyzed, mistaking the moment for a heart attack, landing somewhere between mortal unease and full terror. Through the loss of control and fear of the unknown, my brain leads me to believe that something bad is going to happen!!

Anxiety disorders are the most common category of psychological disorders and account for about “4 million visits to doctor’s offices each year in the United States” (Campbell & Larzelere, 2014, p. 418). It remains an unpleasant emotional state experienced by all humans during the course of their lifetime. Though it is quite healthy to recognize feelings of tension, uncertainty, worry or fear periodically, higher levels than usual can interfere with activities of daily living. Anxiety Disorders such as PTSD, GAD, Panic disorders, and Specific Phobia’s bring about fears that metastasize until they become consuming and often debilitating. For many, excessive worry can cause physical symptoms such as “chest pain, headaches, muscle tension, difficulty swallowing, GI distress, trembling, irritability, hot flashes, insomnia, sweating and nausea”(Ebell, 2008, p. 501).

Uncontrolled anxiety begins with a trigger that initiates a survival response from the limbic system. As you encounter apparent danger, your brain chemistry, blood hormones and cellular metabolism are put into action. Neuroimaging studies of patients with anxiety disorders have revealed dysregulation in numerous frontal brain regions including the orbitofrontal and ventrolateral prefrontal cortex. Other factors affecting anxiety can include emotional, physical, hormonal and nutritional influences (Boes et al., 2011).

Early emotional experience such as childhood trauma involving the death of a parent, divorce, child or sexual abuse, constant criticism, and abandonment etc. can create a pattern of chronic anxiety from infancy to adulthood (Teicher & Samson, 2013). A 2012 study on Posttraumatic Stress Disorder (PTSD) proves that childhood trauma is consistently associated with a higher risk for suicide attempts in adulthood. In this study, 726 adult patients who had attempted suicide were assessed on lifetime clinical diagnoses and childhood trauma, evaluating dimensions with age at first suicide attempt, number of suicide attempts, violent attempts, and suicide intent (Grah, Mihanovic, Syrdlin, Pisk, & Restek, 2010, p.1433). Neuroimaging findings associated with these patients showed evidence of reduced hippocampal volume and amygdala hyperactivity. Consequently, these studies support the theory that maltreated individuals differ from others as a result of “epigenetic modifications and genetic polymorphisms that interact with experience to increase risk for psychopathology” (Huang et al., 2004, p.441).

Let’s talk gender! Sex differences in cognitive and emotional processing have implicated male and female differential activity in ventral anterior cingulate cortex, a region important in fear and emotional processing (Gold, Morey, & McCarthy, 2015). In studying Premenstrual Dysphoric Disorder (PMDD), the occurrence and severity of anxiety disorders have been correlated with fluctuations in female sex hormone levels. The hippocampus, hypothalamus, and the amygdala tend to be affected the most by the estrogen-progesterone surges and drops, influencing a woman’s mood, self-esteem, and how she connects to others. In women who suffer from PMDD, the GABA-A receptors increase, therefore decreasing  panic symptoms (Lai, 2014).

Furthermore, there is evidence to support the decline of volumetric white matter in the fronto-limbic regions such as the thalamus, brain stem, and cerebellum of patients during panic episodes (Konishi et al., 2014). A voxel-based morphometry study was conducted to evaluate differences in regional white matter volume between 40 patients with panic disorders (PD) and 40 healthy control subjects. In result, correlation analyses were performed between the regional white matter volumes and patients’ scores on the Panic Disorder Severity Scale (PDSS). Findings proved that individuals with PD demonstrated “significant volumetric reductions in widespread white matter regions including fronto-limbic, thalamo-cortical and cerebellar pathways” (Kim et al., 2015, p. 139). Additionally, there was a significant negative relationship between right orbitofrontal gyrus (OFG) white matter volume and the severity of the patients’ clinical symptoms, as assessed with the PDSS. In theory, structural white matter abnormalities in the right OFG has contributed to the social, personal, and occupational dysfunction typically experienced with anxiety disorders (Konishi et al., 2014).

What about nutrition? Caffeine affects brain chemistry by raising levels of dopamine. Studies suggest that sufficient amounts of coffee and other caffeinated beverages can bring on panic attack symptoms. The jitteriness you may feel from a shot of espresso comes from elevated dopamine levels. The neurotransmitter imbalances that cause these anxieties are related to those in children with ADHD and ADD which are both conditions also associated with high dopamine levels. It is imperative to recognize anxiety symptoms versus nutritional complications. What may look like ADD in some children may actually be related to severe anxiety as symptoms can be very similar (Childs et al., 2008).

Current pharmacological treatments for anxiety disorders that have shown to be effective include SSRI’s, SNRI’s, Benzodiazepines, and Tricyclic Antidepressant drug classes. First line medications such as Prozac, Celexa, and Zoloft target the serotonin system by blocking the reabsorption, or reuptake of serotonin by certain nerve cells in the brain. For that reason, more serotonin becomes available, therefore improving mood. The problem associated with the use of these drugs is that they take weeks to become effective. Within that time frame, patients become impatient with the lack of medication relief and symptoms often heighten (Denorvsek, Tavcar, & Sajovic, 2008).

Consequently, partial agonists at the 5HT1A receptor, such as Buspirone are now in clinical use as preferred anxiolytics. 5-HT1A receptor antagonists are reported to accelerate the therapeutic effects of antidepressant medications and produce complex effects on brain functions (Reinholds, Mandos, & Lohoff, 2011). A study of acute morphine withdrawal in rats found that co-administration of Buspirone and morphine “reduced synaptic ultra-structural changes in hippocampus leading to a reduction of anxiety and withdrawal symptoms” (Murphy, Segarra, Storch, & Goodman, 2008, p. 206). Several studies after have shown that the administration of Buspirone can also improve spatial learning and memory function. Besides pharmacological interventions, Cognitive Behavioral Therapy (CBT), Exposure therapy, Eye movement desensitization and reprocessing (EMDR), along with Life style modifications have been successful in treating anxiety (Murphy, Segarra, Storch, & Goodman, 2008).

Overall, understanding the pathophysiology of anxiety disorders, including the role of hormonal and genetic influences can lead to improved diagnostic and therapeutic outcomes.

References

Boes, A.D., Grafft, A.H, Joshi, C., Chuang, N.A, Nopoulos, P., & Anderson, S.W. (2011). Behavioral effects of congenital ventromedial prefrontal cortex malformation. BMC Neurology, 11, 151.

Campbell, J.S., Jr, & Larzelere, M.M. (2014). Behavioral interventions for office-based care: Stress and anxiety disorders. Fp Essentials, 418, 28-40.

Childs, E., Hohoff, C., Deckert, J., Xu, K., Badner, J., & de Wit, H. (2008). Association between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology, 33, 2791-2800.

Dernovsek, M.Z., Tavcar, R., & Sajovic, M. (2008). Observation of treatment of depression in primary care setting in first week – what happens in first week of treatment with antidepressants?. Psychiatria Danubina, 20, 227-230.

Ebell, M. H. (2008). Diagnosis of anxiety disorders in primary care. American Family Physician, 78, 501-502.

Gold, A. L., Morey, R. A., & McCarthy, G. (2015). Amygdala-prefrontal cortex functional connectivity during threat-induced anxiety and goal distraction. Biological Psychiatry, 77, 394-403. doi:10.1016/j.biopsych.2014.03.030 [doi]

Grah ,M., Mihanovic, M., Svrdlin, P., Pisk, S.V., & Restek-Petrovic, B. (2010). Serotonin and cortisol as suicidogenic factors in patients with PTSD. Collegium Antropologicum, 34, 1433-1439.

Huang, Y.Y., Battistuzzi, C., Oquendo, M.A., Harkavy-Friedman, J., Greenhill, L., Zalsman, G., Mann, J.J. (2004). Human 5-HT1A receptor C (-1019) G polymorphism and psychopathology. International Journal of Neuropsychopharmacology, 7, 441-451.

Kim, B., Oh, J., Kim, M.K., Lee, S., Tae, W.S., Kim, C.M., Lee, S.H. (2015). White matter alterations are associated with suicide attempt in patients with panic disorder. Journal of Affective Disorders, 175, 139-146.

Konishi, J., Asami,T., Hayano ,F., Yoshimi, A., Hayasaka, S., Fukushima, H., Hirayasu, Y. (2014). Multiple white matter volume reductions in patients with panic disorder: Relationships between orbitofrontal gyrus volume and symptom severity and social dysfunction. PLoS ONE [Electronic Resource], 9, e92862.

Lai, C. H. (2014). Hippocampal and subcortical alterations of first-episode, medication-naive major depressive disorder with panic disorder patients. Journal of Neuropsychiatry & Clinical Neurosciences, 26, 142-149.

Murphy,T.K, Segarra, A., Storch, E.A., & Goodman, W.K. (2008). SSRI adverse events: How to monitor and manage. International Review of Psychiatry, 20, 203-208.

Reinhold, J.A., Mandos, L.A., Rickels, K., & Lohoff ,F.W. (2011). Pharmacological treatment of generalized anxiety disorder. Expert Opinion on Pharmacotherapy, 12, 2457-2467.

Teicher, M.H., & Samson ,J.A. (2013). Childhood maltreatment and psychopathology: A case for ecophenotypic variants as clinically and neurobiologically distinct subtypes. American Journal of Psychiatry, 170, 1114-1133.

A Look at Anxiety: More than the Amygdala

I’m not a fan of horror movies, but with Halloween approaching, my roommates and I decided to treat ourselves to a night of spooky flicks. As we all curled up on the couch and began to watch “The Ring,” I increasingly felt what is the topic for my blog post this week: anxiety. As it turns out, fear and anxiety go hand in hand. Normally, sensory information is sent to the thalamus, where it is then relayed to cortical structures for processing. But when learned or hardwired fear-provoking stimuli are encountered, such as a spider, sensory information is instead rerouted to the amygdala, which in turn sends activating signals to the muscles, hypothalamus, and sympathetic nervous system, causing me to leap and spill my popcorn on my roommates (Higgins & George, 2013). Although the fight or flight system served our evolutionary predecessors well, abnormalities in this circuitry are often implicated in anxiety disorders.

The role of the amygdala must be understood in the context of the neural circuitry in which it is situated. For instance, it is connected within a larger network of subcortical and prefrontal regions, often involved in reward and emotion (Haber & Knutson, 2008). In particular, the amygdala connects to the orbitofrontal cortex (OFC), a structure that may relate to stable patterns of anxiety. In studying this neural relationship, researchers have hypothesized that some personality trait-like tendencies may protect against the development of pathological levels of anxiety.

In a 2015 study, Dolcos, Hu, Iordan, Moore, and Dolcos (2015) asked whether persistent positive expectations about the future, or optimism, might attenuate the relationship between the OFC and anxiety. They collected structural neuroimaging data, as well as baseline measures of optimism and anxiety, on 61 non-psychiatric subjects ages 18 to 34. Individual positive and negative affect traits were also assessed at baseline to determine if results were specific to anxiety, or negative affect broadly. A negative correlation was found between OFC volume and optimism. The relationship was also mediated by optimism, such that the greater the OFC volume, the more optimistic, and less anxious the subject was found to be at the group level. This research suggests that the size of the orbitofrontal cortex may be a protective factor within healthy individuals, perhaps related to tendencies towards optimism. Conversely, a smaller orbitofrontal cortex may contribute to a predisposition to the development of anxiety disorders.

Although the previous study examined both men and women, worldwide incidences of anxiety disorders (including generalized anxiety disorder, panic disorder, social anxiety disorder, agoraphobia and specific phobias) are higher in females (American Psychiatric Association, 2013). Specific neuroanatomical differences in the male and female brain have been considered in anxiety disorders, and research has indicated the OFC and the adjacent ventromedial prefrontal cortex (vmPFC) to be among these differences.

Wellborn et al. (2009) examined whether OFC volume mediated the relationship between emotion regulation and gender. For their study, 117 non-psychiatric men and women completed behavioral measures at baseline, examining emotion regulation, expression and experience in addition to brain imaging. Women were found to have increased ventromedial prefrontal cortex volume, right lateral OFC volume within the orbital cortex, and higher levels of anxiety overall. Interestingly, researchers also found that greater volumes of the ventromedial PFC were selectively associated with the use of reappraisal as an emotional regulation strategy. Could reappraisal related to ventromedial volume be protective for women specifically against anxiety disorders?

The convergence of findings by Dolcos et al. (2015) and Wellborn et al. (2009) lends credibility to the potential relationship between anxiety and orbital prefrontal volumes. It should be noted, however, that the orbital cortex is located adjacent to the sinus cavity, and is often susceptible to signal dropout and head motion artifacts during MRI. A recent paper by Reuter et al. (2014) demonstrates that head motion influences measurements of cortical volume and thickness, and trait levels of anxiety likely correlate with movement and unrest during MRI scans. To validate these findings, future cortical thickness studies should employ larger sample sizes and explicitly account for confounding variables like head motion.

Although differences in brain hardware are likely important for anxiety, measures of neuroanatomy alone do not reflect function of this system. Given the known role of the hypothalamic-pituitary-axis in physiological stress, hormones may also help to explain why women experience more anxiety than men, especially during times of hormone fluctuations such as puberty and menopause. In a series of experiments on rats and humans, Zeidan et al. (2011) investigated how estrogen affects how a fear response is unlearned. On day one of the experiment on rodents, a neutral stimulus was paired with a negative outcome (i.e., a foot shock). On day two, after the stimulus-shock association had been developed, the rats were each administered an alpha-estrogen receptor agonist, beta-estrogen receptor agonist, or sesame oil (control), and the formerly neutral tone was reintroduced continuously, without the shock, for unlearning to occur. On the final day of testing, the extent to which the stimulus-shock association was unlearned was measured by freezing behavior. Compared to the other groups, the rats that received the beta-estrogen receptor agonist became unconditioned to fear the stimulus the most. A similar process conducted with human female subjects showed that women with higher endogenous estradiol had greater fear extinction, which also reflected increased activity of the ventromedial PFC and amygdala.

In summary, areas of the orbitofrontal cortex may relate to anxiety, perhaps mediated by protective personality factors such as optimism and reappraisal. In addition, gender may help elucidate the mechanisms of the disorder, as men and women differ in brain size and hormone levels. Undoubtedly, a key piece of anxiety is an overgeneralized or accentuated fear or anxiety response to contexts and cues within the environment. Ideally, people adaptively disassemble fear provoking connections given time and repeated new experiences, which is also the goal of many therapies (e.g., desensitization therapy). Perhaps future treatments should emphasize optimism, anxiety reappraisal therapies (perhaps especially for women via cognitive behavioral therapy), and pharmacological aids such as estrogen to combat clinical anxiety.

References

American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC: American Psychiatric Association.

Dolcos, S., Hu, Y., Iordan, A.D., Moore, M., & Dolcos, F. (2015). Optimism and the brain: Trait optimism mediates the protective role of the orbitofrontal cortex gray matter volume against anxiety. Social Cognitive and Affective Neuroscience, 10(10), 1-9. doi: 10.1093/scan/nsv106

Haber, S. N., & Knutson, B. (2010). The reward circuit: Linking primate anatomy and human imaging. Neuropsychopharmacology, 35(1), 4–26. http://doi.org/10.1038/npp.2009.129

Higgins, E. S., & George, M. S. (2013). The neuroscience of clinical psychology: The pathophysiology of behavior and mental illness (2nd ed.). Philadelphia, PA: Lippincott William & Wilkins.

Wellborn, B. L., Papademetris, X., Reis, D. L., Rajeevan, N., Bloise, S. M. & Gray, J. R. (2009). Variation in orbitofrontal cortex volume: Relation to sex, emotion regulation, and affect. Social Cognitive and Affective Neuroscience, 4(4), 328 – 339. doi:10.1093/scan/nsp028

Zeidan, M. A., Igoe, S. A., Linnman, C., Vitalo, A., Levine, J. B., Klibanski, A., … Milad, M. R. (2011). Estradiol modulates medial prefrontal cortex and amygdala activity during fear extinction in women and female rats. Biological Psychiatry, 70(10), 920–927. http://doi.org/10.1016/j.biopsych.2011.05.016

 

 

 

 

Stem cells as a cure for autism

I recently had an opportunity to experience one of the most beautiful things in the world: becoming a mother. As with most first time mothers, preparing for motherhood absolutely consumed me. There was an abundance of information I needed to process. There was also a lot of advertisement. It seemed that cord blood banking was one of the more aggressively advertised products. Since I was researching everything from cribs and strollers to insurances and college funds, I decided to look into cord blood banking as well. The websites claimed that stem cells already cure or might cure in the near future a variety of diseases including autism. (“Current and Potential Uses of Stem Cells”, n.d.). It was something that surprised me. I was accustomed to hearing how stem cells are useful in treatment of certain types of cancer, but a complex neurodevelopmental disorder such as autism seem to be a different “ball game”. I found out that, in 2012, FDA approved a clinical study to assess the effects of stem cell treatment on symptoms of autism. (“Sutter neuroscience,” 2012) I decided to dig deeper. As it turns out, stem cells might be a real option as a possible treatment modality for autism.

Autism Spectrum Disorder affects one in 88 children in United States. Children diagnosed with autism have problems with social interaction and their communication skills are impaired. They also present with restricted interests and repetitive stereotypic verbal and non-verbal behaviors. (Siniscalco, Bradstreet, Sych, & Antonucci, 2014) In addition to behavioral signs, children diagnosed with autism present with such unusual symptoms as inappropriate immune responses, imbalance of microbes in the digestive tract and limited ability to produce certain antioxidants. (Siniscalco, D., Sapone, Cirillo, Giordano, Maione, & Antonucci, 2012) Imaging studies of patients with autism have revealed a reduced blood flow to certain areas of the brain. (Lv et al., 2013)

Just like many other psychiatric disorders, the causes of autism include genetic and environmental components. Additionally, it is currently believed that the inflammatory process may play a very important role. Studies have shown that autistic patients present with inflammation of the brain and dysfunctional immune cells. In addition, the signs of inappropriately activated immune responses can be found all over the body including the cerebro-spinal fluid (CSF). (Lv et al., 2013) Some pharmacological treatment options for ASD include ant-inflammatory agents. However, other pharmacological options mostly consist of psychotropic agents, which address neuropsychiatric symptoms. Behavioral treatments have been shown to help, but no particular treatment has proven to cure all the symptoms of autism. (Siniscalco et al., 2012) So, how do stem cells fit into the treatment of autism?

It is important to note that there is very limited data on how the stem cells affect the autistic population. However, some clinical studies have explored this interesting subject. Researchers in China investigated the efficacy of treating the autistic population with stem cells derived from donor cord blood and cord tissue. The study, which lasted 24 weeks, enrolled 37 participants with diagnosed autism aged 3 to 12 years old. They divided them into three groups. The first group received stem cells derived from cord blood and rehabilitation therapy. The second group, a combination group, received stem cells from the umbilical cord and cord blood together with rehabilitation therapy. The third group was a control group and the participants received just rehabilitation therapy. They discovered that the treatment with stem cells derived from umbilical cord and cord blood had significantly improved patients’ symptoms as compared with the control group. (Lv et al., 2013) However, would the results be similar if the stem cells were coming from a different source? As it turns out other stem cells might be as useful.

Researchers in India used stem cells derived form bone marrow. The study, which lasted six months, enrolled 32 participants aged 3 to 33 years old with confirmed diagnoses of autism. All of the participants were treated with rehabilitation therapy and stem cells from their own bone marrow. The results of the study were also encouraging. Patients showed significant improvements in symptoms. Additionally, the brain imaging showed increased brain activity six months after the treatment. (Sharma et al., 2013)

One might ask: “So, how do stem cells do it?” Some stem cells are involved in development of new blood vessels. They are known as endothelial progenitor cells and they can be found in cord blood. They may be helpful in resolving reduced blood flow to certain areas of the brain in autistic patients. (Lv et al., 2013) Other stem cells have an amazing ability to alter one’s immune response. These stem cells are called mesenchymal stem cells. They travel to the site of injury, synthesize and release a variety of molecules. Some of those molecules reduce inflammation; others help to repair the damage. They also “turn on” the host’s ability to repair its own tissue. (Siniscalco et al., 2014) There is one more advantage. Due to their anti-inflammatory properties, administration of stem cells does not require any pretreatment and there is no risk of rejection. (Siniscalco et al., 2012) It may seem like we should start treating ASD with stem cells right away.

            Unfortunately, as with any treatment, there are possible drawbacks. First and foremost we should examine all the known side effects of stem cell treatment. Some of the study participants in China developed low-grade fever, which resolved without any medical intervention. (Lv et al., 2013) Some patients in India developed headaches, nausea, and vomiting. Other side effects included hyperactivity and onset of seizures in patients with abnormal EEGs. All the adverse effects were controlled by medications and did not affect improvements in ASD symptoms. (Sharma et al., 2013) Second, we need to acknowledge that long-term effects of stem cell treatment are still unknown.

Overall, stem cells may offer an exciting new option for patients with autism. Recent studies support the claim that they may be an effective treatment modality. However, there is a lot still to learn about stem cells as a treatment option in patients with ASD. Hopefully, the new FDA-approved study will shed even more light on both stem cells and autism.

References

Current and Potential Uses of Stem Cells (n.d.). Retrieved October 15, 2015 from http://www.cordblood.com/stem-cell-research/cord-blood-uses-and-research

Lv, Y., Zhang, Y., Liu, M., Qiuwaxi, J., Ashwood, P., Cho, S., … Hu, X. (2013). Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism. Journal of Translational Medicine, 11, 196. http://doi:10.1186/1479-5876-11-196

Sharma, A., Gokulchandran, N., Sane, H., Nagrajan, A., Paranjape, A., Kulkarni, P., … Badhe, P. (2013). Autologous Bone Marrow Mononuclear Cell Therapy for Autism: An Open Label Proof of Concept Study. Stem Cells International2013, 623875. http://doi.org/10.1155/2013/623875

Siniscalco, D., Bradstreet, J. J., Sych, N., & Antonucci, N. (2014). Mesenchymal stem cells in treating autism: Novel insights. World Journal of Stem Cells6(2), 173–178. http://doi.org/10.4252/wjsc.v6.i2.173

Siniscalco, D., Sapone, A., Cirillo, A., Giordano, C., Maione, S., & Antonucci, N. (2012). Autism Spectrum Disorders: Is Mesenchymal Stem Cell Personalized Therapy the Future? Journal of Biomedicine and Biotechnology2012, 480289. http://doi.org/10.1155/2012/480289

Sutter neuroscience institute; autism and cord blood stem cells: FDA gives green light for groundbreaking clinical trial. (2012).Mental Health Business Week, , 610. Retrieved from http://search.proquest.com/docview/1037014415?accountid=15172

ADHD and Obesity

Most clinicians are familiar with the idea that stimulants used to treat attention deficit hyperactivity disorder (ADHD) can often have side effects of appetite and weight loss. More recent studies have shown links between obesity and ADHD. In this post, I will explore the interrelated neurobiology of ADHD, weight, and psychostimulants.

Numerous studies have shown that there is a relationship between ADHD and obesity (Cortese et al., 2015). Agranat-Meged (2005) found that ADHD rates among obese children may be as high as 57%, as compared to ADHD rates of 5-10% of children in the population as a whole. Childhood obesity is not predictive of later development of ADHD, but childhood ADHD is predictive of development of adolescent obesity (Seymour, Reinblatt, Benson, Carnell, 2015). This suggests that ADHD predisposes children to obesity later in life, and that there may be a common, underlying pathway to both ADHD and obesity (Seymour et al., 2015).

Sonuga-Barke (2003) proposed a dual pathway theory of ADHD that accounts for the differing levels of impulsivity, hyperactivity, and inattention seen in patients with the disorder. He proposed that the cortical and nigrostriatal regions are responsible for executive function disorder, while the limbic system is responsible for delay aversion. These pathways overlap and reinforce each other through the global pallidus, ventral pallidum, subthalamic nucleus, substantia nigra, and thalamus. Both of these systems are modulated by dopamine.

The executive function disorder in ADHD is exemplified by lack of planning or organizational ability and impulsivity (Sonuga-Barke, 2003). Higher weight is associated with reduced inhibition in this pathway (Seymour, Reinblatt, Benson & Carnell, 2015). This dysfunction may look like an inability to plan and follow through with an exercise routine or diet, the inability to resist tempting food, or the inability to stay focused to prepare a healthy meal (Levy, Fleming & Klar 2009).

The delay aversion seen in ADHD is associated with the meso-limbic reward circuit (Sonuga-Barke, 2003). Additionally, high sugar and high fat food stimulates this reward-processing region (Seymour et al., 2015). Dopamine signaling is highly important in regulating this reward circuit, satiety, and eating behavior (Danilovich, Mastrandrea, Cataldi & Quattrin, 2014). Some studies have shown a link between ADHD and binge-eating disorder, and the delay aversion and dopamine signaling system could play a role in this (Seymour et al., 2015).

Psycho-stimulants, such as methylphenidate (Ritalin), impact both the disordered executive functioning and the delay aversion by inhibiting the reuptake of dopamine (Danilovich et al., 2014). This has the effect of increasing the availability of dopamine in the brain. Leddy et al. (2009) demonstrated that methylphenidate has a dose-response curve impact on food intake in children, and furthermore, that this is dependent on the child’s dopamine genotype. The children with genotypes that have higher dopamine levels showed more appetite suppression in response to higher doses of methylphenidate than children with other genotypes (Leddy et al., 2009)

Additionally, Levy et al. (2009) demonstrated that in adult subjects with refractory ADHD, long-term treatment with methylphenidate can lead to sustained weight loss. They attributed this to improved self-direction, focus, and decreased impulsivity. Schwartz et al. (2014) showed that children with ADHD who treated with stimulants had a slower rate of BMI growth than children with untreated ADHD. The children treated with stimulants had a BMI growth rate in line with children without ADHD. Interestingly, while they found that the children who were prescribed stimulants youngest and took them for the longest duration had a slower BMI increase, they were more likely to have a high BMI in adolescence. This could be due to the possibility that those treated younger and for longer have more impaired functioning due to ADHD (Schwartz et al., 2014).

Stimulants seem only lead to sustained weight-loss in subjects with ADHD (Levy et al., 2009). While stimulants can lead to decreased appetite and initial weight loss, appetite rebounds in 6-8 weeks and weight rebounds as well (Levy et al. 2009). This is interesting in light of the fact that stimulants cause substantial weight-loss in those with ADHD. This seems to further implicate the dopaminergic pathways in both ADHD and obesity in those with ADHD (Davis et al., 2012).

So what does all this mean for clinical practice? These findings suggest that clinicians should screen children and adults with high BMIs for ADHD symptoms. Additionally, many studies have shown links between binge eating disorder, dopamine, and ADHD, so clinicians should also proactively screen patients with binge eating disorder for untreated ADHD. Furthermore, clinicians should teach children and adults with ADHD not only academic and organizational coping skills, but also coping skills related to eating and health (Reinblatt et al., 2014). This is extremely important since obesity can lead to complications such as sleep apnea, which can further impair concentration (Lundahl & Nelson, 2014). Clinicians should be aware of the link between ADHD and obesity and appropriately educate and screen their patients. Further research is needed into the dopamine pathways of the brain to determine how the different ADHD subtypes, binge eating disorder, and obesity are related.

 

 

References

Agranat-Meged, A. N., Deitcher, C., Goldzweig, G., Leibenson, L., Stein, M., & Galili-Weisstub, E. (2005). Childhood obesity and attention deficit/hyperactivity disorder: A newly described comorbidity in obese hospitalized children. International Journal of Eating Disorders, 37, 357-359. doi:10.1002/eat.20096.

Benard, V., Cottencin, O., Guardia, D., Vaiva, G., & Rolland, B. (2015). The impact of discontinuing methylphenidate on weight and eating behavior. International Journal of Eating Disorders, 48, 345-348. doi:10.1002/eat.22301.

Byrd, H. M., Curtin, C., & Anderson, S. E. (2013). Attention-Deficit/Hyperactivity disorder and obesity in US males and females, age 8-15 years: National health and nutrition examination survey 2001-2004. Pediatric Obesity, 8, 10.1111/j.2047-6310.2012.00124.x. doi:10.1111/j.2047-6310.2012.00124.x.

Choudhry, Z., Sengupta, S. M., Grizenko, N., Harvey, W. J., Fortier, M., Schmitz, N., & Joober, R. (2012). Body weight and ADHD: Examining the role of self-regulation. Plos One, 8, e55351. doi:10.1371/journal.pone.0055351.

Cortese, S., Moreira-Maia, C., St. Fleur, D., Morcillo-Peñalver, C., Rohde, L. A., & Faraone, S. V. (2015). Association between ADHD and obesity: A systematic review and meta-analysis. Ajp, appi.ajp.2015.15020266. doi:10.1176/appi.ajp.2015.15020266.

Danilovich, N., Mastrandrea, L. D., Cataldi, L., & Quattrin, T. (2014). Methylphenidate decreases fat and carbohydrate intake in obese teenagers. Obesity, 22, 781-785. doi:10.1002/oby.20574.

Davis, C., Fattore, L., Kaplan, A. S., Carter, J. C., Levitan, R. D., & Kennedy, J. L. (2012). The suppression of appetite and food consumption by methylphenidate: The moderating effects of gender and weight status in healthy adults. International Journal of Neuropsychopharmacology, 15, 181-187.

Graziano, P. A., Bagner, D. M., Waxmonsky, J. G., Reid, A., McNamara, J. P., & Geffken, G. R. (2012). Co-occurring weight problems among children with attention deficit/hyperactivity disorder: The role of executive functioning. International Journal of Obesity, 36, 567-572.

Leddy, J. J., Waxmonsky, J. G., Salis, R. J., Paluch, R. A., Gnagy, E. M., Mahaney, P., . . . Epstein, L. H. (2009). Dopamine-related genotypes and the dose-response effect of methylphenidate on eating in attention-deficit/hyperactivity disorder youths. Journal of Child and Adolescent Psychopharmacology, 19, 127-136. doi:10.1089/cap.2008.046.

Levy, L. D., Fleming, J. P., & Klar, D. (2009). Treatment of refractory obesity in severely obese adults following management of newly diagnosed attention deficit hyperactivity disorder. International Journal of Obesity, 33, 326-334.

Lundahl, A., & Nelson, T. D. (2014). Attention deficit hyperactivity disorder symptomatology and pediatric obesity: Psychopathology or sleep deprivation? Journal of Health Psychology.

Reinblatt, S. P., Leoutsakos, J. S., Mahone, E. M., Forrester, S., Wilcox, H. C., & Riddle, M. A. (2015). Association between binge eating and attention-deficit/hyperactivity disorder in two pediatric community mental health clinics. International Journal of Eating Disorders, 48, 505-511. doi:10.1002/eat.22342.

Schwartz, B. S., Bailey-Davis, L., Bandeen-Roche, K., Pollak, J., Hirsch, A. G., Nau, C., . . . Glass, T. A. (2014). Attention deficit disorder, stimulant use, and childhood body mass index trajectory. Pediatrics, 133, 668-676.

Seymour, K. E., Reinblatt, S. P., Benson, L., & Carnell, S. (2015). Overlapping neurobehavioral circuits in ADHD, obesity, and binge eating: Evidence from neuroimaging research. CNS Spectrums, 20, 401-411. doi:10.1017/S1092852915000383.

Sonuga-Barke, E. J. S. (2003). The dual pathway model of AD/HD: An elaboration of neuro-developmental characteristics. Neuroscience & Biobehavioral Reviews, 27, 593-604. doi:http://dx.doi.org/10.1016/j.neubiorev.2003.08.005.

Violence and Aggression: where does it come from?

I used to stop at Roseburg every summer on our drive to Ashland, Oregon. My mom would take my brothers and I to an old museum with an 1860’s market and school where we would play. Roseburg will now hold many terrible memories for several families and loved ones. As I’m sure you know, nine students in a community college were tragically shot on Friday. Shootings throughout the United States have become much too frequent, which begs the question: why has violence, and aggression become so common? What is happening in the brain?

Traumatic brain injuries (TBI) lend an introduction into what makes someone aggressive and violent. Research suggests aggression, irritability and violent behaviors without provocation increase after TBI (Wood & Liossi, 2006). Furthermore, aggression becomes poorly directed and behavioral self-control decreases with TBI. Trauma to the brain can also result in impaired executive function, higher impulsivity, dis-inhibition, social withdrawal, poor drive and motivation (Wood & Liossi, 2006).

Forensic studies substantiate the relationship between TBI and violent crimes. Farrer and Hedges (2011) revealed a high prevalence of traumatic brain injury in incarcerated groups in comparison to general populations. A longitudinal study examining violence in Sweden from 1973-2009, found of 2,011 individuals who reported TBI, 8.8% committed violent crimes after their diagnosis when compared to unaffected siblings.

In addition to TBI, overwhelming psychological research points to the experience of victimization as an integral theme in violence (To et al., 2015). To et al. (2015) conducted interviews of 1,181 homeless adults over one year. The population was selected for their vulnerable housing status and high prevalence of TBI. Results revealed an overwhelming 61% of participants had a history of TBI. Furthermore, those with history of one or more TBI, were almost twice as likely to be incarcerated or arrested in one year and three times as likely to experience physical assault in one year. To et al. (2015) proved populations with TBI are at risk of aggression towards others and being the target of aggressive behaviors.

To this day, there is strong evidence to suggest that the prefrontal cortex is integral to the understanding of violence, aggression and decision-making. But what does that mean, and is there more neurobiology we are missing?

Grafman et al. (1996) found specific frontal cortex lesion locations associated with aggression in Vietnam War veterans with penetrating head injuries from combat. From family observation and self-report methods, analyses revealed increasing aggression and violent attitudes and behaviors. Results concluded those with orbital and frontal ventromedial lesions, consistently demonstrated more aggression and violence than control and patients with lesions in other areas of the brain. Interestingly, size of the lesion did not affect severity of violence or aggression. The study concluded that the human prefrontal cortex exerts control over primitive behavioral reactions to the environment.

Genetic expression research examining aggressive males and animals found consistent increases in an X-linked monoamine oxidase A (MAO-A) gene (Meyer-Lindenberg et al., 2006). The MAO-A is an enzyme involved in monoamine catabolism and serotonin (Meyer-Lindenberg et al., 2006). Normal male participants were examined for MAO-A polymorphism and monitored with magnetic resonance imaging while shown aggressive stimuli. Results concluded that the low expression variant of MAO-A was associated with an increase in violent aggression, a decrease in limbic volume, and a hyper-responsive amygdala. Furthermore, low-activity of regulatory pre-frontal regions were also observed.

Pardini et al. (2011) investigated the role of MAO-A expression and aggression in penetrating TBI. Pardini et al. observed MAO-A expression activity in patients with prefrontal cortex injury, non-pre-frontal cortex injury and a control. Results demonstrated elevated levels of low MAO-A expression variant when aggressive in the control group and elevated levels of high MAO-A expression variant in non-prefrontal cortex injury patients when aggressive. Interestingly, MAO-A low and high expression variants were equal in aggressive pre-frontal TBI patients. Thus, MAO-A expression variant activity during aggression was affected by lesion location.

Paridini et al. (2011) offers some insight into the explanation of aggression, but more research is imperative to understand the extent of neural chemistry during aggression to curb extreme or unprovoked aggression and violence. While treatment for TBI includes beta-blockers, antipsychotics, anti-seizure drugs, stimulants and mood stabilizers there is little understanding about how these drugs are successful (Wong, 2011). Further research understanding aggression and violence could help stop future behaviors and impulsive harmful actions.

References

 

Grafman, J., Schwab, K., Warden, D., Pridgen, A., Bown, H.R. & Salazar, A.M. (1996). Frontal lobe injuries, violence, and aggression: a report of the Vietnam head Injury Study. Neurology, 46 (5). Retrieved from

http:/​/​dx.​doi.​org/​10.​1212/​WNL.​46.​5.​1231

 

Farrer T.J., Hedges, D.W., (2011). Prevalence of traumatic brain injury in incarcerated groups compared to the general population: a meta-analysis. Progress in Neuropsychopharmacology and Biological Psychiatry, 35 (2), 390– 394. Retrieved from

doi:10.1016/j.pnpbp.2011.01.007

 

Meyer-Lindenberg, A., Buckholtz, J.W., Kolchana, B. et al. (2006). Neural mechanisms of genetic risk for impulsivity and violence in humans. Proceedings of the National Academy of Sciences of the United States of America, 103 (16), 6269-6274.

 

Pardini M, Krueger F, Hodgkinson C, Raymont V, Ferrier C, Goldman, D., Strenziok, M., Guida, S., Grafman, J. (2011) Prefrontal cortex lesions and MAO-A modulate aggression in penetrating traumatic brain injury. Neurology, 76, 1038–1045.

 

To, M.J., O’Brien, K., Paplepu, A., Hubley, A., Farrell, S., Aubry, T., Gogosis, E., Muckle, W., & Hwang, S.W. (2015). Healthcare, Utilization, legal incidents, and victimization following traumatic brain injury in homeless and vulnerable housed individuals: a prospective cohort study. Journal of Head Trauma Rehabilitation, 30, (4), 270-276. Retrieved from

ovidsp.tx.ovid.com/sp-3.17.0a/ovidweb.cgi?

 

Wong, T.M. Brain injury and aggression: can we get some help? Neurology, 76 (12), 1032-1033. Retrieved from

doi  http:/​/​dx.​doi.​org/​10.​1212/​WNL.​0b013e318211c3fd

 

Wood, R.L., Liossi, (2006). Neuropsychological and neurobehavioral correlates of aggression following traumatic brain injury. The Journal of Neuropsychiatry & Clinical Neurosciences 18, (3), 333-341. Retrieved from doi/10.1176/jnp.2006.18.3.333.

 

Brain Abnormalities and Aggression

Image

Abnormalities in the brain, whether it be related to injury, a disease process, or inherit structural difference, can be linked to aggression. The prefontal cortex is most often associated with aggression and impulse control however there are other structures in the brain that can affect expression of aggression including the basal ganglia, amygdala, and the temporal lobe (Yeterian, 2002). It is intriguing that different areas of the brain presenting with abnormal volume or damage to structure can produce the same aggressive symptoms.

Sagittal Cross-Section of Cerrebellum (Wikipedia, 2015).

Sagittal Cross-Section of Cerrebellum (Wikipedia, 2015).

A meta-analysis of 43 imaging studies performed by Yang and Raine (2009) showed significantly diminished prefrontal structure and function in individuals with antisocial, violent, or psychopathic behavior. The analysis found that the specific areas that were most diminished were the right orbitofrontal cortex, right anterior cingulate cortex, and left dorsolateral prefrontal cortex. A newly released study by Leutgeb et al. (2015) supports these findings of diminished brain mass in expression of anger and violence. Leutgeb et al. (2015) compared brain imaging data of 40 high-risk violent offenders currently incarcerated and 37 non-delinquent healthy controls. The study found that in comparison to the control group, high-risk violent offenders were shown to have decreased gray matter volume (GMV) in the prefrontal cortex.  Also of interest, the violent offenders were found to have increased GMV in the cerebellum and basal ganglia.

Further research into the impact increased GMV in the cerebellum and the basal ganglia has on violent behaviors is warranted. This is especially intriguing since there is much to be discovered in regard to the emotional and cognitive role of these two regions that are primarily associated with motor function. While there is some data to support that schizophrenia may be linked to abnormalities of the cerebellum and that autism and attention deficit-hyperactivity disorder may be linked to reduced volume or damage to the area  (Ramachandran, 2002), it would be valuable to research the impact of increased GMV to better understand human manifestation of aggression.

Coronal section of brain scan showing atrophy of the caudate nucleus (Wikipedia, 2015).

Coronal section of brain scan showing atrophy of the caudate nucleus in a patient with HD (Wikipedia, 2015).

Huntington’s Disease (HD), is a genetic neurodegenerative disease affecting motor,  cognitive, and psychiatric dysfunction. While the whole brain is affected in HD, the most vulnerable area of the brain are the basal ganglia, especially in early stages of the disease (Rosenblatt & Leroi, 2000). Disorders of the basal ganglia have classically been focused on the motor abnormalities however in recent years there has been more recognition of the non-motor dysfunctions of basal ganglia disease (Ring & Serra-Mestres, 2002).  As the caudate nucleus of the basal ganglia and amygdala deteriorates in individuals with HD, the ability to relay to the frontal lobes is disrupted causing an inability to control emotions resulting in aggression and episodes of explosiveness (Liou, 2010). While the major neuropsychiatric complications of HD include depression, mania, psychosis, obsessive compulsive behaviors, aggression, delirium, and sexual disorders (Rosenblatt & Leroi, 2000), according to Arora  (2015), aggression is the primary reason for psychiatric admission for these individuals (Arora, 2015). Individuals with HD can exhibit aggressive behaviors such as explosive outbursts, verbal threatening, unpredictable and more intense responses to stimuli, decreased insight and lability of behavior Arora, 2015).

Like the degenerative diseases of the brain and decreased GMV, traumatic brain injury (TBI) can also cause aggression and decreased impulse control. Post-TBI aggression is estimated to be anywhere from 11%-34% of individuals making it the most common condition of TBI (Rao et al., 2009). The psychological sequelae of frontal and temporal lobe damage include aggressive and violent outbursts, the same symptoms previously mentioned in research studies by Leutgeb et al. and Yang & Raine. Rao et. al. also identify that in participants of their study on aggression and depression prevalence in TBI, many cases exhibited decreased GMV in the right frontal lobe which happens to be the same area cited as an area of deficit in the Yang & Raine meta-analysis study.

The expression of aggressive behavior is linked to different areas and abnormalities of the human brain. Despite these differences, the same symptom expression is noted. There is much to be learned about the multifaceted brain structures and how they function as a cohesive unit. Regardless of whether caused by injury, degenerative disease, or heredity, there are structural abnormalities in the brain that are linked to aggression.

References

Arora, G. (2015).  Managing aggression in Huntington’s disease [power point slides]. Retrieved from http://hdsa.org/wp-content/uploads/2015/07/Managing-Aggression-in-HD_Garima- Arora_ver005.pdf    

Cerebellum. (n.d). Retrieved October 1, 2015 from Wikipedia :https://en.wikipedia.org/wiki/Cerebellum#/media/File:Gray707.png.

Cerebellum and Cognition. (2002). In V. Ramachandran, Encyclopedia of the human brain. Oxford, United Kingdom: Elsevier Science & Technology. Retrieved from http:// search.credoreference.com/content/entry/esthumanbrain/v_cerebellum_and_cognition/0

Huntington’s disease (n.d). Retrieved October 1, 2015 from Wikipedia: https://en.wikipedia.org/wiki/Huntington%27s_disease#/media/File:Huntington.jpg

Leutgeb, V., Leitner, M., Wabnegger, A., Klug, D., Scharmuller, W., Zussner, T., & Schienle, A. (2015). Brain abnormalities in high-risk violent offenders and their association with psychopathic traits and criminal recidivism. Neuroscience, 308, 194-201. doi:10.1016/ j.neuroscience.2015.09.011

Liou, S. (2010, June 26). Behavioral symptoms of Huntington’s disease. Retrieved from http:// web.stanford.edu/group/hopes/cgi-bin/hopes_test/the-behavioral-symptoms-of- huntingtons-disease/

Rao, V., Rosenberg, P., Bertrand, M., Salehinia, S., Spiro, J., Vaishnavi, S., … Miles, Q. S. (2009). Aggression after traumatic brain injury: prevalence & correlates. The Journal of Neuropsychiatry and Clinical Neurosciences, 21(4), 420–429. doi: 10.776/ appi.neuropsych.21.4.420

Rosenblatt, A., & Leroi, I. (2000). Neuropsychiatry of Huntington’s disease and other basal ganglia disorders. Psychosomatics, 41(1), 24-30. doi:http://dx.doi.org/10.1016/S0033-3182(00)71170-4

Ring, H.A. & Serra-Mestres, J. (2002). Neuropsychiatry of the basal ganglia. Journal of Neurology, Neurosurgery, and Psychiatry, 72(1), 12-21. doi:10.1136/jnnp.72.1.12

Yang, Y., & Raine, A. (2009). Prefrontal structural and functional brain imaging findings in antisocial, violent, and psychopathic individuals: a meta-analysis. Psychiatry Research, 174(2), 81–88. http://doi.org/10.1016/j.pscychresns.2009.03.012

Yeterian, E. H. (2002). Prefrontal Cortex. In V. Ramachandran, Encyclopedia of the human brain. Oxford, United Kingdom: Elsevier Science & Technology. Retrieved from

http://search.credoreference.com/content/entry/esthumanbrain/prefrontal_cortex/0