When Laughing Is Not Funny: Pseudobulbar Affect

Bursting into laughter disproportionate to the context or even with no apparent reason; you have either experienced this yourself or witnessed it. Imagine this reaction multiplied in intensity, duration, and frequency, but also manifesting emotions from the other end of the emotional spectrum -- uncontrollable laughing and crying.

Pseudobulbar affect (PBA) is a condition occurring in patients with neurological disorders like stroke, amyotrophic lateral sclerosis or Alzheimer’s disease. Patients experience exaggerated, uncontrollable, and involuntary outbursts of laughter or crying inappropriate to the context in which they occur [1].

The pathophysiology of PBA is obscure. Neuroimaging [2] and electrophysiological [3] evidence implicates the cortico-pontine-cerebellar circuit (CPCC). The CPCC integrates contextual information from the cortex and provides an accurate and congruent emotional response. Its dysfunction results in inappropriate or unscaled emotional responses.

Crying when happy, laughing when sad

 

The neurotransmitter serotonin, which modulates functions closely associated with mood, sleep, sex, and appetite, and is disturbed in many mood disorders, seems to be closely related to PBA. Based on this, selective serotonin reuptake inhibitors are often prescribed for PBA [4]. Likewise, glutamate acts on many brain structures around the CPCC and a reduction of its increased excitatory activity may be beneficial for BPA patients [3].

PBA is expected to become more common as the number of patients with neurological disorders increases. This will necessitate a more thorough understanding of its pathophysiology to provide better treatment.

[1] Arciniegas et al, CNS Spectr, 2015

[2] Parvizi et al, J Neuropsychiatry Clin Neurosci, 2009

[3] Haiman et al, J Neurol Sci, 2008

[4] Schiffer and Pope, J Neuropsychiatry Clin Neurosci, 2005

by Andreas Diamantaras, MSc MedNeuro

This article originally appeared  March 2015, Vol. 08, Issue 01, Humour

Tracing the Roots of Aggression

Many evolutionary theories explain the development of human aggression as a necessary trait for survival. However, aggression rarely has practical use in contemporary society. When exhibited, it is often in a violent and illegal context and therefore it is incriminated. Sometimes, it can even be considered part of someone’s temperament.

Aggression is thought to be the result of a complex corticolimbic interaction between subcortical neural systems, decision-making circuits, and frontoparietal regions [1]. Strong genetic and hormonal influences, in addition to the various environmental stimuli, seem to regulate these networks. This raises questions regarding the degree of responsibility that violent people bear.

Aggression Is a Male Phenomenon
According to statistics, the ratio of crimes committed by males compared to females is greater than 10:1. The more aggressive behavior of males starts to manifest itself even before adolescence, with boys being more likely to be involved in some kind of antisocial conduct [2].
Hormones are among the first suspects for male aggression. Exposure to androgens in the early stages of adolescence is thought to constitute a possible cause. However, according to a recent meta-analysis, the association between testosterone levels and antisocial behavior is weak [3]. Next is the stress hormone cortisol, whose action is regulated through the hypothalamus and adrenal axis. Lower cortisol concentration was found in the saliva of males with antisocial conduct [4]. Finally, low levels of the serotonin metabolite 5-HIAA and low blood sugar are other messengers implicated in the regulation of aggressive behavior.

Is It You Y?
More than four decades have passed since males with XYY syndrome, known also as supermales, were associated with criminal behavior. A higher percentage of XYY men was found in prisons and in institutions for criminally insane people than was found among the normal population. This hypothesis has been significantly weakened after the publication of epidemiological studies that suggested otherwise [5], although it has not been totally refuted as emerging evidence still supports the initial claim [6].
Taking a closer look at the genes, recent knockout studies in mice have excluded any contribution of the Y-linked loci to aggression [7]. Nevertheless, the investigation of other chromosome loci revealed genes that might explain the sex-related difference in aggression and should be interpreted along with the hormone hypothesis. A shorter GAG repeat in the Androgen receptor in Swedish and Indian males accused of aggressive behavior has been associated with it [8]. Certain polymorphisms of the monoamine oxidase (MAOA, MAOB)-coding genes have been linked with functional differences in expression. A plethora of enzyme-coding genes (COMT, dopamine-β-hydroxylase and tryptophan hydroxylase) has been linked to male aggressive behavior [9].

Environmental Interactions
Stressful events, especially in the first years of life, confer a higher risk for manifesting antisocial conduct. Interestingly, it seems that stress triggers aggressive behavior in males with a “vulnerable” genetic background and more specifically a low-activity polymorphism in the MAOA gene. The causality in this case is not clear yet, as evidence suggests that an initial stressful event down-regulated the activity of the MAOA genes later on [2].

The Role of Recreational Substances
Substance use is closely related to offending behavior in both sexes, with alcohol being the most common culprit. It is not only widespread alcohol use, but also its high correlation with violent behavior that make it one of the most significant perpetrators of aggression. Drug users on the other hand, rarely exhibit such behavior, with cocaine users being the only exception [10]. 
Aggressive behavior, like every behavior, is difficult to approach and explain with molecular and genetic mechanisms. However, there seems to be a notable interaction between the environment and one's genetic background. This requires further investigation, as the potential implications for preventing the development of an aggressive behavior, even in a small portion of the population, could improve dramatically the fabric of our societies.

[1] Coccaro et al, Biol Psychiatry, 2011
[2] Craig and Halton, Hum Genet, 2009
[3] Book et al, Aggress Violent Behav, 2001
[4] Shirtcliff et al, Dev Psychopathol, 2005
[5] Noël et al, Clin Genet, 1974
[6] Stochholm et al, BMJ Open, 2012
[7] Gatewook et al, J Neurosci, 2006
[8] Rajender et al, Int J Legal Med, 2008
[9] Pavlov et al, J Appl Genetics, 2012
[10] Lammers et al, Tijdschr Psychiatr, 2014

by Andreas A. Diamantaras, MSc student
This article originally appeared in CNS Volume 7, Issue 3, Nature vs Nurture

The Development of Taste Preferences

Have you ever thought that your liking of strawberries and your resentment of cauliflower could be the result of very careful genetic programming? 

Ice Ice Baby by Danny Coen via flickr

Besides our genetic inclination, gastronomic stimuli, starting as early as the 8^th gestational week, can shape the taste preferences that we develop later in life.

Such a Sweet Tooth…
Indeed, all humans seem to have encoded in their genome a preference or aversion for specific tastes that were related, from an evolutionary perspective, to increased chances of survival. An innate liking for sweets is evident in all newborns ensuring the acceptance of maternal milk. One mechanism behind this affection is the upregulation of the production of endogenous opioids. They change the perception of pain and mimic the effects of drugs in the brain. It is no coincidence then that sucrose-containing solutions are used as analgesics for painful procedures in neonates [1]. As we grow, other endogenous factors, like polymorphisms in the sweet taste receptors (TAS1R2, TAS1R3), come into play and influence our inclination towards sweets.
Likewise, the innate aversion towards bitter foods follows the fact that most toxic substances taste bitter [2].

A Restaurant in the Womb
Learning, in the form of repeated exposure to certain foods, is another individual factor influencing our taste preferences and in the end our eating habits. Our first exposure to food flavors takes place inside the womb. Flavor components pass from the mother’s blood to the amniotic fluid. Breast milk is the next, perhaps even more important, milestone. Changing its flavor according to the maternal diet provides a variety of flavor stimuli for the infant that prepares and familiarizes it for solid food [3]. However, it is never too late to influence our food preferences by regularly “training our palate”.
Influencing our food preferences appropriately from the first years of life can aid in the prevention of a plethora of diseases, from cancer to obesity and diabetes, which are closely related to our dietary habits.

[1] Ventura and Worobey, Curr Biol, 2013
[2] Ventura and Mennella, Curr Opin Clin Nutr Metab Care, 2011
[3] Beauchamp and Mennella, J Pediatr Gastroenterol Nutr, 2009

by Andreas A. Diamantaras, MSc student
This article originally appeared September 2014 – Volume 07, Issue 03 in "Nature versus Nurture"

Brain Activity in Love

Is love a mere secretion of chemicals in the brain? And if so, what are the differences between the various forms of it that we experience? Understanding the biological basis of love is a prerequisite to addressing these issues, and recently a lot of scientific research has been directed towards this topic.

Love. Love for God, for wife, for family, for food, for art. The most important aspects of our lives are defined by this strongest of all emotions. Yet we seem unable to define it properly, leading eventually every discussion about it to, at best, a compromise. Is love a mere secretion of chemicals in the brain? And if so, what are the differences between the various forms of it that we experience? Understanding the biological basis of love is a prerequisite to addressing these issues, and recently a lot of scientific research has been directed towards this topic.

The Arrows of Love
As expected, a variety of neurotransmitters are involved in the generation of this unique experience. In particular, waves of dopamine secreted by the hypothalamus flood the brain and recruit certain areas causing a feeling of euphoria and jubilation. At the same time, the neurotransmitter serotonin is depleted, causing the obsessive behavior often described in people who are in love. This association stems from the observation that patients with obsessive-compulsive disorder have similar low serotonin levels. Vasopressin, a hormone associated with aggressive behavior among males, and oxytocin, responsible for the contractions during labor, have also been shown to increase when in love [1]. The above changes have been documented specifically for “romantic” and “maternal” love, indicating a close relation between them and constituting a possible parallel to Freud’s Oedipus complex.

The Coordinates of Love
These hormones and neurotransmitters exert their activity in a plethora of specific brain areas, including the medial insula, anterior cingulate cortex, hippocampus, striatum, and hypothalamus. This activity can be roughly summarized as the activation of the subcortical dopaminergic reward-related system and the areas that it projects to. In a parallel manner, brain areas such as the frontal and prefrontal cortex, amygdala and temporal poles are deactivated [2].
The known functions of most of these areas are consistent with the description of the feelings we experience when in love. For example, the striatum is associated with rewarding feelings and is activated by dopamine - so are the insula and the anterior cingulate gyrus, responsible for mediating emotions and somatosensory integration. On the other hand, the frontal and prefrontal cortex where logical planning and decision making take place are deactivated, partly explaining the irrational behavior and lack of judgment seen in many people that are in love. The parietal cortex and parts of the temporal lobe, linked to negative feelings and depression, are also deactivated [2,3].
On the other hand, the role of the amygdala, a known regulator of fear, is not as simple. Vasopressin and oxytocin seem to exert opposite actions on the activity of the amygdala, increasing and decreasing it respectively, with the effects of the latter prevailing eventually and leading to an experienced lessening of fear [1]. The majority of the above evidence is provided by the results of fMRI studies in which the participants were shown a picture or the name of their beloved partner or of their child.

Are there indeed Different Forms of Love?
Although “romantic” and “maternal” love and sexual arousal share common features in brain activity, there are crucial differences that distinguish them. In the case of maternal love, there is a stronger activation of the brain areas responsible for face recognition, consistent with the need to recognize quickly one's child’s facial expressions and act accordingly. Another region that was found to be activated only in the case of “maternal” love is the periaqueductal gray matter, an area involved in endogenous pain suppression.
Moreover, activation of the same hypothalamic regions has been documented in the case of sexual arousal and “romantic” love, but not in the case of maternal love. In all forms of love, however, the activation of the subcortical dopaminergic reward-related brain system and the deactivation of cortical areas that lead to an impairment in judgment is similar and pronounced, indicating the common aspects they share [3].

The Functional Role of Love
As pragmatic and harsh as it may sound, from an evolutionary point of view, love serves very specific purposes and its intensity as an emotion is totally justifiable. The strong activation of the reward systems that strengthen the bonding between the couple, and between the mother and the child, ensures the unity of the family, increasing their survival chances in a demanding environment [3]. Even the irrational behavior that makes a man defend his partner if a threat is presented, and a mother thoughtlessly sacrifice herself in order to protect her children, could be interpreted in the same way. 

Looking in the Mirror
Although we sometimes regard love as a feeling over which we have no control, fMRI studies suggest otherwise. Cortical areas, such as the angular gyrus, that control complex cognitive behaviors such as social cognition and self-perception are activated even when we are presented with implicit love stimuli, suggesting that love is also a cognitive process.
The mirror neuron system consists of neurons that are activated by the execution and the observation of object-related movements and normally participates in the perception of our surroundings and our actions. This system has been postulated to additionally mediate emotion recognition and social cognition. Located mainly in the insula and anterior cingulate gyrus, areas also activated during the experience of love, it has been suggested that mirror neurons facilitate the understanding of feelings and the prediction of the intentions of others, also providing feedback for the generation of our own feelings [4].

In other words, love is a mutual feeling that gives positive feedback to itself; we need to feel loved in order to feel love in return and vice versa! No matter how logically we try to approach love, using strict scientific terms, in the end love conquers all!


[1] de Boer et al, Neuroscience, 2012
[2] Ortigue, J Sex Med, 2010
[3] Zeki, FEBS Lett, 2007
[4] Ortigue, Med Hypotheses, 2008

By Andreas Antonios Diamantaras, Master's Student Medical Neurosciences
This article originally appeared June 2014 in Vol. 07 - Issue 2 "Neuroscience of Love".  

Rules of Attraction between the Sexes

What is the reason that men and women differ so significantly in their behavior and their views when it comes to matters of love and relationships? Why is it, if the two sexes are meant for each other, often so difficult to co-exist in the context of a relationship or a marriage?

Albrecht Dürer (1507) - Adam und Eva,
Prado museum, Madrid

The Psychosocial Perspective
According to the biopsychosocial model, the social environment and the psychology of the two sexes, in combination with the biological background, contribute to the behavior they manifest when they are sexually mature. From the perspective of evolutionary psychology the between-sex differences in humans can be traced back to primeval times, when the pressure of a different physical and social environment pushed them to assume different social roles that eventually led to the development of different psychology. As reproductive status was an important parameter during this time, the two sexes adjusted their behavior in order to ensure better survival and reproductive success. Therefore the females developed traits and skills that increased the survival of their offspring while males were less concerned with reproduction [1]. This, however, does not mean that the sexes have stopped evolving since then. On the contrary, the results of the radical social changes that have occurred in the last few centuries can be seen in the psychology of both sexes. In principle, in society, the sexes will assume the roles in which they have a better chance of succeeding, and in turn they will further develop social skills that will ensure their success in the given social position.
In the context of psychological studies, participants were asked about the desirability of certain characteristics in a prospective husband or wife. The results showed that physical appearance and earning potential were valued more by males and females respectively, consistent with the aforementioned theory [2]. Another study investigated in more detail which physical features men and women found attractive in a long- and short-term partner. Interestingly enough, first in preference was “Body, build” for both sexes, but in the second and third position were the “Mouth, smile” and “Height” for women and “Face” and “Eyes” for men. Moreover, both sexes prioritized the physical characteristics of their short-term partners over those of their long-term ones [3].

Male and Female Brain Areas of Love
The role of biological background must not be neglected in any case, as it provides more concrete evidence on the matter. Differences in the “rules of attraction” between males and females have been documented by the different activity rates of certain brain areas during “romantic” love. In particular, a stronger activation of the areas that integrate the visual stimuli was recorded in males, signifying their focus on physical appearance. Females, on the other hand, seem to focus more on social status as witnessed by activation of brain areas associated with attention and emotion. These different patterns of activation could indicate, in accordance with the theory of evolutionary psychology, the priorities that each gender has for the formation of a family, namely, the young and healthy woman that is more likely to bear offspring for the male and the security and resources that a man should provide for the female [4].
During sexual arousal as well there seem to be functional differences between the two sexes, as an fMRI study found greater activation of the hypothalamus in men compared to women when they were shown erotic films. In addition, sex drive, defined as the desire for sexual gratification, seems to be related to circulating levels of testosterone in both sexes, and more specifically to the balance between androgens and estrogens. The disruption of this balance during the menstrual cycle in women results in an increase in the sexual drive. In both sexes, a decline in sexual activity occurs with the decrease in androgens during aging [4].

Gender Differences in Animal Studies
Further evidence supporting the biological differences comes from animal studies. Differences in the hormones promoting attachment in prairie voles have been proposed. In particular, vasopressin and oxytocin were found to be more important for males and females respectively. Additionally, gender differences in the types and distribution of hormone receptors were found in the same species [5]. In another study, social interaction with rats of the opposite sex led to a different response to stress stimuli between male and female rats. Male rats that were housed with female ones showed reduced stress levels compared with male rats that were bred in isolation after exposure to the stress stimuli, while for the females such a difference was not found [6]. The different way male rats experience social interaction with females, as a means of relieving stress, suggests the use of different strategies for managing stress that possibly apply also to the early stages of romantic love.
This combined evidence illustrates the presence of meaningful sex differences that stem from biological, social and psychological variations. Further investigation of these topics could have significant applications for resolving the relationship and sexual problems that many couples face.


[1] Eagly et al, American Psychologist, 1999
[2] Buss, BuJ Cross Cult Psychol, 1990
[3] Li and Kenrick, J Pers Soc Psychol, 2006
[4] Fisher et al, Philos Trans R Soc Lond B Biol Sci, 2006
[5] Lim et al, Neuroscience, 2004
[6] Westenbroek et al, Horm Behav, 2005

By Andreas Antonios Diamantaras, Master's Student Medical Neurosciences

This article originally appeared June 2014 volume 7, issue 02, The Neuroscience of Love