Tag Archive for: neuroscience

Understanding Sex Difference in Addiction: The Road to Tailored Treatments

Authors: Tanisse Epp, PhD Student, Carleton University, MSc Neuroscience, University of British Columbia | Editors: Romina Garcia de leon, Shayda Swann (Blog Coordinators) 

Published: Dec 1, 2023

For a long time, society believed that alcohol and drug use was primarily a problem for men. As a result, research has mostly focused on studying addiction in men. But in recent years, there has been more attention to women and how they use drugs and alcohol. As the number of women using drugs and alcohol keeps increasing, closing the gap between men and women has become extremely important. Recently, there has been a promising rise in research looking at sex differences within addiction research. This research has highlighted significant differences in how addiction develops and progresses differently in men and women. These differences have important implications for treatment and relapse risk.

Consumption Patterns 

Despite men having higher rates of substance use disorders than women, women are more vulnerable to many aspects of the disorder. For example, women have a shorter time period from initial drug use to meeting the criteria for substance use disorder and seeking treatment compared to men. This phenomenon is called the ‘telescoping effect.’ It means that women tend to develop problematic substance use issues in fewer years compared to men. This effect has been reported across multiple drug classes, including cocaine, methamphetamine, alcohol, opioids, tobacco, and cannabis, and non-pharmacological addictions, such as gambling. 

Pre-clinical research has proposed a potential mechanism underlying this sex difference in the nucleus accumbens (the dopamine centre involved in addiction) and the dorsal striatum (the action-oriented center driving the physical action of taking substances). For instance, when exposed to drugs, female rats show a smaller response in the nucleus accumbens at first, but they have a quicker and stronger reaction in the dorsal striatum, driving an escalation in drug use. Additionally, gonadal hormones have been proposed to be involved. Research, both in clinical and pre-clinical settings, has demonstrated that estradiol, a female hormone, can lead to an increased ‘high’ from smoking cocaine and a stronger drive to obtain cocaine. This suggests that estradiol may play a role in the quicker progression from casual to chronic cocaine use in females compared to males. 

Craving

While the telescoping effect plays a significant role in the early stages of addiction, craving becomes a crucial factor in sustaining addiction and raising the risk of relapse after quitting. Exploring potential sex differences in craving will contribute to a greater understanding of how we can support both men and women during abstinence to decrease the risk of relapse. Current research on the sex differences within craving is mixed. Some studies have found no significant differences in craving between men and women for cocaine or alcohol use disorder. In contrast, for opioid use disorder, women have greater craving scores than men. These mixed findings may be related to the involvement of sex hormones in the changes in spine density in neurons and how this impacts craving. Changes to neuronal spine density (how neurons connect in the brain) in the nucleus accumbens are thought to promote craving over time. Sex hormones impact spine density, where testosterone decreases and estradiol increases spine density. The interactions between sex hormones, types of substances used, and their impact on neuronal connections likely contribute to variations in craving.

Psychosocial Factors 

Psychosocial factors are known to impact the onset of addiction, such as stressful life events and childhood trauma. One study found that greater severity of childhood emotional trauma, sexual trauma, and overall childhood trauma was associated with higher cocaine use and an increased risk of relapse in women with cocaine use disorder, and this association was not found in men. This association is not limited to childhood trauma, but previous research has shown that women have a greater daily use of cocaine following stress-induced relapse compared to men. Both stress and trauma-related findings are theorized to be related to hypoactivation observed in the ventromedial prefrontal cortex (vmPFC; a key brain region contributing to reward and decision-making) in women. The dysregulation of the vmPFC is suggested to increase relapse and drug-seeking behaviour in women as it creates a more significant obstacle in self-regulation and control over emotionally regulated behaviours.

Implications and Treatment

While acknowledging the neural and behavioural sex differences in addiction has gained research interest, sex has not been well-considered in the development of treatment options for addiction. While some specific targets, such as noradrenergic, cholinergic, antidepressants, and GABA, have been examined in addiction research, there is a lack of focus on how sex differences affect these areas. Only noradrenergic targets consistently show that women tend to have better outcomes with tobacco and cocaine addiction. However, other treatment strategies, like withdrawal treatment or reinforcement blocking, do not have apparent sex-specific effects. Sex considerations should influence addiction medication and treatment development, given that women often experience more stress-related vulnerability, quicker addiction onset, and severe withdrawal symptoms, making research into these areas essential for sex-informed treatments.

 

*This blog was posted in honour of Substance Use Awarenss Week

Behind the Science: The Bidirectional Relationship of Behaviour and Stress

Authors: Romina Garcia de leon and Shayda Swann, Women’s Health Blog Coordinators | Interviewee: Dr. Annie Duchesne, Ph.D., University of Northern British Columbia

Published: Nov 17th, 2023

Can you give us a brief explanation of your research? 

I’m particularly interested in understanding how variations in hormones influence or regulate our behaviour, but also how our behaviour may regulate our hormonal processes. 

Over the years, I’ve been interested in understanding how contexts such as stressful situations might be influencing ovarian hormones (estrogens and progesterone). There’s a lot of interplay between the stress and endocrine systems. They often tend to regulate the same or similar affective and cognitive processes, but they’re often studied independently. I have a lot of interest in understanding the two systems together, and I’ve developed various approaches. 

The first approach involves measuring hormone levels and exposing people to different tasks. The second approach is to use observational studies where we take advantage of already accessible databases to try to answer these questions. These studies allow us to add a bit more complexity, given the larger sample sizes.

Studying this interplay is also relevant when we’re interested in questions of sex and gender. The sociocultural constructions of sex-related traits is a central dimension of gender. These constructions inform the way in which people are expected to behave in general and with respect to sex-related traits and situations. And often, our gendered constructions transform sex-related phenomena into specific sources of stress. So I do believe there’s a lot of relevance in studying the handover between stress and the gonadal system, particularly when interested in understanding the ramifications of sex and gender. 

How did you get into the field of women’s health? 

My undergraduate degree was in molecular biology. From these studies, the question that remained was how do people adapt to their environments. My first foray into this question was through conducting research on materno-fetal physiology within Dr. Julie Lafond’s laboratory. Specifically, understanding the metabolic physiology of the placenta. At that time Dr. Lafond’s laboratory was interested in how maternal variation in lipidic and toxicological profiles could influence fetal development through placental physiology. This research experience allowed me to realize the central role that the endocrine system plays in communicating what’s going on in the environment and adaptively relaying this information to all other physiological systems so that the organism is best prepared for a variety of upcoming situations. 

During my Master’s degree, I channelled my interest in endocrinology, development and adaptation to investigate the development of the biobehavioural stress processes. Fascinated by Michael Meaney’s research – which transformed our neurobiological understanding of the interplay between the environment, maternal behaviour and the development of the hormonal stress response, I went to work with Dr. Ron Sullivan who was one of the few researchers who looked at the sex difference in the role that maternal behaviour could have in the development of the stress responses. There, I discovered that variation in the environment can differently impact male and female rats, but also realized how we systematically excluded female animals from most behavioural neuroscience research. I continued to research the interplay between stress and sex-related variables during my PhD which I conducted in humans under the supervision of Dr. Jens Pruessner where I studied the interplay between stress and the menstrual cycle on affective processes. Finally, during my postdoctoral research, I continued to investigate neurobehavioural underpinnings of reproductive phenomena by investigating the cognitive correlates of menopause-related endocrine changes in Dr. Gillian Einstein’s lab. Findings from this project support that the type of menopause, in particular whether you have had a spontaneous or surgical menopause moderates the neurocognitive correlates related to menopause.

Could you highlight some of your most important findings or highlights from your research?

One central idea is that the relationship between hormones and behaviour is context-contingent. For instance, during my PhD, I demonstrated that the relationship between cortisol levels and participants’ reported levels of stress changed completely depending on which menstrual cycle they were in. These are crucial findings! Once you have recognized that how hormones can influence brain and behaviour is contingent on context, the second important question is what are the contextual dimensions that are relevant?  

What has been an increasingly important field of investigation in behavioural neuroendocrinology, particularly about women’s health, is the use of feminist theory and feminist research to articulate and operationalize aspects of women’s experiences as relevant contextual dimensions, to then investigate how that particular context may moderate the interplay between hormones, brain and behaviour.  

For example, the menstrual cycle is best characterized as a biosocial phenomenon. Seminal work by feminist scholars has demonstrated how sociocultural attributions about women’s bodies inform how menstruating people feel and behave when menstruating, for example, feeling pressured to conceal one’s menstruation. By understanding women’s endocrine phenomenon as biosocial, relevant, yet often overlooked, contextual dimensions can be incorporated into our understanding of the neuroendocrine underpinnings of reproductive phenomena such as the menstrual cycle.    

Such an approach allows for the necessary resolution to advance bio-behavioural understandings of women’s health that avoids biological essentialist biases and prevents the belief that women are determined by their sex-related biology.

What impact do you hope to see with your work 10 years from now?

I hope I continue to complexify and nuance my understanding and investigation on behavioural neuroendocrinology, stress and reproductive phenomena. I wish that my ideas allow for a more refined and inclusive perspective. We all come to our object of study from a specific perspective or standpoint and therefore carry biases. I hope that more researchers within women’s health and behavioural neuroendocrinology (including myself here!) continue to critically engage and self-reflect on their own biases as well as the ones carried by their fields of research. 

I hope that approaching reproductive phenomena as biosocially entangled becomes more of the norm than the exception in biobehavioural research particularly concerning sex and gender. More generally, I hope that culture is no longer pinpointed against nature but rather that an organism’s biology, culture and environment are embraced as constitutive, dynamic and interdependent. 

Lastly, I hope for a continued diversification of the research in behavioural neuroendocrinology and women’s health. This includes but is not restricted to, who is conducting the research, the geographical locations from where the research is being conducted, the participants being included in the research, and the questions, methods and epistemologies used to advance understanding. 

If you’re interested in joining the NeuroGenderings Book Club, check it out here. 

Check out more of Dr. Duchense’s work here and here. 

If you’re interested in more about the processes and impact of racism and whiteness within the Canadian academic context, check out this collective.

Behind the Science: Clearing the Fog of Midlife Ovarian Removal and Cognition

Interviewee: Alana Brown, Ph.D. Candidate, University of Toronto, Authors/Editors: Romina Garcia de leon, Shayda Swann (Blog Co-coordinators).

Published: July 14th, 2023

Could you tell us about your research?

In Dr. Gillian Einstein’s Lab of Cognitive Neuroscience, Gender, and Health, my PhD work explores the relationships between ovarian hormones (e.g., 17β-estradiol) and cognition, specifically in women with breast cancer gene mutations who opt to have bilateral salpingo-oophorectomy, which is the removal of both ovaries and fallopian tubes. This surgery usually occurs for cancer prevention purposes around 10 years prior to the typical age of spontaneous/natural menopause (~51 years). Bilateral salpingo-oophorectomy results in an abrupt and early loss of ovarian hormones. Our group in Dr. Einstein’s lab is trying to understand the cognitive impact of this hormone loss, especially given that oophorectomy is associated with an increased risk of developing Alzheimer’s disease (AD) in later life.

What drove you to study women’s health research? 

There is a dearth of research examining factors contributing to cognition among middle-aged women. The spontaneous menopause transition is a time period often defined by self-reported brain fog. So, women are specifying that their memory is changing during this period. Not only is there a gap in research to try to understand this change, but this is also a unique opportunity to answer more nuanced questions about memory in a healthy population. This research gap is even wider for women with bilateral salpingo-oophorectomy.

It is really interesting that we can ask richer questions about memory by looking at an ovarian hormone shift that affects a large number of people in the world. For example, how can the memory changes associated with ovarian hormone loss be differentiated from the memory changes associated with aging? How can we use ovarian hormone-related structural and functional brain changes to answer questions about how the brain supports memory more broadly? In the realm of neuroimaging, menopause and sex-specific factors are conflated with aging and largely overlooked and disregarded. It is very common to see neuroimaging research focusing on aging by studying groups of young adults who are 35 or younger and comparing them to groups of older adults who are 65 or older. The large gap between those age groups, representing midlife, during which menopause is typically occurring, is often ignored. There is a really small percentage of research looking at female-specific outcomes during that time.

What impact do you hope to see with this work?

I hope that this work can contribute to a larger picture of precision medicine. Given that we are studying a group of women who are at increased risk for AD, there may be implications for AD biomarkers. Female-specific AD risk factors must be studied and clarified. I hope this work can contribute to a larger body of research focused on studying people and the complexities of their lives while integrating that complexity into neuroimaging. Further, I hope we know more about the functional effects of reproductive aging and/or ovarian hormone loss in the future, above and beyond the effects of aging. This is new territory for neuroimaging. Those considering bilateral salpingo-oophorectomy deserve to be fully informed and aware of what they may experience after the surgery.

Have you seen any interesting findings yet in your research? 

We are finding that oophorectomy without 17β-estradiol  replacement therapy is associated with decreased hippocampal activation, specifically while learning/encoding during a face-name pair memory paradigm that is thought to be sensitive to AD progression. The hippocampus is a brain area critical for learning/memory and is also among the first regions affected by AD. We do not see the same pattern in individuals with oophorectomy who are taking 17β-estradiol replacement therapy. It is possible that 17β-estradiol has a role in maintaining function in the hippocampus and potential markers of AD risk could be detected in midlife. 

Where can people find more about your work?

Twitter: @4alanabrown and @EinsteinLabUofT, 

Online: https://einsteinlab.ca

LinkedIn: https://www.linkedin.com/in/alana-brown-23544a111/

Check out this recent publication by Alana and the Einstein Lab on how midlife ovarian removal affects cognition!

Using the Power of Sex Differences in Research: What a difference 10 years Did Not Make

Authors: Rebecca Rechlin, BSc Behavioural Neuroscience; Tallinn Splinter, BSc Biology, University of British Columbia | Editors: Negin Nia, Romina Garcia de leon  (Blog Coordinators).

Published: August 26th, 2022.

Females have been overlooked in health research for decades, and despite 10 years of advancements and improvements in knowledge, this has still not changed significantly.  Historically, there has been a long-standing bias of using males predominantly in scientific research instead of females, and as male and female health differ, this has led to health disparities for both males and females. Biological differences between females and males exist in diseases, such as in disease progression, symptomatology, and drug efficacy in many neurological and physiological diseases.

The study of these sex differences is essential for the understanding and advancement of disease treatment and precision medicine. For example women have double the risk for adverse drug reactions compared to men, which may in part be due to incorrect dosing (for instance despite both men and women being recommended the same dose for acetaminophen, an active ingredient in Tylenol, women break down the drug 60% slower than men). The biomedical and clinical research community is beginning to make corrections for these inequalities by issuing mandates for including females in clinical trials (such as by the NIH in 1993), and frameworks from funding agencies to address sex and gender in upcoming research (CIHR: Sex and Gender based Analysis (SGBA)) in 2010, and NIH: Sex As a Biological Variable (SABV) in 2016), however, there is still a long way to go to reach equality. Despite these mandates and increased approving attitudes towards these policies, the literature shows very little improvement in the analysis or examination of any potential sex differences.

Our study aimed to investigate whether and how possible sex differences were being investigated in neuroscience and psychiatry research. We looked at over 3,000 neuroscience and psychiatry studies in 2009 and in 2019 to see whether researchers were including both sexes in their studies. We found that only 53% of these studies actually included both males and females, and only 16.5% of these used an equal number of males and females throughout their study. Of the papers that used both sexes only 6% actually analyzed sex as a discovery variable. We found that the majority (60%) of the papers that used both sexes did not do any analysis by sex. This is concerning, as this means that we will lose out on important scientific discoveries if researchers are failing to embrace the power of studying potential sex differences. 

 

Figure 1: An infographic depicting the change in percentages of total papers sampled reporting studies in 2009 and 2019 that used both sexes, a single sex, omitted sex, papers reporting studies that used an optimal design or analyses for the discovery of possible sex differences irrespective of discipline. Reprinted with permission from Rechlin et al. 2022

It is important to note that biology sex and gender are two different things, and neither one is binary. Sex refers to the biological and physiological attributes of females and males, whereas gender is a psychosocial construct that includes one’s gender identity, and the norms and expectations set out by society. In our analysis we focused on studies using males and females (or sex) in rodents, humans and in research using cell lines, but the study of gender differences is also important to study and examine in regards to disease and treatments.

However studying sex differences, while important is not the only path towards equitable findings and discoveries in both men and women’s health research. With that in mind we found that although 27% of all studies in 2019 were conducted in males, only 3% were in females only! That means there were 9x more studies in males than in females! This greater focus on male health likely contributes to the health disparity and contributes to the historical male bias in assuming females and males are the same. Single sex studies are still essential for the discovery of sex-specific diseases/conditions such as prostate cancer in males and cervical conditions in females. Females specific factors, such as pregnancy and menopause, contribute to health outcomes and disease risk. For example, depression has a higher prevalence in women than men, and the risk of depression is largely increased during perimenopause and during the postpartum period.

So what can we do to improve these disparities? For starters, researchers need to actually analyze their data by using sex as a factor (or discovery variable). This essentially means including sex as one of the independent variables of the study (and not just controlling for it), allowing for the discovery of potential sex differences. It is also important for researchers to use a balanced and consistent study design, meaning they need to use both males and females consistently and in relatively equal numbers throughout their study. And even if they don’t find any sex differences, then the paper should make that statement with supporting statistics and a table to show the means and variation of the dependent variables by sex. This information of no sex differences is just as important as the discovery of them.

For funding agencies, one solution is to have funding dedicated specifically for SABV and SGBA proposals and not as a supplement to regular funding. More training modules from funders or scholarly organizations with an SABV focus may help, however, enticing researchers to explore the influence of sex and gender in their data may be a more fruitful approach. If journals, especially those with higher visibility, adopt calls for papers using sex and gender-based analyses this may serve as a catalyst to ensure more researchers consider possible sex differences and further promote the notion that this research is important to publish. Since we published our paper – Nature journals have committed to ensuring sex and gender are considered in their study design, by requiring authors to state how and why sex/gender was considered, or to state why it was not. If implemented as intended, this is a good first step to increase the amount of studies considering sex and gender in their analysis, and may be a great leap towards fixing these health disparities.