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- Cover Article Research Articles, Behavioral/Cognitive Association between Inhibitory–Excitatory Balance and Brain Activity Response during Cognitive Flexibility in Young and Older Individuals Geraldine Rodríguez-Nieto , David F. Alvarez-Anacona , Dante Mantini , Richard A. E. Edden , Georg Oeltzschner , Stefan Sunaert and Stephan P. Swinnen Journal of Neuroscience 12 August 2024, 44 (36) e0355242024; https://doi.org/10.1523/JNEUROSCI.0355-24.2024
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The Scientific Reports team is pleased to announce the most read* articles from 2021 in Neuroscience. Featuring authors from around the world, these papers highlight valuable research from an international community.
In 2021, Scientific Reports published over 3,460 Neuroscience papers and we are pleased to share with you 100 of the most downloaded articles* from last year.
Top 100 in Neuroscience
Congratulations to all authors who contributed to these highly valuable research papers!
*Data obtained from SN Insights, which is based on Digital Science's Dimensions.
Antonia is a Senior Editor at Communications Psychology . She holds a PhD in Psychology from Goldsmiths, University of London. She joined Springer Nature in 2020 as an Associate Publishing Manager at Nature Masterclasses , from which she then moved to Scientific Reports as an Associate Editor before joining Communications Psychology in 2023.
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| Title | Type | --> | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | journal | 12.261 Q1 | 479 | 281 | 622 | 12439 | 10101 | 497 | 14.93 | 44.27 | 39.09 | ||
| 2 | journal | 8.658 Q1 | 261 | 20 | 76 | 2705 | 1168 | 76 | 13.12 | 135.25 | 40.00 | ||
| 3 | journal | 7.860 Q1 | 474 | 109 | 405 | 9497 | 4615 | 256 | 11.20 | 87.13 | 41.21 | ||
| 4 | journal | 7.728 Q1 | 530 | 357 | 1184 | 23601 | 12277 | 943 | 9.43 | 66.11 | 38.91 | ||
| 5 | journal | 5.705 Q1 | 30 | 199 | 282 | 7723 | 2481 | 174 | 8.80 | 38.81 | 43.10 | ||
| 6 | journal | 5.489 Q1 | 429 | 332 | 875 | 24492 | 8011 | 778 | 8.50 | 73.77 | 42.02 | ||
| 7 | journal | 4.891 Q1 | 318 | 103 | 301 | 9591 | 3589 | 294 | 10.81 | 93.12 | 42.21 | ||
| 8 | journal | 3.932 Q1 | 206 | 1655 | 6193 | 114687 | 41633 | 6031 | 6.16 | 69.30 | 39.97 | ||
| 9 | journal | 3.822 Q1 | 305 | 471 | 1083 | 28978 | 8954 | 1064 | 6.34 | 61.52 | 40.54 | ||
| 10 | journal | 2.982 Q1 | 361 | 867 | 2759 | 42659 | 14075 | 2060 | 4.65 | 49.20 | 37.10 | ||
| 11 | journal | 2.982 Q1 | 250 | 116 | 408 | 9048 | 2307 | 392 | 5.02 | 78.00 | 36.13 | ||
| 12 | journal | 2.831 Q1 | 154 | 306 | 983 | 21252 | 9731 | 983 | 9.08 | 69.45 | 45.45 | ||
| 13 | journal | 2.605 Q1 | 256 | 79 | 303 | 8388 | 2210 | 290 | 7.08 | 106.18 | 39.76 | ||
| 14 | journal | 2.450 Q1 | 357 | 501 | 2013 | 16389 | 11117 | 1671 | 5.33 | 32.71 | 37.59 | ||
| 15 | journal | 2.438 Q1 | 108 | 209 | 733 | 8048 | 3529 | 407 | 4.50 | 38.51 | 35.81 | ||
| 16 | journal | 2.321 Q1 | 503 | 664 | 2250 | 44148 | 10887 | 2213 | 4.32 | 66.49 | 41.91 | ||
| 17 | journal | 2.164 Q1 | 80 | 98 | 425 | 7835 | 2424 | 417 | 4.34 | 79.95 | 43.83 | ||
| 18 | journal | 1.937 Q1 | 148 | 92 | 277 | 4334 | 1484 | 223 | 5.02 | 47.11 | 38.01 | ||
| 19 | journal | 1.851 Q1 | 34 | 0 | 14 | 0 | 80 | 13 | 5.71 | 0.00 | 0.00 | ||
| 20 | journal | 1.695 Q1 | 70 | 229 | 692 | 9196 | 3196 | 657 | 4.39 | 40.16 | 43.95 | ||
| 21 | journal | 1.686 Q1 | 93 | 206 | 591 | 12260 | 3453 | 547 | 5.64 | 59.51 | 61.44 | ||
| 22 | journal | 1.639 Q1 | 93 | 77 | 217 | 7174 | 1265 | 217 | 4.97 | 93.17 | 48.62 | ||
| 23 | journal | 1.595 Q1 | 145 | 86 | 169 | 7388 | 749 | 133 | 4.62 | 85.91 | 40.68 | ||
| 24 | journal | 1.595 Q1 | 72 | 176 | 295 | 8897 | 1729 | 276 | 5.17 | 50.55 | 33.22 | ||
| 25 | journal | 1.574 Q1 | 31 | 68 | 121 | 5650 | 512 | 119 | 3.27 | 83.09 | 36.29 | ||
| 26 | journal | 1.561 Q1 | 71 | 47 | 80 | 4955 | 401 | 78 | 4.17 | 105.43 | 46.49 | ||
| 27 | journal | 1.531 Q1 | 81 | 101 | 393 | 8657 | 1383 | 369 | 3.47 | 85.71 | 43.03 | ||
| 28 | journal | 1.520 Q1 | 18 | 299 | 579 | 11528 | 1993 | 576 | 3.44 | 38.56 | 44.51 | ||
| 29 | journal | 1.488 Q1 | 212 | 183 | 764 | 11838 | 3173 | 759 | 3.71 | 64.69 | 47.27 | ||
| 30 | journal | 1.416 Q1 | 289 | 134 | 614 | 8026 | 3430 | 590 | 4.77 | 59.90 | 44.10 | ||
| 31 | journal | 1.396 Q1 | 91 | 47 | 180 | 3170 | 941 | 156 | 4.59 | 67.45 | 48.06 | ||
| 32 | journal | 1.370 Q1 | 66 | 196 | 489 | 13331 | 1948 | 405 | 3.72 | 68.02 | 41.46 | ||
| 33 | journal | 1.365 Q1 | 22 | 81 | 209 | 5971 | 1446 | 207 | 6.45 | 73.72 | 45.77 | ||
| 34 | journal | 1.361 Q1 | 107 | 221 | 542 | 12548 | 1820 | 465 | 3.20 | 56.78 | 49.50 | ||
| 35 | journal | 1.339 Q1 | 140 | 692 | 1289 | 55850 | 6572 | 1288 | 4.86 | 80.71 | 48.30 | ||
| 36 | journal | 1.315 Q1 | 164 | 477 | 893 | 22947 | 5340 | 890 | 5.44 | 48.11 | 34.57 | ||
| 37 | journal | 1.303 Q1 | 176 | 287 | 620 | 21871 | 2430 | 614 | 3.42 | 76.21 | 43.71 | ||
| 38 | journal | 1.250 Q1 | 48 | 88 | 116 | 5389 | 556 | 109 | 4.79 | 61.24 | 38.30 | ||
| 39 | journal | 1.250 Q1 | 92 | 115 | 372 | 4358 | 1379 | 151 | 2.36 | 37.90 | 33.17 | ||
| 40 | journal | 1.218 Q2 | 228 | 122 | 521 | 9254 | 1292 | 510 | 2.51 | 75.85 | 44.20 | ||
| 41 | journal | 1.217 Q2 | 55 | 26 | 113 | 1968 | 477 | 111 | 3.57 | 75.69 | 53.94 | ||
| 42 | journal | 1.183 Q2 | 61 | 318 | 1056 | 18979 | 2795 | 1023 | 2.34 | 59.68 | 40.63 | ||
| 43 | journal | 1.172 Q2 | 177 | 772 | 2451 | 43700 | 9343 | 2443 | 3.40 | 56.61 | 48.01 | ||
| 44 | journal | 1.147 Q2 | 114 | 145 | 573 | 12665 | 1726 | 558 | 2.91 | 87.34 | 47.00 | ||
| 45 | journal | 1.129 Q2 | 228 | 319 | 1253 | 24266 | 4032 | 1204 | 3.29 | 76.07 | 45.22 | ||
| 46 | journal | 1.109 Q2 | 60 | 239 | 686 | 8534 | 2489 | 647 | 3.48 | 35.71 | 43.76 | ||
| 47 | journal | 1.108 Q2 | 88 | 44 | 160 | 7044 | 757 | 160 | 3.98 | 160.09 | 46.43 | ||
| 48 | journal | 1.093 Q2 | 4 | 31 | 21 | 2444 | 83 | 20 | 3.95 | 78.84 | 50.00 | ||
| 49 | journal | 1.063 Q2 | 153 | 2252 | 5578 | 140414 | 21332 | 5336 | 3.19 | 62.35 | 42.61 | ||
| 50 | journal | 1.041 Q2 | 96 | 74 | 417 | 5947 | 1375 | 399 | 3.21 | 80.36 | 39.93 |
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- J Undergrad Neurosci Educ
- v.14(1); Fall 2015
An Instructor’s Guide to (Some of) the Most Amazing Papers in Neuroscience
Ian a. harrington.
1 Augustana College, Rock Island, IL 61201;
William Grisham
2 University of California, Los Angeles, Los Angeles CA 90095;
D. J. Brasier
3 Carnegie Mellon University, Pittsburgh, PA 15213;
Shawn P. Gallagher
4 Millersville University, Millersville, PA 17551;
Samantha S. Gizerian
5 Washington State University, Pullman, WA 99164;
Rupa G. Gordon
Megan h. hagenauer.
6 University of Michigan, Ann Arbor, MI 48106;
Monica L. Linden
7 Brown University, Providence, RI 02912;
Barbara Lom
8 Davidson College, Davidson, NC 28035;
Richard Olivo
9 Smith College, Northampton, MA 01063;
Noah J. Sandstrom
10 Williams College, Williamstown, MA 01267;
Shara Stough
Ilya Vilinsky
11 University of Cincinnati, Cincinnati, OH 45221;
Michael C. Wiest
12 Wellesley College, Wellesley, MA 02481.
Although textbooks are still assigned in many undergraduate science courses, it is now not uncommon, even in some of the earliest courses in the curriculum, to supplement texts with primary source readings from the scientific literature. Not only does reading these articles help students develop an understanding of specific course content, it also helps foster an ability to engage with the discipline the way its practitioners do. One challenge with this approach, however, is that it can be difficult for instructors to select appropriate readings on topics outside of their areas of expertise as would be required in a survey course, for example. Here we present a subset of the papers that were offered in response to a request for the “most amazing papers in neuroscience” that appeared on the listserv of the Faculty for Undergraduate Neuroscience (FUN). Each contributor was subsequently asked to describe briefly the content of their recommended papers, their pedagogical value, and the audiences for which these papers are best suited. Our goal is to provide readers with sufficient information to decide whether such articles might be useful in their own classes. It is not our intention that any article within this collection will provide the final word on an area of investigation, nor that this collection will provide the final word for the discipline as a whole. Rather, this article is a collection of papers that have proven themselves valuable in the hands of these particular educators. Indeed, it is our hope that this collection represents the inaugural offering of what will become a regular feature in this journal, so that we can continue to benefit from the diverse expertise of the FUN community.
Although the textbook has enjoyed a long period of dominance in the science classroom, trends in the direction of more active, methods-based teaching have bolstered the use of the raw material of science: the journal article. The benefits of teaching neuroscience (or any discipline) using its own literature are diverse and numerous. Perhaps the most obvious benefit has to do with the flexibility and accessibility papers afford. Decisions about whether to include one or more papers can be made quickly and these can be added to a course, as circumstances demand, even when the course is already underway. With the ever-rising costs of textbooks and college in general, a related benefit is that such papers do not lead to additional financial burdens for students. Individual papers or collections of them can serve to either supplement textbooks or, under some conditions, substitute for them altogether. Textbooks are very efficient at conveying large quantities of information; however, they tend to achieve that efficiency by sacrificing depth. Papers allow students to gain a clearer understanding of the methods and practices used in research, and provide an opportunity for a more critical assessment of a study’s conclusions (e.g., Hoskins, 2008 ; Willard and Brasier, 2014 ). This can be valuable in that it helps support the development of information literacy, critical thinking, and a general scientific disposition in students (e.g., Dirks and Cunningham, 2006 ; Hoskins et al., 2007 ; Hoskins et al., 2011 ; Kozeracki et al., 2006 ).
Late last summer one of us (Grisham) received an interesting request from a group of students as they neared the end of their summer research experience. Having read numerous articles relevant to their specific research projects, these students now wanted to read the most amazing neuroscience article ever. We are not certain they appreciated how tall an order this was. Is there a single most amazing neuroscience article ever? How would such a title be decided? When this request was put to the members of the Faculty for Undergraduate Neuroscience (FUN) by way of the organization’s listserv, more than a dozen nominations were made in short order. Although some of these papers could be considered landmarks (e.g., according to Google Scholar, Hodgkin and Huxley (1952d) has been cited more than 16,000 times), others were far more contemporary. Not surprisingly, however, there was little evidence of consensus (although Hubel and Wiesel’s 1962 paper on the physiology of the visual cortex, cited some 9,800 times, received multiple nominations). The nominations that were received are undoubtedly just the tip of the iceberg.
Given the nature of our training, it can be difficult to identify key readings on topics outside of our immediate areas of expertise. One of us (Harrington) was reminded of a quote that was prominently displayed in the lab of one of his undergraduate professors, Vincent LoLordo: “I am so small, and the literature…so vast.” In teaching practice, however, and this is especially true for those who teach survey courses, there is an expectation that we can find our way through this vast literature. The purpose of this article is to provide diverse recommendations for pedagogically valuable papers—recommendations made by undergraduate neuroscience educators, for undergraduate neuroscience educators—in order to promote a “collective expansion” of our appreciation of the neuroscientific literature. Each of the contributors has offered what they identified to be among the most amazing papers in a particular corner of the literature. Those who responded to the listserv request were asked to submit short descriptions of their recommended papers. In addition to describing the general content of these papers, they were also asked to describe how these papers have been useful in their teaching (what we have here termed their ‘value’). Finally, they were asked to describe the appropriate audience for their recommended papers.
We have organized the fourteen submissions included here by topic to the extent that was possible. The first four submissions address more fundamental issues including neural transmission (Gizerian), electrical excitability and K+ channels (Vilinsky), long-term potentiation (Brasier), and adult neurogenesis (Lom). These papers are followed by two concerning biological rhythms, the first addressing the effects of time-cue deprivation (Hagenauer) and the second related to sensory control of circadian rhythms (Gallagher). From here we turn to a paper about the study of the visual cortex (Olivo), and two papers that address plasticity: sensory plasticity following brain rewiring (Harrington) and cognitive plasticity following brain damage (Gordon). Following this are three papers related to the endocrine system including the effects of steroids (Sandstrom), neural correlates of sexual orientation (Grisham), and sex differences in spatial abilities (Stough). Like the paper reviewed by Stough, the final two submissions also relate to the hippocampus but instead of its role in spatial behavior they focus on memory, specifically on the induction of false memories (Linden) and the transplanting of memories (Wiest) by hippocampal stimulation. We hope that these brief descriptions will be sufficient to guide decisions about whether to include some of these papers in your courses. Moreover, we hope that collections like this one will become a regular feature of JUNE in the future.
How neurons conduct messages
Contributor:.
Samantha Gizerian
Membrane currents; membrane potential; ionic current; action potential; conduction; Loligo
References:
Hodgkin, Huxley, and Katz, 1952 ; Hodgkin and Huxley, 1952a , 1952b , 1952c , 1952d
Description:
In a series of five elegant papers, Hodgkin and Huxley (and Katz) describe the movement of current through the squid ( Loligo forbesi ) giant axon as well as the relationship between membrane potentials and currents. These papers together were the first to describe the electrical properties of neurons and neuronal membranes. In addition to their invaluable contribution to science, these papers represent the development of technologies still in use today. At 400–800 μm in diameter, the Loligo giant axon was the first nerve structure discovered that was large enough to be penetrated by a microelectrode and, thus, could be investigated using the tools available at the time (1939–1952). In the first paper of this series, Hodgkin and Huxley describe the electrode, amplifier, and signal recorder they created and then demonstrate proof of concept for both the current clamp and voltage clamp techniques. Modern current/voltage clamp experiments are done with equipment based on these early instruments. The next three papers in the series use the techniques set forth in the initial paper to describe the currents that travel through neuronal membranes, the ions whose movement are the basis of those currents, membrane potentials, and the relationship between membrane potentials and the movement of ions through the neuronal membrane. The fifth and final paper in the series summarizes all of the previous results into the mathematical model that serves as the foundation for our understanding of membrane properties and action potential production and propagation today.
This series of papers is invaluable to the history of neuroscience as well as to our understanding of the electrical properties of neurons. Hodgkin and Huxley’s findings serve as the foundation of modern neurophysiology and have broadly influenced scientists in many disciplines. Moreover, studying these papers gives students a unique insight into how data analysis is used to build models. The electrical properties of neurons, as presented in most textbooks, are represented by a series of increasingly complicated mathematical equations. Students, even those with a strong calculus background, often find these equations cumbersome to manipulate and apply because they have little understanding of the physiological processes represented. In reading these papers, students can approach the problem from the other direction. That is, how does the physiology of the neuron serve as the basis for the mathematical model? Students typically know about as much about membrane currents at the beginning of a course as Hodgkin and Huxley did at the beginning of their studies, so it is easy for students to walk alongside these pioneers in their own journey of discovery, learning how neurons work as they build and apply the mathematical model of electrical signaling in neurons and, thus, gain a deeper understanding both of the function of neurons and the basis of many of our investigations of them. Moreover, if the appropriate facilities are available, students can reconstruct Hodgkin and Huxley’s experiment as a laboratory exercise, collecting and analyzing data de novo.
These papers would be suitable for an upper-level course (or an introductory graduate course) on electrophysiology or biophysics, or in a neural physiology unit in an upper-level anatomy/physiology course. It is important that students have a strong background in math and physics, including differential calculus and electricity/magnetism in order to work through the mathematics of the model, so these papers are less suitable for lower division or introductory classes in neuroscience or physiology.
Discovering the mechanisms of electrical excitability
Voltage-gated ion channels; genetics; biochemistry
Kamb et al., 1987 ; Tempel et al., 1987 ; Wei et al., 1990 ; Zhou et al., 2001
The first two papers in this series ( Kamb et al., 1987 ; Tempel et al., 1987 ) are independent accounts of how “forward genetics” was first used to fish out the first voltage-gated K+ channel sequence in Drosophila. In forward genetics, investigators start with an interesting phenotype and use it as a “hook” to find the corresponding gene. Electrophysiology on the mutant line known as “Shaker,” where the flies display characteristic leg twitches when anesthetized, reveals defects in potassium currents. The predicted structure of the molecule responsible bore the hallmarks of a transmembrane protein and fit within a framework of how K+ channels were thought to work. For students, it is especially interesting to read these classic papers in light of our current knowledge of K+ channel structure and function. A fun exercise is to see how many of the early predictions from the initial sequence have been proven correct.
Wei et al. (1990) extends the fast-growing field of K+ channel physiology by using sequence homology to find related channels. The K+ channel family is vast. In fact, it is the most abundant member of the voltage-gated ion superfamily. Wei et al. describe four major types of K+ channels—Shaker, Shab, Shal and Shaw—in Drosophila, mouse, and by extension all animals (the naming of these genes, and the naming schemes for Drosophila genes in general, make for interesting stories on their own).
Zhou et al. (2001) exemplifies more recent structural and biochemical work on K+ channels, a field that has expanded greatly since the late 1980’s and now includes computational theorists, biochemists, and ecologists. The MacKinnon group described a high-resolution crystal structure of a K+ channel for the first time. This paper, surprisingly readable by undergraduates despite the highly specialized techniques used, is one of the reasons Rod MacKinnon was awarded the 2003 Nobel Prize in Chemistry. Some of the questions addressed by this and similar reports include: 1. How can an ion channel be so selective, especially for ions like K+ and Na+, which have similar physical characteristics? 2. Given this extreme selectivity, how is it that K+ channels have such a high conductance, with the speed of K+ ion transport being similar to that of K+ ion diffusion through water? 3. How does the K+ channel actually change shape in response to electrostatic charge across the membrane? 4 How does the detailed knowledge gained from the high-resolution structure affect the view of channel function inspired by previous experiments?
This series of papers ranges from “classical” to “cutting-edge.” Voltage-gated ion channels drive electrical excitability in neurons, and thus determine how information is processed in the brain. This is especially true for voltage-gated K+ channels; these molecules are astoundingly diverse, yet share fundamental functional principles and largely determine the excitation characteristics of neurons. The story of how K+ channel structure was characterized is a great example of interdisciplinary research, incorporating genetics, electrophysiology, evolutionary biology, genomics, and biochemistry. In my courses, I use these papers to drive home the importance of utilizing multiple levels of analysis and diverse model systems.
I have taught selections from these papers in a neurophysiology lab course, where they served as a great complement to the applied work, and allowed students to put their experimental results into context. These papers would work well in a mid-level to advanced undergraduate neuroscience or neurobiology course, and are perfect for graduate level courses.
Is LTP expressed pre- or post-synaptically?
Plasticity; LTP; synapse function; electrophysiology
Kauer et al., 1988 ; Malinow and Tsien, 1990 ; Stevens and Wang, 1994 ; Liao et al., 1995
This material is incredibly fun to teach because it is as much a human history as it is a scientific one. Prior to beginning, students should have a background understanding of synaptic release and transmission, including AMPA and NMDA receptors. In the drama that will unfold, the pre-synaptic cells are the CA3 neurons in the hippocampus and the post-synaptic cells are the CA1 neurons. Students get to learn more detail about synaptic physiology (one vs. multiple points of contact and release probability vs. post-synaptic sensitivity) in the context of the debate. Typically, I begin with the Stevens and Wang (1994) and Malinow and Tsien (1990) studies to explore the pre-synaptic side of the debate. These studies, in particular, require students to review basic probability and statistics. Then, I present apparently contradictory results from Kauer et al. (1988) . We discuss the assumptions and caveats of each study. Students are frequently asked to evaluate and re-evaluate their positions as the discussion unfolds. Typically, after the Stevens/Wang and Malinow/Tsien papers are discussed, the majority of the class believes LTP is pre-synaptic. Subsequent discussion of the Kauer et al. study usually leaves the class split with many students unsure or believing both changes happen. I often conclude with the discovery of silent synapses ( Liao et al., 1995 ). This is finding especially dramatic because it provides a novel theoretical framework that upends some of the assumptions made by the Stevens/Wang and Malinow/Tsien studies; a postsynaptic change can explain most – but not all – of the results the pre-synaptic camp relied on to support their view. After this, a majority of students tend to believe the post-synaptic theory, but a minority still cites particular unanswered questions. I do not insist that students accept the consensus postsynaptic view, but encourage them to evaluate the data and come to their own conclusions.
Students have the opportunity to follow an historic story in neuroscience. They experience difficulty reconciling two contradictory models each with its own supporting evidence. The personalities of the scientists involved can also be discussed. One central figure, Roberto Malinow, is especially interesting as he provides a rare case of someone experimentally overturning his own opinion. The resolution of the controversy provides a great example of how new data can force a re-evaluation of past assumptions and suddenly allow a single consistent model to explain seemingly contradictory pieces of data. Although the material is difficult for students at all levels, the insight into the scientific process is profound ( Willard and Brasier, 2014 ). Also, a good deal of experimental cellular neuroscience is explored and students are given a chance to apply math to neuroscience. Finally, although students are not required to learn the current consensus view that LTP at this synapse is postsynaptic, at the end I do tell them that that is the consensus; the minority who feel that this consensus is not completely satisfying (there are some results it cannot fully explain) are encouraged to share their views. Students also begin to consider not only the value of data, but the reproducibility of data.
The sequence as described works for introductory students with no specific background other than synaptic transmission which is discussed leading up to this. The sequence takes three 50-minute class periods on top of the pre-requisite knowledge of how synapses work, AMPA vs. NMDA receptors, and a basic introduction to LTP. For introductory students, a good deal of class time is spent on the mathematical and theoretical foundations of the work as well as some superficial explanations of the methods of data collection and analysis. The key to success with this difficult material is targeted homework assignments before each class period to prepare the students for thinking about the data. More advanced students with a stronger statistics background can go further and explore other synapses ( Weisskopf et al., 1995 ) or continuing challenges to the post-synaptic model ( Enoki et al., 2009 ).
Neurogenesis in the adult human brain
Postnatal neurogenesis; neuronal differentiation; staining, tracing, and imaging techniques
Eriksson et al., 1998
This paper is a simple and powerful clinical study that asked the question, “Is the adult human brain capable of making new neurons?” in response to the longstanding view that neuron loss was irreversible in the primate brain. (Adult neurogenesis in many other vertebrates had long been known and its absence in primates had been hypothesized as a potential evolutionary trade-off.) In the 1990s new evidence of adult neurogenesis in non-human primates began to emerge, acknowledging earlier evidence of neurogenesis in the adult primate brain that had gone largely ignored. To answer this important question Eriksson et al. were fortunate to have access to rare postmortem brain tissue of cancer patients who had consented to receive injections of BrdU, a marker of dividing cells, to assess tumor proliferation near the end of their lives. BrdU is a widely used synthetic nucleoside analog of thymidine (T) that can incorporate into the DNA of S-phase cells undergoing DNA synthesis. Due to its short half-life as a monomer, but long stability when incorporated into a new DNA strand, BrdU offers a unique opportunity for scientists to obtain a snapshot of cells preparing to divide at the time of BrdU administration. Given BrdU’s ability to integrate into the genome, it is a potential mutagen, thus, not appropriate for most human studies, yet widely used in animal studies of neurogenesis. Examining the brains of five consenting cancer patients after their natural deaths (roughly two weeks to two years after BrdU administration), this team of scientists in Sweden and California report a singular and striking result: hippocampal cells in the subventricular zone (SVZ), hilus, and granule cell layer (GCL) had incorporated BrdU. Thus, these images provided the first direct evidence that the adult human hippocampus is capable of generating new neurons, many decades into its life. The research team also combined BrdU staining with immunostaining for specific and widely used neuronal markers (NeuN, NSE, Calbindin) to confirm that BrdU-stained cells also stained for these markers of differentiated neurons, suggesting neuronal differentiation had occurred.
This paper firmly put out of business the popular conception that humans are born with all the neurons they will ever have. Even though the age of this paper is now approaching the age of college students, in my recent experiences many undergraduates have still heard from at least one source that adult neurogenesis is impossible in humans. Consequently, introducing this paper as a paradigm-shattering example motivates considerable student engagement. This paper can also be paired nicely with other papers examining neurogenesis in rodents and non-human primates, opening up lively conversations on the utility of animal models and species differences. In addition, this paper is particularly valuable as an example of a clinical research study which thereby stimulates natural and engaging discussions of critical research issues such informed consent, human subjects institutional review boards (HSIRBs), institutional animal care and use committees (IACUCs), appropriate sample sizes, and other important considerations for responsible conduct and scientific rigor in contemporary research.
Students in my 200-level seminar (Neuroscience of Exercise) and 300-level lab courses (Cellular and Molecular Neuroscience) have read this paper with ease and enthusiasm. The paper is accessible in part because it is short and simple; using just two related staining techniques (BrdU labeling of mitotic cells and immuno-staining of neuronal markers). I expect this paper could be similarly interesting, accessible, and relevant in just about any undergraduate neuroscience course as well as in cell biology and developmental biology courses.
Living without time: Internal timekeeping in students isolated in a WWII bunker
Megan Hagenauer
Circadian rhythms; sleep; chronobiology
Aschoff, 1965
Like many classic papers, this one is not only a forceful scientific argument, but also a personal account of an adventure exploring the unknown. It describes the rationale, methods, and results for a series of studies in which German students volunteered to live in complete timeless isolation in an underground WWII bunker for 3–4 weeks to discover whether the human body was capable of independently tracking time by means of a biological clock. The paper introduces all of the major concepts of modern chronobiology, including free-running period, entrainment, zeitgebers, and desynchrony. It is also full of fascinating details regarding what the experiment felt like to the subjects—from their initial optimism regarding how much studying they would accomplish while living in total isolation, to the system of double doors for the delivery of goods and messages from the outside world, and the inclusion of beer as part of their daily provisions. The author, Jurgen Aschoff, is considered a father of chronobiology, and one of my favorite parts of this paper is his description of his own experiences in the bunker, trying out the experimental set-up. He describes his disorientation in response to waking up in isolation and having no idea how long he had slept, as well as his complete surprise when he emerged from the bunker on the “last morning” of the experiment and discovered that it was actually 3 p.m. Through the figures, including a beautiful chart of the daily fluctuations in metabolites in Aschoff’s own urine, we can clearly see evidence of the human body generating its own daily physiological schedule in isolation, and how it slowly drifts later relative to the outside world due to the complete absence of environmental time cues. We are also introduced to the evolutionary adaptiveness of a self-sustained timekeeping system, as well as the importance of biological clocks for human health. To make this last point, Aschoff presents evidence from an individual who had his sleep/wake cycle spontaneously desynchronize from his other physiological rhythms while in the bunker. On the days when his rhythms were properly re-synchronized, his diary notes that he felt “especially well and fit.” Using these data, Aschoff correctly predicts that forced internal desynchronization may explain the malaise felt by shift-workers, astronauts, and jet-lagged international travelers. In the end, it is impossible to read this paper without wondering whether you would be willing to take the challenge, and (in the name of science!) insert a rectal thermometer and enter an underground bunker to experience true timelessness.
I have used Aschoff (1965) as the first paper in a series of class periods aimed at introducing both the fundamental concepts of biological rhythms and skill of active reading. Since this is the first paper in the series, I typically recommend that the students start by reading a two-page popular science article that provides a colorful, illustrated description of the history of circadian biology and the bunker experiments ( Globig, 2007 ). I also provide a brief introduction to the research question and basic rhythm terminology (e.g., oscillator, frequency/period, phase, amplitude), and a few pieces of advice on how to extract the most important information from scientific papers.
The text of Aschoff (1965) is unusual for a scientific paper because it is short (five pages) and relatively unintimidating. In contrast, the figures can be quite challenging, so on the day that we discuss the paper, I have the students initially work through the paper in groups with a particular focus on deciphering and explaining the most important figures (Figs. 1–4 and 7). I structure the lesson this way because over the years I have found that approximately 1/5 of my upper-level science students still have serious difficulties interpreting graphs (even scatterplots or bar charts). Approximately 15 minutes into the class period, we come back together as a class and work our way through the key concepts, methods, results, and conclusions in the paper. My goal for this exercise is to encourage students to treat scientific writing and figures as a puzzle to decipher strategically, and to create an atmosphere where students feel comfortable building their own understanding of the concepts instead of simply hiding their ignorance by parroting the paper’s own formal scientific language and figure legends. I also use the theme of self-quantification and exploration in the Aschoff paper to introduce the first project for the semester: tracking personal sleep/wake rhythms using free, downloadable smart-phone applications (e.g., Sleep Cycle, Sleep as Android, SleepBot) or commonly-sold wrist actigraphy (e.g., Jawbone Up, Fitbit, iWatch).
I have used this paper in a 400-level seminar that I teach on sleep and circadian rhythms using classic primary literature, but I believe that it could be easily adapted for a unit in an introductory neuroscience course.
Circadian rhythms are driven by photosensitive retinal ganglion cells
Sensory and motor systems; vision; retina; photoreceptors; biological rhythms; sleep; SCN anatomy, physiology, neurochemistry
Freedman et al., 1999 ; Berson et al., 2002
These two short papers describe the prediction and subsequent discovery of light-sensitive retinal ganglion cells that project to the suprachiasmatic nucleus (SCN) and influence circadian behavior. In the first report, Freedman et al. (1999) conducted behavioral experiments with blind transgenic mice. Despite having no rods or cones, the mice exhibited normal circadian wheel-running behavior that vanished when the eyes were removed. This study, using a combination of transgenics, behavior, and the crude but effective practice of enucleation, made a compelling case that something in the eye, other than rods or cones, could detect changes in ambient illumination. The second report, by Berson et al. (2002) , takes the next step and provides evidence that the circadian clock is set by a subset of retinal ganglion cells that contain the photopigment melanopsin and project directly to the SCN. Using retrograde tracings (hypothalamus to retina) in rats, the authors marked the cells and recorded from them in isolated retina preparations. The recordings showed that, unlike the unmarked ganglion cells, these cells had unusually slow response times and were photosensitive, even when they were functionally disconnected from rods and cones. These ganglion cells, although inappropriate for image-forming visual pathways, are suitable for providing the SCN with information about slow-changing, ambient levels of illumination.
These studies elucidate the link between the mammalian retina and circadian rhythms. Taken together, the papers also present an excellent example of progressive science. One group conducts behavioral studies and makes a prediction while the next group completes the story with anatomical and electrophysiological evidence. In the classroom, these papers could bridge a description of the retina to discussions of the hypothalamus, circadian rhythms, or parallel processing in the optic nerve. Even novice neuroscience students should be familiar with basic retinal anatomy and be impressed by the discovery of photoreceptive ganglion cells. For psychology students, the results could be used to address the clinical significance of these cells since they may present a key to understanding seasonal affective disorder. Students interested in comparative neuroanatomy could explore the evolutionary history of melanopsin, a pigment that is present in the pineal gland of non-mammalian vertebrates. Darwin, himself, was troubled by his inability to imagine intermediate stages of the eye’s evolution; I think he would have liked the story of the ganglion cells that monitor sunrise and sunset.
These papers are clear and describe experiments that tell a simple story. The significance of the findings, however, can be discussed at many different levels. I recommend these papers for any course that introduces the anatomy of the retina. Students in basic psychology and neuroanatomy courses should understand how some retinal cells serve functions that lie, perhaps exclusively, beneath conscious visual perception. More advanced students, like those in a mid-level neurophysiology class, can compare the electrophysiology of the photosensitive and non-photosensitive ganglion cells to understand how the different response types serve different functions. Finally, students in experimental design classes should appreciate how the many techniques employed in these studies converge on a single, profound discovery.
Structure and function of the mammalian visual cortex
Cortical physiology; receptive fields; visual cortex
Hubel, 1982 [Although David Hubel died in 2013, this paper is still available (2015) on his website at Harvard Medical School: http://hubel.med.harvard.edu/papers/Hubel1982Nature.pdf ]
This paper, David Hubel’s 1981 Nobel Prize address, is a clearly written account of his collaboration with Torsten Wiesel to unravel the structure and function of the primary visual cortex (V1) in cats and monkeys. It is written from a personal viewpoint, explaining the decisions that were made and why they made them. It covers the physiology of single unit recordings, including a number of figures from Hubel and Wiesel’s early papers (e.g., Hubel and Wiesel, 1962 ; 1968 ) showing responses to oriented bars and edges, as well as anatomical figures showing layers in V1, ocular dominance columns, and even cytochrome oxidase blobs. It also includes their original summary figures showing models of synaptic circuits and the famous “ice cube” model of a cortical module. A few aspects have been refined by subsequent research (“hypercomplex” cells are now regarded as an extreme form of complex cells, and the “ice cube” model that shows wide ocular dominance columns perpendicular to narrow orientation columns demonstrates the concept but not the actual microanatomy of V1), but most of the information remains valid. The paper presents a detailed overview of what many consider the most important research program into the mammalian cortex, written by a pioneer in the field.
Although many people would regard Hubel and Wiesel’s two massive research papers on primary visual cortex in cat (1962) and monkey (1968) as the true classics of this era, this review of their work is in its own way a classic that serves students very well. While it is not as detailed as the original research papers, it does provide many original figures embedded in the context of the overall research program. The review covers both their physiological experiments to record from and classify single units in primary visual cortex (V1), and also their experimental attempts to determine the functional architecture of V1. The physiological models of how simple and complex cells might be driven by excitatory input from their presynaptic elements are also included, which have remained viable, if simplified, models of V1’s neural circuitry. The anatomical experiments have been superseded by newer optical techniques that more clearly reveal the overlap of ocular dominance bands and orientation pinwheels, but the “ice cube” module they proposed is of historical importance and still provides basic insight into the organization of V1. Finally, the paper includes anecdotes of Hubel and Wiesel’s personal experience, starting as postdocs with Stephen Kuffler at Johns Hopkins before they moved to Harvard Medical School. The personal accounts are a further reflection of Hubel’s clear and unpretentious writing style that makes this a very accessible paper for students.
I have used this paper as a reading assignment in an upper-level Neurophysiology course, where we spend several weeks on visual processing from retina through extrastriate cortex. The paper provides an appropriately detailed supplement to the relatively brief account of visual cortex in most textbooks; it hits the sweet spot between overly simplified textbook accounts and the original research papers.
Seeing with a rewired auditory cortex
Ian Harrington
Plasticity; cross-modal rewiring; cortical receptive fields; animal behavior
Sharma et al., 2000 ; von Melchner et al., 2000
Although any number of papers by this group could have been considered for inclusion here, I have found that these two papers, published in the same issue of Nature, work particularly well together. The first paper, by Sharma et al. (2000) , addressed whether cortical receptive field properties are determined by afferent inputs or reflect characteristics of the fields themselves. Considered another way, does auditory cortex look like auditory cortex regardless of the modality of its inputs? To address this question, neonatal ferrets had the projections from their eyes redirected to the auditory thalamus. This changed the modality of the input to the auditory cortex while maintaining the integrity of the projections from the thalamus to the cortex. The study demonstrated that cells in the rewired auditory cortex were not only visually responsive, but that their tuning for orientation and their local connections were similar to those found in normal visual cortex. The second paper, by von Melchner et al. (2000) , addressed a natural follow-up question raised by the previous one: When an animal with a rewired auditory cortex is exposed to visual stimuli, does it have visual or auditory experiences? In this study, ferrets were only rewired unilaterally to allow the animals to serve as their own controls. The animals were trained to make one response to centrally presented sounds, and another response to lights presented contralateral to their intact visual pathway. Once the animals were performing the task well, visual stimuli were presented from the central location and one contralateral to the rewired pathway. The animals were tested again following the destruction of all visual pathways other than the novel one from the auditory thalamus to the auditory cortex. The results showed that when visual stimuli were presented to the rewired auditory cortex alone, they were experienced visually. As was suggested by Sharma et al. (2000) , although the rewired auditory cortex is not an exact reproduction of the normal visual cortex (suggesting some intrinsic influences), it shares certain characteristics and is able to support visual experiences.
With only a small risk of hyperbole, these papers have it all: interesting surgical interventions, plasticity, cortical physiology (optical imaging and some single-cell recording), retrograde tracing of cortical connections, complex behavioral testing (with good experimental controls), animal psychophysics, and lesions. Perhaps the greatest value of these papers is to demonstrate the multidisciplinary approaches that are necessary to address complex questions in neuroscience. The methods can be challenging for undergraduate students to follow but these challenges are not insurmountable. The papers, given the format of Nature, are fairly brief, but are well written and include clear graphs and other figures. Because of the format, however, some methodological details are referred to other sources. These papers can also be read at different levels. I have mentioned some of the key findings of these studies in 5–10 minutes of class time (or had students work to understand a single data figure in small groups), but could also imagine spending one or more class periods working through the details of the papers with students.
I have used these papers in several courses including a 200-level Brain & Behavior and a 300-level Sensation & Perception, but could also imagine them being used in other upper level courses, especially in a senior seminar. As mentioned above, the papers and their findings can be pitched at several levels, as their use demands.
The prefrontal cortex and moral judgments
Rupa Gupta Gordon
Human cognition and behavior; decision making and reasoning; moral judgments; prefrontal cortex; plasticity
Koenigs et al., 2007 ; Taber-Thomas et al., 2014
These two studies address the role of the ventromedial prefrontal cortex (vmPFC) in moral decision-making using the lesion method. The first, by Koenigs et al. (2007) , compares the moral judgments of patients with adult-onset vmPFC damage to healthy comparison participants on personal versus impersonal moral dilemmas. These two forms of dilemma differ in that the personal form requires direct action (e.g., pushing a fat man off of a footbridge) rather than indirect action (e.g., pushing a button that diverts a train to a different track) in the interests of saving lives. Patients with vmPFC damage are more likely to endorse utilitarian actions in personal moral dilemmas, due to the lack of emotional response to the personal aspect of the moral dilemma. This finding suggests that the emotionally aversive reaction typically experienced when considering personal moral dilemmas depends upon the vmPFC. The second article, by Taber-Thomas et al. (2014) , builds upon this line of research by studying the effect of developmental vmPFC damage on moral judgments. Unlike adult-onset vmPFC patients, those with developmental vmPFC exhibit more self-serving behavior (e.g., pushing an annoying boss off of a building). This demonstrates the importance of the vmPFC for learning social and moral norms during development. However, once learned, the ability to use knowledge of these norms can occur in adults independent of the vmPFC, as adult-onset vmPFC patients do not endorse self-serving situations, but the vmPFC must be intact during development for the acquisition of intact moral knowledge.
Not only are these excellent examples of lesion studies using groups rather than single cases, but they also address a topic that evokes a flurry of debate in class. Furthermore, it leads nicely to a discussion of the role of free will in moral responsibility and the influence of neuroscience on other disciplines like law. It is beneficial for teaching about the research process, as it demonstrates the progression of a systematic line of research across time. Beyond the topic, there are valuable teaching opportunities in these articles to demonstrate basic research concepts. For example, in Koenigs et al. (2007) , students can discuss how “personal” vs. “impersonal” moral judgments were operationally defined based on the content of the story, while “high” and “low” conflict moral judgments were operationally defined based on the consistency of participants’ responses.
I have used these articles in an upper level seminar course on Cognitive Neuropsychology, where students read and analyze primary literature. However, the content is also appropriate for an introductory course in human neuroscience.
Steroids as a rejuvenating or anti-aging agent
Noah Sandstrom
Testosterone; steroids; aging; human behavior; history of neuroscience
Brown-Séquard, 1889
The world of professional sports is fraught with cases of athletes seeking to gain a competitive edge through the use of performance enhancing drugs. In many instances, the drugs of choice are anabolic steroids (e.g., testosterone). In recent years, steroid allegations have been made about Barry Bonds, Jose Canseco, Lance Armstrong, and countless others. At the same time, a legitimate scientific literature has explored the potential clinical utility of steroid replacement/supplementation for a variety of conditions (e.g., Alzheimer’s disease, hypogonadism) as well an intervention against naturally occurring declines in androgen production associated with aging. This report by Brown-Séquard is an absolute classic in which the author engages in self-experimentation to explore whether administration of extracts from the testicles of animals (guinea pigs and dogs) might positively impact some of the abilities and faculties that he notes have been waning with age. Brown-Séquard, noting these deficiencies (e.g., a developing inability to concentrate, constipation, fatigue, forgetfulness) uses a certain logic, misguided as we may now understand it to be, to design a study in which he grinds up testicles from animals, filters them (no sense in injecting anything gross!), and injects the extract into his bloodstream. He soon reports remarkable changes in his intellect, his stamina, and his powers of defecation and urination.
This is a wonderfully engaging paper that has value in several important regards. First, it speaks to the long history of interest and research in the effects of gonadal steroids on human behaviour. These ideas are at the foundation of the steroid scandals that plague so much of professional sports – an area of interest to many students. Second, it provides a rich case with which to begin discussing issues of experimental design and clinical trials. The “study” had no controls. The researcher wasn’t blind;; the subject wasn’t blind. In fact, they were the same person and we can quite confidently conclude that much of the effect that was reported was placebo in nature. But the paper can be a wonderful tool to start students on the assignment of trying to design an appropriate clinical trial to explore the fundamental questions of interest to Brown-Séquard. The paper is a not a state-of-the-art paper – rather, the complete opposite. It is a classic. Don’t use it to educate as to the current state of knowledge regarding hormone replacement therapy. Instead, use it to introduce the topic and get people to appreciate that some of the same questions we find fascinating today are the same ones that researchers were intrigued by over 100 years ago.
I have used this paper in an upper-level seminar on Hormones & Behavior. It’s on the reading list for day 1 alongside a couple of news reports or sports magazine articles on steroid abuse. I use it primarily to introduce the concept of hormones influencing behaviour but we revisit the topic later in the term when we talk specifically about hormones and cognition (and talk about current research in that area). I could also imagine it being used in a research methods class when talking about clinical trials.
Neural correlates of human sexual orientation
Homeostatic and neuroendocrine systems; anatomy; sexual orientation
LeVay, 1991 ; Byne et al., 2001
These papers were selected because they both investigate differences in a hypothalamic nucleus that is related/correlated with differences in sexual orientation. The second is an attempt at a replication of the first, which we almost never see in neuroscience. In the original paper, LeVay (1991) extends the work of Allen et al. (1989) who found marked sex difference in two cell groups in the anterior hypothalamus of humans. The interstitial nuclei of the anterior hypothalamus (INAH 2 and INAH 3) were larger in males than females. LeVay extended their investigation by examining this nucleus in homosexual men as well as heterosexual men and women. LeVay did not replicate the sex difference in INAH 2 but did replicate the sex difference in INAH 3. More importantly, LeVay found that INAH 3 was much smaller in homosexual men than heterosexual men. Indeed, the difference in INAH 3 was about the same as the one between heterosexual men and women. A decade later, Byne et al. (2001) confirmed the sex difference in INAH 3—men again were found to have a larger INAH 3 than women have. However, they failed to find a difference in INAH 3 between heterosexual men and homosexual men in either the volume of the nucleus, the neural number, or the neural density (LeVay only measured volumes).
Despite a beautifully written and well-reasoned discussion in which LeVay clearly defines the limitations of the conclusions, this article is still severely criticized in both academic and non-academic circles. Indeed, although it was published nearly 25 years ago, critiques can still be found on the web with ill-founded allegations about what the data actually mean and what the article actually says. These critiques and allegations, however, provide good starting points for discussions. I don’t lead the students to the refutations, but rather asked them to figure out if the critiques or allegations are valid or not. These critiques and allegations are listed below. 1) The study shows that homosexual men are “born that way”—sexual orientation is either genetic and/or congenital. Refutation: LeVay makes it clear that the finding is a correlate and that the difference could either be a cause or a consequence of engaging in homosexual sex. 2) All of the homosexual men in LeVay’s study had died of AIDS, so sexual orientation and HIV+ status are confounded. Refutation: A sub-group of the heterosexual men in LeVay’s study had also died of AIDS, and the difference between this subgroup of heterosexual men with AIDS vs. homosexual men was still present. Also, LeVay found there was no correlation between the volume of INAH 3 and the length of survival from the time of HIV+ diagnosis. 3) Promiscuity could actually be responsible for the decrease of INAH 3 size in homosexual men rather than sexual orientation. Refutation: LeVay admits that it could be a possible explanation. 4) LeVay is openly homosexual, so his results cannot be trusted. Refutation: The study was done blind. 5) INAH 3 is much too small to be measured reliably. Refutation: My students and I measure much smaller objects (neuron soma sizes) with great reliability ( Grisham et al., 2003 )—it just takes the right lens on a microscope. 6) The heterosexual HIV+ men in LeVay’s study were actually “in the closet” and should have been assigned to the homosexual group. Reassigning all of the allegedly heterosexual HIV+ men would make the difference in INAH size between homosexual and heterosexual men disappear. Refutation: Combining the data across these groups would indeed markedly reduce the difference between homosexual and heterosexual men. Nonetheless, the question would then be why there is a difference between HIV+ men who were identified as homosexual on their medical records versus those who were not. 7) The final two arguments revolve around statistical considerations. The first is that there is some overlap between the groups in INAH 3 size, therefore the differences aren’t real because every last individual wasn’t different. Refutation: Notably, we perform statistics on differences between group means, so this is possible. LeVay discusses these outliers and suggests that sexual orientation may not be the only variable that determines the size of this nucleus. 8) Byne et al. did not replicate LeVay’s finding. Refutation: I have my students take the values from Table 3 of Byne et al. and run a simple t-test on INAH 3 volume between the homosexual vs. heterosexual. (Students will have to figure out the standard deviation, but they have the standard error of the mean and the sample size, so they can.) When doing this, students will find that the t-test actually does show a significant difference. Byne et al. used a post-hoc Tukey–Kramer HSD test, which did not reveal the difference. This can generate discussions about statistical power, whether or not stringent criteria are appropriate in statistical testing, and how sacred the 0.05 criterion should be. As a footnote, Garcia-Falgueras and Swaab (2008) found similar results with male-to-female transsexuals: they had a smaller INAH 3 volume than did controls.
Clearly these papers will be of interest to students, especially in light of current legal decisions, and could be used in a variety of curricular contexts. Conceivably, they could be used in a Neuroscience and Society course. I have used this pair of papers as a part of a focused course on sex differences and sexual differentiation of the nervous system in vertebrates. I have also used the LeVay paper in my behavioral neuroscience lab class as a supplementary reading when examining sex differences in the spinal cord (cf. Grisham et al., 2003 ), and https://mdcune.psych.ucla.edu/modules/ratscia ).
Investigating sex differences in spatial ability using multiple approaches
Sex differences; neuroethology; animal behavior and cognition; spatial learning; hippocampus
Gaulin and FitzGerald, 1986 ; Jacobs, Gaulin, Sherry, and Hoffman, 1990
On average, males demonstrate superior spatial navigation skills compared to females. These sex differences are demonstrated across species. The papers I chose for this collection attempt to answer the question of why these differences exist and point to a possible neurobiological basis for this sexually dimorphic behavior. The first paper, by Gaulin and FitzGerald (1986) , makes use of two closely related species, meadow voles and pine voles, with distinct mating systems to test the evolutionary hypothesis that differences in spatial ability arise due to the larger home ranges of males in polygynous species. In a field study, the authors first measure the home ranges of male and female voles of each species using implanted radio transmitters. They find that in the polygynous meadow voles, males range much farther than females, but in the monogamous pine voles, males and females have similar home ranges. The researchers then recapture the monitored voles to test their spatial ability in a maze in the lab. As expected, the male meadow voles demonstrate better maze performance than female meadow voles, while male and female pine voles perform similarly in the maze. The second paper, by Jacobs et al. (1990) , provides evidence suggesting that differences in hippocampal volume may play a role in the sexual-dimorphism observed in spatial ability in meadow voles. In this study, the researchers measured the relative hippocampal volume (hippocampal volume/brain volume) of wild-caught male and female meadow voles and pine voles. As predicted from previous behavioral results, male meadow voles had larger hippocampal volumes than female meadow voles and there was no difference between hippocampal volumes in male and female pine voles, providing a possible neurobiological basis for the observed differences in behavior.
I think the greatest value of this set of papers is that they demonstrate the utility of investigating a question from multiple perspectives. The papers use both field and laboratory studies, and move from an investigation of behavior to the neurobiology underlying behavior. The papers are fairly straightforward, so students have a relatively easy time understanding the experiments and following the logic connecting each approach. This gives us the opportunity to move beyond simple understanding to discuss the strengths and weaknesses of each approach and to appreciate how evidence can be strengthened with the combination of multiple approaches. The papers also present fairly low-hanging fruit for students to identify follow-up experiments that would provide stronger support for the authors’ hypotheses. The papers are selected from a time point early enough in this line of research and leave enough unanswered questions for students to engage with the results and process as actual researchers would.
I use these papers in a senior seminar course. The course is focused more on skill development than content memorization. Students learn to read primary articles, evaluate information within articles, and synthesize information across articles to form their own hypotheses and follow-up experiments. Although the first article is a little long, neither article is particularly difficult. Both articles can easily be discussed together in a single 75-minute class period.
Creating false memories
Monica Linden
Learning and memory; hippocampus; amygdala; fear; optogenetics; associative learning
Reijmers et al., 2007 ; Liu et al., 2012 ; Ramirez et al., 2013
There are multiple papers by this group that could be considered including review articles, however the Ramirez et al. article is a tractable primary source article and is a slightly more exciting finding than the Liu et al. article. The Ramirez paper focuses on how the researchers can create a false memory of fear in a “safe” box by activating the neurons representing the “safe” box while the animal is learning to fear a “scary” box. This is accomplished using c-fos-tTA mice in combination with an AAV-TRE-ChR2-mChery virus to express channelrhodopsin with temporal specificity in the hippocampus. There are several versions of the experiment, but in general, channelrhodopsin is expressed in neurons active in a “safe” context. These neurons are then reactivated using light while the animal is fear conditioned in a separate context. The animal’s response is then tested in the safe context, where we now see a fear response. The researchers compare the results of the experiment when the virus is injected into the dentate gyrus versus the CA1 region of the hippocampus, showing that these results are observed for dentate gyrus but not for CA1. They also use fluorescent imaging to compare expression patterns of the channelrhodopsin-expressing neurons and cFos. In an additional experiment, the researchers show that conditioned place avoidance can be induced using a similar protocol wherein the animal is fear-conditioned in a separate context, but will express a fear memory for the context reactivated during the fear conditioning. These results produce the remarkable conclusion that neurons reactivated during the delivery of an unconditioned stimulus can create a false associative fear memory to a conditioned stimulus that was not present during the delivery of the unconditioned stimulus.
This paper excites the students as it exposes them to cutting-edge technology coupled with clear experimental design and easy-to-understand behavioral experiments. Students are drawn in by the idea of the “Marilyn Monroe Experiment” (i.e., can you artificially give the memory of one night with Marilyn Monroe?), as they see a real implementation of mice fearing a location where they have never received a shock. They also enjoy learning about optogenetics. While the technique itself is complicated, using Reijmers et al. (2007) and Liu et al. (2012) as background material allows students to appreciate the need for both temporal and anatomical specificity in gene expression. Furthermore, reviewing the results of Liu et al. helps the students understand the basic setup of the experiments in Ramirez et al. With guidance, the students can understand how each type of specificity is accomplished and why it is necessary. The paper also uses clear figures to illustrate the behavioral paradigms, so it is quite easy to follow what is happening during each iteration of the experiment. Furthermore, this paper can serve as a nice capstone in a learning and memory class because it brings together the functioning of the hippocampus with fear conditioning in an exciting, new way. Because the paper is in Science , it is a condensed format that is not overwhelming to the students. At the same time, it is useful to direct the students to some of the supplementary figures. (Alternatively, interpretation of the supplementary figures can make for good exam questions!)
I have used this paper in a junior/senior level Neurobiology of Learning and Memory course. I could imagine this paper being used in a variety of upper level courses including senior seminars. The methods could also be used in a techniques-focused course. Additionally, the findings could be discussed in a lower-level course or a non-majors course as a way to get students excited about the future of neuroscience research.
Knowledge transplant
Learning and memory; rodent; hippocampus; micro stimulation; electrical stimulation; memory-transfer; ensemble; neuro-prosthetic
Deadwyler et al., 2013
Deadwyler et al. (2013) demonstrates a transfer of task-relevant knowledge from a well-trained donor rat to a relatively naïve recipient rat in the form of neural activity patterns induced by multi-site electrical micro-stimulation in the recipient hippocampus. The task is a well-studied delayed non-match to sample (DNMS) task that involves remembering the position of a sample lever over the course of a 1 to 60 second delay. Distributed spiking activity patterns were measured using multi-site recordings in the donor rat, and these formed the basis for a computational model of the hippocampal “ensemble codes” or spatial activity patterns corresponding to successful and unsuccessful memory encoding during the sample phase of the task. “Successful” activity patterns were then induced in the donor hippocampus by multi-site electrical stimulation, resulting in dramatic performance improvements compared to un-stimulated trials or stimulation with unfavorable activity patterns. This suggests the exciting possibility of transferring memories from one brain to another in order to enhance memory performance or recover lost memory functions — as distinct from transferring immediate sensory information or motor commands as in a related “brain-to-brain interface” paper ( Pais-Vierra et al., 2013 ). Another paper from the Deadwyler and Hampson group ( Hampson et al., 2013 ) shows that neuro-prosthetic memory enhancement is feasible in primates; however that paper does not show transfer between animals as in the rat paper above ( Deadwyler et al., 2013 ).
The idea of directly inducing specific experiences and knowledge by brain stimulation is naturally exciting. It evokes images from popular science fiction movies like The Matrix and Inception and can lead one to fascinating philosophical issues. But for more practical-minded students, it is not that difficult to imagine huge medical and societal benefits if we become able to implant skills and knowledge as needed in people — people with memory loss or people with important and difficult jobs. Given these motivations for studying the paper, there is also a substantial pedagogical payoff in terms of understanding the experimental design, the multi-channel recording and stimulation methods, distinct functional roles for hippocampal areas CA1 and CA3, and the concept of an ensemble code that undergoes transformations over time that predict success or failure in the task. The “non-linear multiple-input multiple-output” model in the paper may be taken as an example of the importance of mathematical and computational modeling approaches in systems neuroscience.
I have had a small group of senior undergraduate neuroscience majors present Deadwyler et al. (2013) for discussion in our senior capstone seminar course. I consider it a challenging paper even for that relatively advanced group of students. However, I think the gist of the paper is accessible and valuable even if some technical details are skimmed over. For example, students can get some appreciation of how computational modeling can be useful from Deadwyler et al. (2013) , even if they are not immediately motivated to master those methods themselves. Thus, I think this paper could be discussed in lower-level classes, but in that case I would probably not expect students to read the whole paper and I would present some of the core ideas myself rather than expecting students to lead the discussion. For non-majors, I would probably present a digested version of the results rather than assigning sections of the paper.
Acknowledgments
The authors thank the membership of the Faculty for Undergraduate Neuroscience whose open discussions make this kind of collaboration possible.
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A Year in Neuroscience: Top 20 Neuroscience News Articles of 2022
Summary: 2022 has been a fantastic year for neuroscience and brain science research. Here, we take a look back over some of the most popular neuroscience research articles of the year.
Source: Neuroscience News
For over 20 years, Neuroscience News has reported on the latest, ground-breaking neuroscience research. Every year, we like to take a look back at some of the most popular articles we have published on the website.
Taking data from our website and from the most popular posts via our social media accounts, we are proud to present this year’s top neuroscience articles for you to enjoy. The articles are not presented in a particular order. The Neuroscience News team would like to thank all our readers, both old and new, for your support over the past year. We look forward to providing you all with the best research news in 2023! Happy New Year.
20: A Surprising Link Between Immune System and Hair Growth
Regulatory T cells interact with skin cells using glucocorticoid hormones to generate new hair follicles and promote hair growth. The findings could have positive implications for the development of new therapies to treat alopecia and other hair loss disorders.
Read the full post here
19: A New Theory in Physics Claims to Solve the Mystery of Consciousness
Consciousness can not simply be reduced to neural activity alone, researchers say. A novel study reports the dynamics of consciousness may be understood by a newly developed conceptual and mathematical framework.
18: Alzheimer’s and Daytime Napping Linked in New Research
Study reveals a bi-directional link between daytime napping and cognitive decline associated with Alzheimer’s disease. Researchers say longer, more frequent napping was associated with worse cognition after one year, and worse cognition was linked to longer and more frequent daytime naps.
17: Pain Relief Without Side Effects and Addiction
Researchers have developed a new substance that activates adrenalin receptors rather than opioid receptors to help relieve chronic pain. The new compounds have similar pain-relieving qualities as opioids but do not appear to induce respiratory depression or addiction.
16: A Glimpse Into the Dog’s Mind: A New Study Reveals How Dogs Think of Their Toys
Dogs have multi-modal mental imagery of items and objects that are familiar to them. When a dog thinks about an object, they imagine the object’s different sensory features.
15: How Many Daily Walking Steps Needed for Longevity Benefit?
A new meta-analysis of 15 studies reveals the optimum number of steps people of different age ranges should take per day in order to maximize longevity.
14: Nose Picking Could Increase Risk for Alzheimer’s and Dementia
The Chlamydia pneumoniae bacteria can travel directly from olfactory nerve in the nose and into the brain, forcing brain cells to deposit amyloid beta and inducing Alzheimer’s pathologies. Researchers say protecting the lining of the nose by not picking or plucking nasal hairs can help lower Alzheimer’s risks.
13: The End of Baldness? The Chemical Controlling Life and Death in Hair Follicles Identified
Researchers discovered how the TGF-beta protein controls the process by which hair follicles, including stem cells, divide and form new cells or orchestrate apoptosis. The findings could provide new treatment options for baldness and therapies to speed up wound healing.
12: Lucid Dying: Patients Recall Death Experiences During CPR
1 in 5 people who receive CPR report lucid experiences of death while they are seemingly unconscious and on the brink of death. The lucid experiences appear to be different from hallucinations, dreams, illusions, and delusions. Researchers found during these experiences the brain has heightened activity and markers for lucidity, suggesting the human sense of self, like other biological functions, may not completely stop around the time of death.
11: Hands of People With Diabetes More Often Affected by Trigger Finger
Trigger finger, a condition in which the fingers get locked into a bent position and become difficult to straighten, is more common in those with diabetes than in the general population. High blood sugar levels increase the risk of developing trigger finger, researchers say.
10: Vaping Alters Inflammatory State of Brain, Heart, Lungs, and Colon
Daily vaping of pod-based e-cigarettes alters inflammatory states across multiple organs, including the brain. The effects vary depending upon the vape flavors and influence how the body responds to infections. Mint vapes, for example, leave people more sensitive to the effects of bacterial pneumonia than mango flavoring.
9: The Green Mediterranean Diet Reduces Twice as Much Visceral Fat as the Mediterranean Diet and 10% More Than a Healthy Diet
A modified version of the Mediterranean diet called the green Mediterranean diet, which consists of enriched dietary polyphenols such as green tea, walnuts, and duckweed, and decreased red meats, reduced more visceral fat than the traditional Mediterranean diet or a traditional diet plan.
8: Genetic Variants That Offered Protection During Black Death Are Also Associated With Current Autoimmune Disorders
People with selected variants of the ERAP2 and TICAM2 genes were 40% more likely to survive the Black Death, researchers discovered. However, in modern humans, those with the ERAP2 gene are more likely to suffer autoimmune disorders such as Crohn’s disease.
7: Toward Early Detection of the Pathological Social Withdrawal Syndrome Known as ‘Hikikomori’
Hikikomori is a complex condition where a person withdraws from society and remains isolated at home for more than six months. The condition is becoming more prevalent in Western societies. Researchers have developed a new method designed to help detect hikikomori at an earlier stage and provide treatment.
6: Popular Dietary Supplement Causes Cancer Risk and Brain Metastasis
The commercial dietary supplement nicotinamide riboside, touted to improve cardiovascular and neurological health, may actually increase the risk of developing breast cancer that metastasizes to the brain.
5: Breakthrough in Search for Tinnitus Cure
Study reports a new digital polytherapeutic that delivers white noise could significantly improve symptoms for those with tinnitus.
4: Cannabis Use Produces Persistent Cognitive Impairments
Cannabis use leads to cognitive impairments that extend beyond the period of intoxication.
3: Troubling Rise in Suicides Linked With Common Food Preservative
Health experts call for stricter regulations for the use of sodium nitrite, a product commonly used for meat curing, following its link to suicides and increased numbers of poisonings.
2: Childhood Circumstances and Personality Traits Are Associated With Loneliness in Older Age
A combination of personality traits and childhood circumstances account for why some older people experience loneliness more than others. Lonely adults over 50 were 1.24 times more likely to have rarely, or never, had comfortable friendships during childhood, and 1.34 times more likely to have had poor relationships with their mothers as children.
1: Coffee and Cigarettes: Research Sheds New Light on Nicotine and Morning Brew
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Neuroscience is a multidisciplinary science that is concerned with the study of the structure and function of the nervous system. It encompasses the evolution, development, cellular and molecular biology, physiology, anatomy and pharmacology of the nervous system, as well as computational, behavioural and cognitive neuroscience.
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Research Topics & Ideas: Neuroscience
50 Topic Ideas To Kickstart Your Research Project
If you’re just starting out exploring neuroscience-related topics for your dissertation, thesis or research project, you’ve come to the right place. In this post, we’ll help kickstart your research by providing a hearty list of neuroscience-related research ideas , including examples from recent studies.
PS – This is just the start…
We know it’s exciting to run through a list of research topics, but please keep in mind that this list is just a starting point . These topic ideas provided here are intentionally broad and generic , so keep in mind that you will need to develop them further. Nevertheless, they should inspire some ideas for your project.
To develop a suitable research topic, you’ll need to identify a clear and convincing research gap , and a viable plan to fill that gap. If this sounds foreign to you, check out our free research topic webinar that explores how to find and refine a high-quality research topic, from scratch. Alternatively, consider our 1-on-1 coaching service .
Neuroscience-Related Research Topics
- Investigating the neural mechanisms underlying memory consolidation during sleep.
- The role of neuroplasticity in recovery from traumatic brain injury.
- Analyzing the impact of chronic stress on hippocampal function.
- The neural correlates of anxiety disorders: A functional MRI study.
- Investigating the effects of meditation on brain structure and function in mindfulness practitioners.
- The role of the gut-brain axis in the development of neurodegenerative diseases.
- Analyzing the neurobiological basis of addiction and its implications for treatment.
- The impact of prenatal exposure to environmental toxins on neurodevelopment.
- Investigating gender differences in brain aging and the risk of Alzheimer’s disease.
- The neural mechanisms of pain perception and its modulation by psychological factors.
- Analyzing the effects of bilingualism on cognitive flexibility and brain aging.
- The role of the endocannabinoid system in regulating mood and emotional responses.
- Investigating the neurobiological underpinnings of obsessive-compulsive disorder.
- The impact of virtual reality technology on cognitive rehabilitation in stroke patients.
- Analyzing the neural basis of social cognition deficits in autism spectrum disorders.
- The role of neuroinflammation in the progression of multiple sclerosis.
- Investigating the effects of dietary interventions on brain health and cognitive function.
- The neural substrates of decision-making under risk and uncertainty.
- Analyzing the impact of early life stress on brain development and mental health outcomes.
- The role of dopamine in motivation and reward processing in the human brain.
- Investigating neural circuitry changes in depression and response to antidepressants.
- The impact of sleep deprivation on cognitive performance and neural function.
- Analyzing the brain mechanisms involved in empathy and moral reasoning.
- The role of the prefrontal cortex in executive function and impulse control.
- Investigating the neurophysiological basis of schizophrenia.
Neuroscience Research Ideas (Continued)
- The impact of chronic pain on brain structure and connectivity.
- Analyzing the effects of physical exercise on neurogenesis and cognitive aging.
- The neural mechanisms underlying hallucinations in psychiatric and neurological disorders.
- Investigating the impact of music therapy on brain recovery post-stroke.
- The role of astrocytes in neural communication and brain homeostasis.
- Analyzing the effect of hormone fluctuations on mood and cognition in women.
- The impact of neurofeedback training on attention deficit hyperactivity disorder (ADHD).
- Investigating the neural basis of resilience to stress and trauma.
- The role of the cerebellum in non-motor cognitive and affective functions.
- Analyzing the contribution of genetics to individual differences in brain structure and function.
- The impact of air pollution on neurodevelopment and cognitive decline.
- Investigating the neural mechanisms of visual perception and visual illusions.
- The role of mirror neurons in empathy and social understanding.
- Analyzing the neural correlates of language development and language disorders.
- The impact of social isolation on neurocognitive health in the elderly.
- Investigating the brain mechanisms involved in chronic fatigue syndrome.
- The role of serotonin in mood regulation and its implications for antidepressant therapies.
- Analyzing the neural basis of impulsivity and its relation to risky behaviors.
- The impact of mobile technology usage on attention and brain function.
- Investigating the neural substrates of fear and anxiety-related disorders.
- The role of the olfactory system in memory and emotional processing.
- Analyzing the impact of gut microbiome alterations on central nervous system diseases.
- The neural mechanisms of placebo and nocebo effects.
- Investigating cortical reorganization following limb amputation and phantom limb pain.
- The role of epigenetics in neural development and neurodevelopmental disorders.
Recent Neuroscience Studies
While the ideas we’ve presented above are a decent starting point for finding a research topic, they are fairly generic and non-specific. So, it helps to look at actual studies in the neuroscience space to see how this all comes together in practice.
Below, we’ve included a selection of recent studies to help refine your thinking. These are actual studies, so they can provide some useful insight as to what a research topic looks like in practice.
- The Neurodata Without Borders ecosystem for neurophysiological data science (Rübel et al., 2022)
- Genetic regulation of central synapse formation and organization in Drosophila melanogaster (Duhart & Mosca, 2022)
- Embracing brain and behaviour: Designing programs of complementary neurophysiological and behavioural studies (Kirwan et al., 2022).
- Neuroscience and Education (Georgieva, 2022)
- Why Wait? Neuroscience Is for Everyone! (Myslinski, 2022)
- Neuroscience Knowledge and Endorsement of Neuromyths among Educators: What Is the Scenario in Brazil? (Simoes et al., 2022)
- Design of Clinical Trials and Ethical Concerns in Neurosciences (Mehanna, 2022) Methodological Approaches and Considerations for Generating Evidence that Informs the Science of Learning (Anderson, 2022)
- Exploring the research on neuroscience as a basis to understand work-based outcomes and to formulate new insights into the effective management of human resources in the workplace: A review study (Menon & Bhagat, 2022)
- Neuroimaging Applications for Diagnosis and Therapy of Pathologies in the Central and Peripheral Nervous System (Middei, 2022)
- The Role of Human Communicative Competence in Post-Industrial Society (Ilishova et al., 2022)
- Gold nanostructures: synthesis, properties, and neurological applications (Zare et al., 2022)
- Interpretable Graph Neural Networks for Connectome-Based Brain Disorder Analysis (Cui et al., 2022)
As you can see, these research topics are a lot more focused than the generic topic ideas we presented earlier. So, for you to develop a high-quality research topic, you’ll need to get specific and laser-focused on a specific context with specific variables of interest. In the video below, we explore some other important things you’ll need to consider when crafting your research topic.
Get 1-On-1 Help
If you’re still unsure about how to find a quality research topic, check out our Research Topic Kickstarter service, which is the perfect starting point for developing a unique, well-justified research topic.
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Best Universities for Neuroscience in the World
Updated: February 29, 2024
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Below is a list of best universities in the World ranked based on their research performance in Neuroscience. A graph of 246M citations received by 8.23M academic papers made by 5,102 universities in the World was used to calculate publications' ratings, which then were adjusted for release dates and added to final scores.
We don't distinguish between undergraduate and graduate programs nor do we adjust for current majors offered. You can find information about granted degrees on a university page but always double-check with the university website.
1. Harvard University
For Neuroscience
2. University College London
3. Johns Hopkins University
4. Stanford University
5. Yale University
6. University of Toronto
7. University of California - San Francisco
8. University of Pennsylvania
9. Columbia University
10. University of California-San Diego
11. University of California - Los Angeles
12. University of Michigan - Ann Arbor
13. University of Washington - Seattle
14. University of Pittsburgh
15. University of Oxford
16. McGill University
17. Washington University in St Louis
18. University of Cambridge
19. Karolinska Institute
20. New York University
21. Cornell University
22. University of Wisconsin - Madison
23. University of British Columbia
24. Emory University
25. Northwestern University
26. Massachusetts Institute of Technology
27. King's College London
28. University of California - Berkeley
29. University of California - Irvine
30. University of Minnesota - Twin Cities
31. University of Melbourne
32. Boston University
33. University of North Carolina at Chapel Hill
34. Heidelberg University - Germany
35. University of Southern California
36. University of Iowa
37. University of Tokyo
38. Duke University
39. Baylor College of Medicine
40. University of Florida
41. Pierre and Marie Curie University
42. University of Chicago
43. University of California - Davis
44. Rutgers University - New Brunswick
45. University of Sydney
46. Case Western Reserve University
47. Ohio State University
48. University of Texas Southwestern Medical Center
49. Vanderbilt University
50. University of Illinois at Urbana - Champaign
51. Kyoto University
52. Icahn School of Medicine at Mount Sinai
53. Mayo Clinic College of Medicine and Science
54. Radboud University
55. University of Zurich
56. Oregon Health & Science University
57. University of Montreal
58. Lund University
59. University of Amsterdam
60. University of Miami
61. University of Edinburgh
62. University of Munich
63. University of Virginia
64. Rockefeller University
65. University of New South Wales
66. Catholic University of Leuven
67. University of Utah
68. Pennsylvania State University
69. Western University
70. University of Manchester
71. University of Arizona
72. Tel Aviv University
73. University of Queensland
74. University of Calgary
75. Charite - Medical University of Berlin
76. University of Tubingen
77. Osaka University
78. University of Illinois at Chicago
79. University of Sao Paulo
80. University of Rochester
81. University of Copenhagen
82. Imperial College London
83. University of Alabama at Birmingham
84. University of Maryland, Baltimore
85. Brown University
86. Monash University
87. University of Kentucky
88. University of Texas at Austin
89. University of Milan
90. University of Alberta
91. University of Groningen
92. University of Gothenburg
93. University of Bristol
94. Princeton University
95. University of Helsinki
96. Indiana University - Purdue University - Indianapolis
97. California Institute of Technology
98. Providence College
99. Sapienza University of Rome
100. Wayne State University
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Neurobiological research on N,N -dimethyltryptamine (DMT) and its potentiation by monoamine oxidase (MAO) inhibition: from ayahuasca to synthetic combinations of DMT and MAO inhibitors
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The potent hallucinogen N,N- dimethyltryptamine (DMT) has garnered significant interest in recent years due to its profound effects on consciousness and its therapeutic psychopotential. DMT is an integral (but not exclusive) psychoactive alkaloid in the Amazonian plant-based brew ayahuasca, in which admixture of several β -carboline monoamine oxidase A (MAO-A) inhibitors potentiate the activity of oral DMT, while possibly contributing in other respects to the complex psychopharmacology of ayahuasca. Irrespective of the route of administration, DMT alters perception, mood, and cognition, presumably through agonism at serotonin (5-HT) 1A/2A/2C receptors in brain, with additional actions at other receptor types possibly contributing to its overall psychoactive effects. Due to rapid first pass metabolism, DMT is nearly inactive orally, but co-administration with β -carbolines or synthetic MAO-A inhibitors (MAOIs) greatly increase its bioavailability and duration of action. The synergistic effects of DMT and MAOIs in ayahuasca or synthetic formulations may promote neuroplasticity, which presumably underlies their promising therapeutic efficacy in clinical trials for neuropsychiatric disorders, including depression, addiction, and post-traumatic stress disorder. Advances in neuroimaging techniques are elucidating the neural correlates of DMT-induced altered states of consciousness, revealing alterations in brain activity, functional connectivity, and network dynamics. In this comprehensive narrative review, we present a synthesis of current knowledge on the pharmacology and neuroscience of DMT, β -carbolines, and ayahuasca, which should inform future research aiming to harness their full therapeutic potential.
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Introduction
Because of their profound effects on the human mind, psychedelic substances have been the object of fascination in the Western world since the 1950s [ 1 ], when Humphrey Osmond coined the term psychedelic. Despite pioneering work by Alexander and Ann Shulgin on the synthesis and subjective effects of phenylethylamines and tryptamines [ 2 , 3 ], a long-standing moratorium on funding of psychedelics research impeded progress in understanding basic aspects of the physiology and phenomenology of psychedelic substances. In this narrative review, we summarize the state of knowledge of N,N -dimethyltryptamine (DMT), which has been used for millennia by indigenous peoples of South and Mesoamerica for healing and spiritual purposes in the form of the herbal brew variously known as yajé or ayahuasca [ 4 , 5 ]. Footnote 1 Uniquely, ayahuasca brew often contains a mixture of DMT along with several β -carboline alkaloids, which together enhance the bioavailability of orally administered DMT by blocking its first pass metabolism by monoamine oxidase A (MAO-A) in the gut and other organs. Whereas oral DMT alone is nearly inactive, DMT is potently psychoactive when inhaled as vapor [ 6 ], and when taken via intravenous administration [ 7 , 8 ], i.e., routes that circumvent the first-pass metabolism.
The classical psychedelics lysergic acid- N,N -diethylamide (LSD) [ 9 ] and psilocybin (prodrug of the psychoactive substance psilocin) are agonists or partial agonists at 5-hydroxytryptamine (serotonin) 2A (5-HT 2A ) receptors in brain [ 1 ], which are the key mediators of their psychedelic effects. While DMT is generally included among the classical psychedelics, as shall emerge below, it is not yet certain that 5-HT 2A receptor agonism exclusively mediates DMT/ayahuasca effects. Investigations of ayahuasca’s pharmacological effects and therapeutic potential are at a relatively nascent stage, mainly confined to its use in naturalistic and traditional settings.
Like classical psychedelics, consumption of ayahuasca leads to profound alterations in consciousness, characterized by changes in perception and the “inner (cognitive and emotional) experiences” [ 5 , 10 , 11 ], with “visuals, kaleidoscopic lights, geometrical forms, tunnels, animals, humans and supernatural beings coinciding with sensations of peace, harmony and inner calm” [ 12 ]. Other commonly experienced phenomena include synesthesia [ 13 ], decentered introspective states [ 14 ], emotional release [ 15 ], attribution of meaning [ 14 , 16 ], alterations in meaningful, guiding values in life [ 14 , 17 ], ego dissolution, better understanding of oneself and others, acceptance of oneself and past life events [ 14 , 18 ], and expansive states with transpersonal experiences [ 19 ]. Unlike other psychedelics, ayahuasca effects also include notable physical sensations like nausea and vomiting, which may be integral to its traditional use in healing and spiritual rituals [ 20 ]. Indigenous and neo-shamanic groups attribute transformative healing properties to the spirit of ayahuasca, often experienced through vivid encounters with plant spirits in a culturally rich ritual setting [ 21 ].
Recent pre-clinical and observational studies have shown encouraging results with ayahuasca in treating a variety of conditions and their animal models, including depression, anxiety, PTSD [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ], substance use disorders [ 34 , 35 , 36 , 37 , 38 ], eating disorders [ 39 , 40 ], and grief [ 41 , 42 ]. In an initial clinical trial, ayahuasca has shown efficacy against depression and anxiety symptoms [ 28 ] and in altering brain network dynamics linked to depression pathophysiology [ 43 ]. In a randomized placebo-controlled trial (RCT) conducted in Brazil, a single ayahuasca dose produced rapid antidepressant effects persisting for weeks in (n = 29) patients with treatment-resistant depression [ 30 ]. In a recent observational study, the majority of (n = 20) individuals with initial diagnosis of major depression disorder (MDD) enjoyed remission lasting a year after their participation in a ritual with administration of botanical ayahuasca analogues (i.e., various plant sources of DMT and β -carbolines) in the context of an ayahuasca ritual [ 32 ]. Preclinical and in vitro investigations suggest that ayahuasca chemical constituents may also possess neuroprotective properties in neurodegenerative disease models [ 44 , 45 , 46 ]. Thus, a comprehensive review of 21 clinical and preclinical studies with chemical constituents of ayahuasca revealed consistent findings of anxiolytic, antidepressant, anti-addictive, and neuroprotective properties [ 47 ].
Psychological support is critically important during a therapeutic ayahuasca experience, given the influence of contextual factors on mental health outcomes [ 48 ]. The burgeoning interest in ayahuasca's therapeutic benefits marks a pivotal shift from traditional to clinical contexts, opening new avenues for research and application in Western medicine. Its uniquely complex blend of pharmacological, psychological, and cultural elements makes ayahuasca an intriguing research area for scientists from various disciplines. Our objective in this narrative review is to bridge the gap between the phenomenology of the ayahuasca experience and western models of neuropharmacology and brain function. Therefore, we have compiled the current state of knowledge of the pharmacology, biochemistry, and neuroscience of DMT, emphasizing its synergism with MAOIs in the contexts of ayahuasca and its botanical and synthetic analogs. We first summarize the historical and cultural background of ayahuasca, and then elaborate upon the known pharmacological, molecular, cellular, and functional mechanisms of action of the DMT/MAOI combination from studies in vitro and imaging studies in vivo.
Ayahuasca: traditional botanical forms
Ayahuasca (also known as yajé, hoasca, etc.) is a Hispanicized term borrowed from Quechuan dialects of the Amazon basin, which refers to the woody vine (liana) Banisteriopsis caapi and its decoctions, as used for ritual and healing purposes [ 5 ]. The psychoactive beverage is prepared by extensive boiling of the B. caapi bark, resulting in a thick, brown, and oily liquid [ 49 ]. The prolonged boiling process is necessary to extract the plants’ alkaloids, which have low solubility in water. Indeed, the β -carboline harmine mainly resides in the solid phase of the ayahuasca brew [ 50 ]. Recipes for traditional ayahuasca differ between indigenous peoples and geographic regions [ 51 ]. Some traditional shamanic rituals using ayahuasca as a sacred medicine employ decoctions mainly from B. caapi , which contains β -carboline MAOIs, but little or no DMT. Traditional ayahuasca decoctions often contain DMT derived from the leaves of plants such as Psychotria viridis, P. carthagenensis, or the amazonian shrub Diplopterys cabrerana [ 52 , 53 ] . In popular conception, the B. caapi MAOIs serve only to enhance the bioavailability of DMT derived from other ayahuasca components. However, DMT-containing plants are not always included in ayahuasca brews; some indigenous groups in the Amazon basin use B. caapi alone for initiation or healing practices , without admixture of any other plant material [ 54 , 55 ]. Furthermore, some ayahuasca decoctions contain tobacco or other psychoactive plants [ 56 ]. Nonetheless, we suppose that a binary DMT/MAOI model may best capture the complex ayahuasca experience that derives from ancient traditional knowledge of indigenous people who have used these brews in one form or another since millennia [ 57 ].
The essential ayahuasca component B. caapi contains several β -carbolines from the harmala alkaloid family of tryptophan metabolites [ 58 ], which may be psychoactive in their own right [ 59 ], in addition to their inhibition of DMT metabolism by MAO-A [ 60 ]. The various β -carbolines in B. caapi , especially harmine and harmaline, enable the attainment of sufficient plasma DMT concentrations to evoke psychedelic effects lasting 4–6 h [ 5 , 61 ]. Re-dosing four hours after the first ayahuasca administration prolongs the subjective effects, likely due to accumulation of alkaloid concentrations in the body [ 62 ] (repeated dosing is typical of traditional ayahuasca rituals). Tetrahydroharmine (THH), the second-most abundant B. caapi β -carboline, is also a weak inhibitor of plasma membrane serotonin transporters (SERT) [ 63 ], i.e., the site of action of selective serotonin reuptake inhibitor (SSRI) antidepressants. THH may also contribute to net MAO inhibition despite its weaker affinity as compared to harmine and harmaline [ 10 , 64 ]. The B. caapi β -carbolines are almost exclusively MAO-A inhibitors, with 100-fold lower affinity for MAO-B [ 65 , 66 ]. However, it is by no means certain that DMT and β -carbolines are the only pharmacologically relevant compounds in ayahuasca; the chemical diversity in the plant matrix predicts an “entourage effect” [ 67 ] that remains uninvestigated. For the present, we focus on the most abundant ayahuasca β- carbolines (harmine, THH and harmaline) and their interactions with DMT [ 68 ].
β -carbolines and DMT concentrations in ayahuasca samples
We summarize in Table 1 findings of studies reporting concentrations of harmine, harmaline, THH, and DMT in ayahuasca samples from different geographical and indigenous origins. In considering the results of these field sample studies, there is clearly no standard alkaloid composition or standard dose, and that factors such as quantity and quality of used plants, the geographic region, and likewise the cultural affiliations of the people producing ayahuasca all contribute to its varying composition [ 69 ] . The rank order of β -carboline concentrations is generally harmine ≥ THH > harmaline, where harmine concentrations tended to only slightly exceed the THH concentrations, and harmaline was overall the least-abundant β -carboline alkaloid. Indeed, the reported concentrations range from 0.06 to 22.9 mg/mL harmine, 0–1.72 mg/mL harmaline, 0.02–23.8 mg/mL THH and 0.05–14.2 mg/mL DMT (Table 1 ). Despite considerable variability, the analytical findings generally predict that one cup (200 mL) of typical ayahuasca brew would contain alkaloid doses up to a few hundred mg. During the extended boiling process of ayahuasca preparation, harmine converts via consecutive reduction reactions to harmaline and then to THH, thus shifting the β -carboline ratios as compared to the untreated B. caapi [ 70 ]. Furthermore, THH is more chemically stable than harmine/harmaline, surviving in ayahuasca stored for nine days at 37 °C [ 71 ]. Variable DMT concentrations likely reflect the proportion of P. viridis to the total plant material, which ranged from 7 to 20%, depending on the preparation recipe [ 70 ]. It remains unknown if alkaloid concentrations in B. caapi differ across geographic regions or depending on season of harvest.
Ayahuasca analogues and pharmahuasca
The eponymic harmala β -carboline alkaloids in B. caapi also occur in plants such as Peganum harmala (Syrian rue), which is native to Eurasia and northern Africa, or the flowers of the mainly American Passiflora incarnata (passionflower). DMT in ayahuasca often derives from plants of genera Psychotria , the Brazilian/Mesoamerican Mimosa hostilis (jurema), or Anadenanthera and Diplopterys [ 53 , 77 ]. The ubiquity of these alkaloids likely reflects their derivation from the amino acid tryptophan, but there is evidence that tryptamine alkaloids confer increased resistance against herbivores or other predators [ 78 , 79 ]. Brews comprising plant sources other than B. caapi and Psychotria are ayahuasca analogues, whereas synthetic formulations are commonly known as “pharmahuasca” [ 53 , 56 ]. Ayahuasca analogue formulations commonly include P. harmala as a β -carboline source and M. hostilis or A. confusa as a DMT source [ 53 , 56 , 80 ]. P. harmala (mainly its seeds) has traditional medicinal uses in Iran [ 81 ] for its supposed cardiovascular, neurologic, antimicrobial, gastrointestinal (GI), and antidiabetic effects [ 82 ], and M. hostilis finds use in South and meso-American spiritual and shamanic rituals [ 83 , 84 ].
In the 1960s, Claudio Naranjo reported on the use of harmaline for Western psychotherapy [ 85 ], highlighting its potential therapeutic benefits for facilitating introspection, emotional release, self-awareness, and personality integration. It remains uncertain if such effects derive from MAOI or other pharmacological properties of harmaline. Advancements in DMT synthesis and the broader availability of pharmaceutical MAOIs were drivers for the increasing popularity of pharmahuasca. Particularly in Europe, ayahuasca analogues and pharmahuasca are often less costly and more accessible than authentic ayahuasca [ 53 , 86 , 87 ]. Furthermore, uncontrolled harvesting of B. caapi is a recognized threat to its viability in the wild [ 88 ]. While ayahuasca analogues and pharmahuasca can produce experiences akin to traditional ayahuasca, their specific effects differ according to the alkaloid composition [ 86 , 87 ]. Synthetic formulations potentially offer more standard alkaloid composition and a better safety profile, notably with respect to the occurrence of emesis (a”purge” is considered an essential and therapeutic aspect of the ayahuasca ritual) [ 89 ]. Indeed, having a standard composition remains a key requirement for inclusion of medicine in an approved Western pharmacopeia, although there is not yet a consensus on the optimal composition of ayahuasca alkaloids.
N,N- dimethyltryptamine (DMT)
DMT derives from tryptamine, which forms by decarboxylation of L -tryptophan catalyzed by the enzyme aromatic amino acid decarboxylase (AAADC; commonly known as DOPA decarboxylase) (Fig. 1 ). As first described by Axelrod [ 90 ], DMT biosynthesis proceeds by a two-step process from tryptamine via the enzyme indolethylamine N -methyltransferase (INMT), a transmethylation enzyme using S -adenosyl- L -methionine (SAM) as methyl donor. The product N -methyltryptamine (NMT) undergoes further methylation by the same enzyme to give DMT. In situ hybridization studies revealed expression of INMT in neurons, co-localizing with DOPA decarboxylase in presumably DMT-synthesizing neurons in cerebral cortex, and in choroid plexus, but with highest concentration in lung tissue [ 91 , 92 ]. However, INMT knockout in a rodent model, failed to ablate tryptamine methylation in brain and lung tissue, suggesting the presence of alternate enzymatic pathways [ 93 ]. DMT is present in many mammalian tissues. Indeed, the interstitial DMT concentration in rodent brain was approximately 1 nM to cerebral microdialysis coupled with HPLC [ 92 ]. Cerebral microdialysis analysis of canonical biogenic monoamine neurotransmitter concentrations (e.g., serotonin, dopamine, norepinephrine) showed similar concentrations in the range of ~ 1–4 nM [ 94 ]. UHPLC-MS analysis of brain tissue extracts indicated DMT concentrations ranging from zero to 30–60 nM [ 95 , 96 ]. The detection of DMT in the pineal gland [ 97 ] inspired the concept that pineal DMT release might induce vivid dreams, or near-death and other mystical-type experiences [ 98 ], but the total quantity of pineal DMT seems insufficient to evoke such effects. Studies of endogenous DMT concentrations in body fluids (mainly blood and urine) are generally uninformative about the cellular sites of DMT production in biologically significant amounts [ 98 ].
Molecular structures of N,N- dimethlytryptamine (DMT) and other psychedelics, the main ayahuasca β -carbolines, and key metabolic pathways. A Indole and benzene rings (gray) are the chemical scaffolds of the two main categories of psychedelics, i.e. tryptamines (red) and phenethylamines (yellow). Serotonin, DMT and 5-MeO-DMT are structurally similar; LSD, while also containing the tryptamine (and phenethylamine) motif, is an ergoline derivative. Among the phenethylamine psychedelics, we present the structures of 4-bromo-2,5-dimethoxyphenethylamine (2C-B) and mescaline. B The β -carboline scaffold of harmine, harmaline, and tetrahydroharmine (THH) are shown in blue. C) These main β -carbolines in ayahuasca undergo demethylation to harmol, tetrahydroharmalol, and harmalol, respectively. Several cytochrome (CYP) enzymes are implicated in the demethylation of harmine and harmaline, but details are lacking for THH. Harmine and harmaline can also undergo ring-hydroxylation catalyzed by CYP450 [ 107 , 108 ]. An additional metabolic route of harmaline is its oxidation to harmine. DMT is predominantly metabolized by oxidative deamination via monoamine oxidase type A (MAO-A), followed by formation of indole-3-acetic acid (3-IAA) by non-specific aldehyde dehydrogenases. Alternately, DMT is oxidised to DMT- N -oxide (DMT-NO) by CYP450 or demethylated by CYP2D6 and CYP2C19 to N- methyltryptamine (NMT), or hydroxylated to 6-hydroxy-DMT by yet unknown enzymes [ 60 , 107 , 109 , 110 ]. Red arrows indicate inhibition of DMT metabolism by the β -carboline MAO-A inhibitors, resulting in lesser formation of 3-IAA
Exogenous DMT rapidly accumulates in the rat brain after i.p. or i.v. administration, transiently attaining a brain:blood partition ratio of approx. 5–6:1, followed by rapid clearance from the brain and circulation [ 96 , 99 , 100 , 101 ]. Nonetheless, DMT remained detectable in the rabbit CNS up to seven days after peripheral administration, while urinary excretion was not detectable after 24 h [ 102 ], which could be consistent with storage in a very stable vesicular pool. After i.p. administration, there was DMT accumulation in the cerebral cortex, amygdala, and caudate-putamen, while medulla oblongata and cerebellum only showed low uptake [ 101 ], suggesting compartmentation within specific neuronal populations. We have reported spatially heterogeneous DMT accumulation in rat brain after i.p. administration, with 50% higher concentrations in the frontal cortex than in the cerebellum [ 103 ], again suggesting some mechanism for its retention in brain tissue. Indeed, DMT can enter serotonin neurons via SERT, and then accumulate in synaptic vesicles as a substrate for the vesicular monoamine transporter 2 (VMAT2) [ 104 ]. Storage in a vesicular compartment would protect DMT from MAO degradation, and might support its release from serotonin fibers as a “false neurotransmitter” [ 101 ]. To qualify as a classical neurotransmitter, an endogenous substance must be present in physiologically significant amounts, with release in a calcium-dependent manner after presynaptic depolarization, and then evoking responses at specific post-synaptic sites [ 105 ]. Given the current evidence, endogenous DMT may meet these criteria [ 106 ], despite its low affinity at 5-HT 2A receptors. For an extensive discussion of DMT as a candidate neurotransmitter, see [ 106 ].
MAO inhibitors
MAO enzymes (enzyme commission number EC 1.4.3.4) are amine oxidoreductases, with main expression in the outer mitochondrial membrane of mammalian cells. MAO substrates include the biogenic monoamine neurotransmitters dopamine, epinephrine, norepinephrine, and serotonin, and the exogenous psychedelics DMT, psilocin and mescaline. The MAO-reaction consumes molecular oxygen in the restoration of the reduced FADH 2 cofactor to its active FAD form; the imine intermediate spontaneously eliminates ammonia, and the resultant aldehyde is oxidised to the carboxylic acid by non-specific NAD + -dependent dehydrogenase enzymes [ 111 ]. The two isoforms of MAO, which arose from a gene duplication event, have very similar amino acid sequences [ 112 ], but somewhat distinct primary substrates. Whereas serotonin and DMT are preferred substrates for MAO-A, phenylethylamine is a MAO-B substrate; both isozymes metabolize dopamine and tyramine with little selectivity [ 113 , 114 ]. MAO-A occurs in the brain, GI tract, liver, the vasculature of the lungs, as well as in the placenta, while MAO-B mainly occurs in blood platelets [ 111 ], astrocytes [ 115 ], and certain specific populations of neurons [ 116 ]. With respect to ayahuasca, MAO-A in the GI tract is the principal determinant of DMT absorption.
Whereas harmine and moclobemide are reversible MAO-A inhibitors, certain propargyl compounds form a covalent bond with the enzyme, rendering it permanently inactive. The non-selective irreversible MAOIs phenelzine, isocarbaxazid, and tranylcypromine emerged in the mid-twentieth century as the first effective pharmacotherapeutic agents for depression [ 117 ]. These medications have since largely fallen out of favor due to the perceived risk of interactions with dietary vasoactive amines (the”cheese effect”) or the serotonin syndrome, a potentially fatal crisis of hypertension, fever, delirium, and rhabdomyolysis that can occur upon co-administration of direct or indirect serotonin agonists. As such, irreversible MAOIs now seldom serve as first or second line antidepressants, but remain in use in certain severe and treatment-resistant cases, which calls for strict observation of dietary restrictions [ 118 ]. However, serotonin syndrome and hypertensive crisis are exceedingly rare events in patients treated with irreversible MAO blockers [ 118 ].
The reversible MAO-A inhibitor moclobemide is an antidepressant with some efficacy in treating social anxiety, being notable for its favorable side-effect profile and relatively brief plasma half-life. Moclobemide has occasionally been detected in neo-shamanic recipes in Europe [ 53 ]. In general, pretreatment with any inhibitor of MAO-A, reversible or irreversible, would likely serve for potentiation of DMT bioavailability after oral administration, we are not aware of MAOIs other than harmine and moclobemide finding use in pharmahuasca.
Safety and risks associated with ayahuasca or DMT use
Despite the theoretical risk of serotonin syndrome, there are preclinical reports showing potentiation of DMT effects by co-administration of irreversible MAO inhibitors iproniazid or pargyline treatment [ 119 , 120 ]. In an ayahuasca neurotoxicity study, some rats showed behavioral signs of serotonin syndrome and eventually died after receiving doses some 30- and 50-fold the typical human doses [ 121 ]. However, only at such extreme doses can the reversible MAOIs in ayahuasca (or generally also pharmahuasca) evoke the nearly complete inhibition that may be a precondition for the serotonin syndrome. Observational studies have not raised major safety concerns for ayahuasca practitioners taking SSRIs [ 122 ].
Neither short-term nor long-term ayahuasca use led to dependency, and its use in controlled settings such as ceremonial contexts suggests an acceptable safety profile [ 49 , 76 , 123 ]. Acute treatment-emergent adverse events (TEAEs), mainly nausea and vomiting (69.9%), typically resolved without an intervention, with few (2.3%) such participants needing medical attention [ 124 , 125 ]. The American National Poison Data System (NPDS) registered 538 adverse events for ayahuasca between 2005 and 2015, with 28 cases requiring intubation, four cases of cardiac arrest, 12 seizures, and three fatalities [ 126 ]. When considering the global prevalence of ayahuasca use, estimated to be over 4 million annually, the number of deaths (n = 58) reported in association with its use is low. Notably, those fatalities have not been linked to traditional ayahuasca ingredients but may involve toxic plant admixtures, drug interactions, or pre-existing conditions [ 127 ].
On the other hand, challenging psychedelic experiences are common (55.9%), with adverse psychological reactions typically subsiding within a few days; however, 12% of such individuals sought additional professional support [ 124 , 125 ]. Severe psychological distress, including severe depression and psychotic episodes, can occur with ayahuasca use [ 128 , 129 ]. Contemporary neo-shamanic and tourist-oriented settings therefore adopted a broad spectrum of general safety and good practice guidelines. However, some participants in contemporary ayahuasca rituals may lack adequate cultural support and guidance [ 129 , 131 ]. Traditional indigenous settings usually provide structure and safety within ancestral medicinal practices (e.g. plant dietas) contemporary touristic settings. While certain structured approaches like specific dietary protocols, careful attendance, and setting might mitigate risks and enhance the experience [ 130 ], the Western concept of psychological support may not neatly align with such Indigenous methods. Traditional indigenous settings often lack formal health screenings and discussions on medication interactions, challenging the assumption that they are inherently safer for tourists.
Importantly, there is need to integrate safety measures for interactions between ayahuasca with prescription medications (i.e., SSRIs or dopaminergic stimulants), other drugs of abuse, or specific foods rich in tyramines such as overripe fruits, fermented food, tofu, or nuts, which might conceivably increase the risk of serotonin syndrome [ 11 , 128 ]. The use of ayahuasca is not recommended for individuals with uncontrolled hypertension, cardiovascular or cerebrovascular diseases, epilepsy, glaucoma, and liver or gastrointestinal diseases (e.g. ulcers or gastritis), and during pregnancy [ 131 ]. Furthermore, ayahuasca may be risky for individuals with severe psychiatric conditions, including bipolar or psychotic disorders [ 131 ].
Mechanisms of action: ayahuasca and DMT alone
Pharmacological mechanisms, human pharmacokinetics and pharmacodynamics of dmt and ayahuasca.
In the 1950s, the Hungarian chemist and psychiatrist Stephen Szára undertook the first investigations of psychological and hallucinogenic effects of DMT, which he self-administered intramuscularly (i.m.) as an extract from M. hostilis [ 132 ]. In the 1970s, Dittrich, Bickel, and colleagues presented the first systematic psychological investigations of i.m. DMT administration [ 133 , 134 ]. Rick Strassmann reported that intravenous (i.v.) DMT at doses ranging from 0.03 to 0.25 mg/kg DMT freebase (as fumarate) induced peak psychedelic effects at five minutes for the 0.25 mg/kg dose, with plasma DMT concentrations peaking at 16 ng/mL (85 nM) [ 135 ]. Subjective effects returned to baseline by 30 min. Recent studies tested i.v. DMT with different administration regimens. Such protocols entailed 0–19.2 mg bolus 0.5–0.8 mg/min constant infusion of DMT freebase (as hemifumarate) for up to 90 min (Basel) [ 7 ], 11.2 mg bolus 1.2 mg/min infusion of DMT freebase (as fumarate) for up to 30 min (London) [ 8 ], and constant infusion totaling 13.4 mg DMT freebase (as fumarate) over 10 min (London) [ 110 ]). The Basel study showed dose-dependent increases in heart rate up to 119 BPM and blood pressure up to 159/98 mmHg [ 7 ], peaking shortly after the bolus administration and stabilizing within 10–15 min. This aligns with findings from the London study [ 8 ], suggesting a good physiological safety margin in individuals without cardiovascular disease or hypertension. In the first randomized controlled trial of a standardized ayahuasca-analogue formulation containing DMT/harmine, oral doses included up to 38.4 mg DMT freebase (as hemifumarate) and 250 mg harmine, or up to 69.1 mg intranasal DMT freebase (as hemifumarate) [ 89 ]. DMT was given in 7.7 mg portions at 15 min intervals intranasally, in combination with buccal harmine (up to 200 mg). Autonomic parameters increased transiently after DMT administration and returned to baseline within 120–180 min, with fewer side-effects (e.g. nausea, headache) compared with botanical ayahuasca. In recent intravenous DMT studies, peak plasma concentrations (C max ) were 61 ng/mL at T max (2.9 min) [ 7 ], 32 ng/mL after 11.2 mg DMT bolus followed by 1.2 mg/min [ 8 ], and 63 ng/mL after constant infusion of 1.34 mg/min DMT (freebase weight) [ 110 ]. These C max values correspond to DMT concentration range of 170–335 nM, with apparent plasma half-life (t 1/2 ) of 5–12 min [ 8 , 109 ]. In comparison, C max for intranasal DMT (combined with buccal harmine) was 33 ng/mL at 130–140 min after first administration of the highest dose combination [ 89 ]. Surprisingly, the intravenous DMT studies revealed large inter-individual variability in plasma concentrations [ 7 , 110 ]. This is likely due to individual differences in whole body MAO activity, suggesting a need for personalized dosing. The intranasal/buccal routes of administration considerably improved upon the PK variability of combined oral DMT/harmine [ 89 ]. However, determining the appropriate extent of MAO inhibition to optimize DMT bioavailabilty, remains challenging due to inter-individual differences in harmine metabolism (i.e. rapid vs. slow metabolizers [ 136 ]). Overall, i.v. DMT and parenteral DMT/harmine administration routes can evoke subjective states of controlled intensity and duration, but further refinement of dosing protocols is needed.
The pharmacokinetics of ayahuasca decoctions, which contain a mixture of β-carboline alkaloids, are more complex than for pharmaceutical combinations of DMT and harmine. The presence of THH and harmaline also influence the pharmacodynamics of DMT, while possibly having psychoactive effects unrelated to MAO inhibition. Administration of natural ayahuasca at doses corresponding to 1.4 mg/kg DMT, 4.6 mg/kg harmine, 0.75 mg/kg harmaline and 5.4 mg/kg THH evoked C max values of 25 ng/mL DMT and 110 ng/mL harmine [ 137 ], which are comparable with C max values from the highest dose in the DMT/harmine PK study [ 89 ]. We suppose that THH, given its C max of 329 ng/mL (1.5 µM) from natural ayahuasca, could well contribute to ayahuasca psychopharmacology. An earlier study with administration of lyophilized ayahuasca capsules reported significant plasma concentrations of DMT and THH, but no detectable harmine and harmaline, despite their presence in the capsules [ 61 ]. Indeed, the concentrations of DMT and THH were lower than expected by the authors, based on the ayahuasca PK study conducted earlier by Callaway and colleagues [ 10 ]. The authors interpreted the disparate plasma results as reflecting differing bioavailability of alkaloids in the lyophilized capsules as compared to the botanical ayahuasca brew [ 61 ]. In another study involving administration of two successive ayahuasca doses at four hours apart, there was substantial potentiation of DMT plasma concentrations (approximately 25% higher C max after the second dose) and subjective effects after the second dose [ 62 ]. These results suggest a lack of acute tolerance to subjective effects, and furthermore indicate that carryover of alkaloids from the first dose augments the MAO inhibition from the second dose, which is consistent with the 3–5 h plasma half-lives of harmine and harmaline (40 mg/kg, i.p.) seen in rats [ 138 ]. Indeed, repeated dosing schemes are very common in the ayahuasca ritual, with (anecdotally) little or no development of tolerance on a time scale of days. Such a lacking rapid tolerance development contrasts with LSD or psilocybin, which show significantly declining subjective effects when taken on consecutive days, in association with cross-tolerance [ 139 , 140 ]. On the other hand, the continuous i.v. DMT administration studies reported the strongest subjective effects directly after onset, which subsequently declined despite increasing blood plasma DMT levels over time [ 7 , 8 ]. Such results imply the occurrence of partial acute short-term tolerance to DMT alone, even though there is a general correspondence between pharmacodynamic subjective effects induced by DMT and ayahuasca with the plasma concentrations of the relevant alkaloids. This holds especially well for plasma DMT curves, which are in good accord with the T max for overall intensity, visual effects, side effects, and other subjective acute effects [ 8 , 10 , 61 , 89 , 110 , 137 , 141 ].
Metabolism of ayahuasca alkaloids
The metabolic pathways for DMT and the β -carbolines in ayahuasca are well understood (Fig. 1 ). In additional to the extensive first pass metabolism or oral DMT, there is also rapid second pass oxidative deamination via MAO-A in brain [ 103 ] and other tissues, irrespective of the route of administration. After oxidative deamination, the second-most important metabolic route for DMT is to DMT- N -oxide (DMT-NO) via unspecified hepatic cytochrome P450 (CYP450) enzymes, with minor routes resulting in the production of N -methyltryptamine (NMT) or 6-hydroxy-DMT (Fig. 1 ). Of these metabolites, the former compound is anecdotally psychoactive, according to Shulgin [ 3 ]. Recent studies indicate that the CPY2D6 and CYP2C19 cytochrome oxidase isoforms can contribute to the formation of NMT from DMT [ 109 , 110 ]. However, the specific isoform/s responsible for the conversion of DMT to 6-hydroxy-DMT remain unknown. Inhibition of MAO-A, by reducing or slowing the production of 3-IAA, shifts the branching ratio in favor of the secondary metabolic pathways. Thus, MAO inhibition augments the formation of DMT-NO, NMT, and 6-hydroxy-DMT [ 107 ]. In a rat study with DMT administration alone (1 mg/kg i.p.), the brain concentration of 3-IAA at 100 min was ~ 50-fold higher than that of unmetabolized DMT. However, with co-administration of harmine (1 mg/kg i.p.), the brain exogenous alkaloid concentrations were 34% DMT, 65% 3-IAA, and 1% DMT-NO [ 103 ]. Thus, even with substantial (but incomplete) MAO inhibition, 3-IAA remained the main metabolite in brain. In an analysis of 24-h urine samples collected after ayahuasca administration, there was 1% recovery of unchanged DMT, versus 55% as 3-IAA and 12% as DMT-NO [ 108 ], suggesting that DMT-NO formation may be more important systemically than in brain (DMT-NO is unlikely to cross the blood–brain-barrier). In another urine analysis study, there was 97% excretion of the DMT dose as 3-IAA and 3% as DMT-NO after oral administration [ 6 ]. In contrast, that study showed significantly higher generation of DMT-NO (28%) after smoking, with 63% excreted as 3-IAA and 10% leaving the body unchanged. Despite the lacking MAO-A inhibition in that study, renal elimination as DMT-NO exceeded that seen after ayahuasca administration.
Harmine and harmaline are metabolized in the body to hydroxy-harmine or and hydroxy-harmaline by enzymes from the CYP450 family, or to harmol and harmalol [ 107 ]. Similarly to harmine and harmaline, THH is preponderantly metabolized to tetrahydroharmol [ 107 , 108 ], but the responsible enzymes remain to be established. In 24-h urine samples collected after ayahuasca administration, there were low total recoveries of harmine, THH, and their metabolites as compared to DMT and harmaline recovery, which comprised approximately two-thirds of the administered dose [ 108 ].
Molecular and cellular mechanisms
Molecular targets of dmt and ayahuasca.
Conventional understanding links the psychedelic properties of DMT (and ayahuasca) to agonism at brain serotonin 5-HT 2A receptors [ 52 ]. However, DMT has only modest affinity at these receptors in vitro (K i = 127–1200 nM and IC 50 = 75–360 nM) [ 142 , 143 , 144 , 145 , 146 ]. Additional binding at serotonin 5-HT 1A (K i = 183 nM, IC 50 = 170 nM) and 5-HT 2C receptors (K i = 360–2630 nM, IC 50 = 360 nM), along with other receptor subtypes, have been proposed to contribute to the overall psychoactive effects of DMT [ 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 ]. 5-HT 1A receptors predominantly occur in the limbic system and brain regions that receive projections from other parts of the limbic system, such as the amygdala, hippocampus, cingulate cortex, and certain other neocortex regions [ 151 , 152 ]. In these regions, the 5-HT 1A receptors have post-synaptic localization, while 5-HT 1A receptors in the raphe nuclei are pharmacologically distinct autoreceptor sites that control serotonin release and firing rate [ 153 ]. The 5-HT 1A receptors are mechanistically relevant for the biological understanding of depression [ 151 , 152 ], as 5-HT 1A agonism proposedly improves stress resilience [ 154 ], and modulates HPA axis functioning [ 155 ] and neuroplasticity [ 156 ]. Not only DMT, but also the ayahuasca β- carbolines influence serotonin neurotransmission, either directly (DMT as a 5-HT 1A/2A/2C agonist) or indirectly (THH as a SERT blocker and weak MAO-A inhibitor, and harmine and harmaline as potent MAO-A inhibitors), which could relate to reported anti-depressant effects of ayahuasca [ 157 ]. Interestingly, the co-administration of the 5-HT 1A/1B receptor partial agonist pindolol potentiated the subjective effects of DMT in a human trial [ 135 ], suggesting an autoreceptor regulation of the post-synaptic effects of DMT.
5-HT 2A receptors have highest expression in brain in layer 5 pyramidal neurons in the neocortex, but also occur in limbic and basal brain structures [ 154 ]. As noted above, DMT shows moderate affinity towards 5-HT 2A sites, as does harmine (K i = 230 nM), whereas harmaline and THH show very low 5-HT 2A affinities of 7.8 and > 10 µM, respectively [ 158 , 159 ]. Νotably, pre-administration of the serotonin 5-HT 2A/C blocker ketanserin (as tartrate, 40 mg) significantly diminished (but did not ablate) the neurophysiological and subjective effects of ayahuasca reported by participants via the hallucinogen rating scale (HRS) and the altered states of consciousness (ASC) questionnaire [ 141 ]. There were significant reductions in the HRS subscales affect, perception and intensity, and in the ASC subscale “visionary restructuralization” upon ketanserin pretreatment. However, these subscale scores were still significantly higher than on study days without ayahuasca administration, which implies that 5-HT 2A receptors may not be the solitary site of DMT action. There was no significant ex vivo occupancy by DMT plus harmine (1 mg/kg, each) at rat cortical 5-HT 2A receptors labelled with [ 3 H]ketanserin [ 103 ], a close analogue of the PET ligand [ 18 F]altanserin [ 160 ]). In the rat study higher doses of DMT plus harmine (3 mg/kg, each) also evoked no detectable occupancy at binding sites for [ 18 F]MHMZ, a 5-HT 2A antagonist PET ligand with higher selectivity and binding signal than [ 18 F]altanserin/[ 3 H]ketanserin. Those negative results may call into question the contention that DMT acts exclusively via serotonin 5-HT 2A receptors. In another study, administration to rats of ayahuasca at doses containing 0.3 mg/kg DMT led to extinction of contextual freezing behavior [ 161 ]. With repeated ayahuasca doses, the co-administration of the 5-HT 2A receptor antagonist MDL-11,939 or the 5-HT 1A receptor antagonist WAY-100635 in the limbic cortex blocked the fear extinction effects, again suggesting an action at both receptor types [ 161 ]. The 5-HT 2C receptors have expression in epithelial cells in the choroid plexus and GABAergic neurons in prelimbic prefrontal cortex (PFC), and in other cortical, limbic, and basal ganglia regions, where they may present targets for various neuropsychiatric disorders [ 162 ]. DMT and harmine both show low affinity to 5-HT 2C receptors [ 158 ], but we cannot presently exclude an action of ayahuasca at these sites.
While LSD interacts at dopamine D 2/3 receptors in vitro [ 143 , 163 ] and in vivo [ 164 ], DMT has little affinity at dopamine receptors [ 128 ]. However, the indisputable involvement of brain dopamine in affective disorders, reward learning, and avoidance behaviors in relation to anhedonia [ 165 , 166 ], we may infer an indirect action of ayahuasca at dopaminergic pathways. While ayahuasca β -carbolines likewise have little affinity for dopamine receptors [ 167 ], they may yet mediate indirect effects on brain dopamine via MAO-A inhibition [ 157 ]. Thus, for example, ayahuasca administration increased the dopamine concentration in amygdala of rats [ 168 ]. Nonetheless, as noted above, complete blockade of both forms of MAO did not potentiate the amphetamine-evoked dopamine release in the [ 11 C]raclopride PET competition paradigm [ 169 , 170 ]. On the other hand, local application of harmine (300 nM) substantially increased the electrically evoked release of dopamine in nucleus accumbens brain slices, in a manner seemingly unrelated to MAO inhibition, but apparently involving 5-HT 2A receptors [ 171 ]. Harmine may inhibit dopamine reuptake via DAT [ 107 ] and may somehow contribute to the normalization of aberrant DAT membrane trafficking and DA reuptake rate in addictive disorders [ 172 , 173 ]. Sigma-1 receptors, which are abundant throughout the CNS [ 157 , 174 ], are another potential site of DMT action. However, the reported affinities for DMT towards sigma-1 receptors (K D = 14 µM [ 174 ], K i = 5.2–15.1 µM [ 143 , 175 ]) may not suffice to impart significant effects. Nonetheless, DMT induced reductions in electrophysiological measures (spreading depolarization), which were normalized by co-administration of sigma-1 antagonists NE-100 and asenapine [ 175 ]. The selective sigma-1 receptor agonist PRE-048 evoked a similar reduction in spreading depolarization. Additional immunohistochemistry results in the same study indicate that DMT might have neuroprotective properties against hypoxia or ischemic stroke [ 175 ].
The β -carbolines harmine and harmaline are antagonists at alpha-1 adrenergic receptors, with IC 50 values in the range 31–36 µM [ 176 ], and may inhibit acetylcholinesterase, which would thereby potentiate cholinergic neurotransmission [ 157 ]. Other possible actions of harmine include modulation of GABAergic neuronal transmission [ 177 ] and inhibition of intracellular protein aggregation (perhaps relevant in neurodegeneration models) [ 178 ], which may call for further investigation of therapeutic mechanisms [ 157 ]. Harmine exerts anti-inflammatory, neuroprotective, antidiabetic, and antitumor effects in various models [ 179 , 180 , 181 , 182 ]. Overall, the ayahuasca β -carbolines may have effects extending beyond simple MAO-A inhibition, but with uncertain relevance to ayahuasca psychopharmacology.
Neuroplasticity induced by DMT and β -carbolines
Recent research addresses the possibility that psychedelic substances can induce or reinstate neuroplasticity, e.g., by altering gene and protein expression, post-translational processes, synapse formation, or neurogenesis. While most such studies have concerned psilocybin, there are a few reports on neuroplastic effects of DMT and the ayahuasca β -carbolines (for review, see [ 183 ]. Especially in human research, plasma levels of brain-derived neurotrophic factor (BDNF), a neurotrophin known to regulate synaptic plasticity and neuronal growth [ 184 ], have served as a marker for potential effects of neurogenesis in the context of antidepressant treatment [ 185 ]. While one study showing increased plasma BDNF levels after ayahuasca intake by healthy and depressed individuals [ 186 ], other studies with ayahuasca or DMT showed no significant changes [ 7 , 187 ]. In a preclinical study, there was likewise no increase in plasma BDNF after DMT administration. However, co-treatment with an antagonist of tropomyosin receptor kinase B (TrkB, the high affinity receptor for BDNF), or with an inhibitor of downstream target of TrkB signaling (mTOR), completely blocked the neuroplastic effects of DMT, suggesting significant engagement of the BDNF signaling pathway in mediating neuroplasticity [ 188 ]. In that same study, a single treatment i.p. with DMT (10 mg/kg as free base) increased dendritic spine density and neuronal excitability in PFC neurons, which might explain the antidepressant and fear extinction effects reported in another rat study with DMT [ 189 ]. Increased dendritic spine growth was observed after activation of intracellular 5-HT 2A receptors with DMT, psilocin or psilocybin. These intracellular receptors are mostly inaccessible by endogenous serotonin, thus suggesting that DMT might induce neuroplasticity via an intracellular mechanism, possibly also at the low endogenous concentrations [ 190 ]. Chronic microdosing (0.77 mg/kg DMT freebase (as hemifumarate) 2–3 times per week for 7 weeks) did not alter BDNF levels or 5-HT 2A receptor expression in rats, but nonetheless exerted antidepressant-like behavioral effects and improved fear extinction learning without other seemingly negative behavioral changes [ 191 ]. Interestingly, the authors also reported retraction of dendritic spines in the PFC, but only in female DMT-treated rats. These latter effects may raise concern about the possibility of unfavorable effects with excessive or prolonged microdosing regimens [ 191 ]. Many of the presented findings potentially link to biomolecular underpinnings of affective disorders, e.g. decreased BDNF levels or TrkB signaling could underly depression, or neuroinflammation due to immunological hyperactivity could mediate anxiety symptomatology [ 25 , 185 , 192 , 193 ]. DMT treatment enhanced performance in memory tests and spatial learning in adult mice, while promoting neurogenesis in the subgranular zone of the hippocampus in vitro (tested after 7 days) and in vivo (2 mg/kg repeated doses of DMT either daily over 4 days, or every other day for 21 days) [ 194 ]. Co-administration of a sigma-1 receptor antagonist blocked these effects, which may belie the low affinity reported for DMT at that binding site.
Preclinical studies have implicated harmine as an enhancer of BDNF signaling in rat hippocampus, in association with antidepressant-like effects in a behavioral assay, both for acute and chronic administrations [ 25 , 193 ]. However, other rat studies showed that a high dose of harmine (15 mg/kg as harmine hydrochloride) induced anhedonia in the sucrose preference test, and reduced locomotor activity, without increasing hippocampal BDNF levels [ 195 ]. All three main β -carboline alkaloids in B. caapi promoted neurogenesis in an in vitro assay with progenitor cells from the subventricular and subgranular zone, which are the main niches of adult neurogenesis in mice. Harmine, harmaline and THH all significantly increased stem cell proliferation, migration, and eventual differentiation into neurons to assays in vitro [ 196 ]. Complementing these findings, earlier studies in chick embryo cells [ 197 ] and human neural progenitor cells [ 44 ] showed that harmine (2–5 µM in chick embryo and 7.5–22.5 µM in human progenitor cells) increased mitosis rates. In a mouse model of anxiety, harmine (20 mg/kg i.p. daily for 7 days) reduced anxiety-like behavioral effects and blunted neuroinflammation in the basolateral amygdala [ 192 ].
We emphasize that some studies have reported adverse effects from very high or repeated doses of DMT or ayahuasca [ 121 , 191 , 195 ], in keeping with Paracelsus’ dictum dosis sola facit venenum (only the dose makes the poison). As with any medication, exceeding some therapeutic dose range may offset beneficial effects of appropriate dosage regimens. The involvement of BDNF signaling in the effects of DMT/ayahuasca seem relevant to the association of BDNF with models of depression and anxiety disorders arising from a hyperactive immune system and chronic low-grade inflammation [ 25 , 185 , 192 , 193 ]. As substantiated by the burgeoning publications on neuroplasticity in the psychedelics literature [ 183 ], there is growing interest in the basic biological mechanisms of action of psychedelic substances. A simple model in which DMT and other ayahuasca constituents act exclusively at serotonin 5-HT 2A receptors falls short of explaining the full spectrum of acute and chronic effects.
Functional mechanisms—human brain imaging and EEG studies
We now give a narrative account of the available molecular imaging, fMRI, and EEG studies reporting effects of ayahuasca (14) or DMT (9) on human brain function. We present the studies in chronological order in Supplementary Table 1, including a brief description of the study design, sample, and interventions, along with key results, with a more detailed discussion in the following section.
Neuroimaging studies with ayahuasca and DMT
The first ayahuasca neuroimaging study used single photon emission tomography (SPECT) to determine the acute effects of lyophilized ayahuasca capsules on regional cerebral blood flow (CBF) [ 198 ], a surrogate marker for neuronal network activation. Ayahuasca administration increased perfusion in the right hemisphere anterior cingulate cortex (ACC) and medial frontal gyrus, bilaterally in the anterior insula and inferior frontal gyrus, and in the left amygdala and parahippocampal gyrus. These regions are thought to play key roles in interoception, body awareness, and emotional processing [ 199 , 200 ], well aligning with the acute subjective effects of ayahuasca [ 46 , 201 ]. A similar SPECT study in depressed patients showed significantly increased perfusion in the left nucleus accumbens (NAc), right insula and left subgenual area 8 h after ayahuasca treatment compared to baseline [ 29 ]. Additionally, acute reductions in depressive symptoms (80–180 min after administration) persisted up to three weeks. Previous neuroimaging studies (deep brain stimulation, PET, fMRI) have shown hypoactivity in precisely these regions in depressed patients, which rectified upon treatment with conventional antidepressants such as SSRIs or deep brain stimulation [ 202 , 203 , 204 , 205 , 206 ]. Post-acute results from the depressed group showed only partial overlap (in the right insula) with the acute effects of ayahuasca on cerebral perfusion in the healthy volunteer study [ 29 , 198 ], which might reflect changes in neuronal responsivity to the pharmacological challenge or time-dependent measurement differences.
In two task-based fMRI studies during acute DMT (i.v.), the first study showed no significant changes in blood oxygenation level dependent (BOLD) signal, despite the participants’ reduced reaction time to stimuli [ 207 ], whereas the second study showed signal reductions in brain regions associated with processing visual and auditory information in addition to reduced reaction time [ 208 ]. These combined behavioral and fMRI results recapitulated earlier behavioral findings with two different DMT doses [ 209 ]. Participants in another study with somewhat higher doses of i.v. DMT reported experiencing pronounced elementary and complex imagery [ 8 ], which might explain the reduced capability to focus on such attention-based tasks.
Another fMRI study investigating mental imagery during acute ayahuasca effects reported increased BOLD signal in many brain regions compared to baseline, including bilateral cuneus and left precuneus, lingual gyrus, fusiform, parahippocampal and temporal, occipital and frontal gyri [ 210 ]. These changes occurred during an imagery experience and may underly the often-reported vivid internal visual alterations with closed eyes. Partially overlapping results were reported in [ 198 ], and correspond to functional representations such as the peripheral visual field, retrieval of episodic memories, processing of contextual associations, and mental imagery. Changes in functional connectivity during mental imagery after ayahuasca intake, indicate alternations in the top down temporal information flow between frontal and occipital regions. Visions produced by ayahuasca seemingly arise in the primary visual cortex (V1) [ 210 ] and propagate to higher order visual regions. Another report of the same study sample showed changes in the default mode network (DMN) with task-based (verbal fluency) and with resting-state (rs) fMRI recordings [ 43 ]. Six of the nine pre-defined DMN regions showed significant activity decreases when comparing rest to task periods and ayahuasca to baseline. Two of the remaining DMN ROIs (left MFG and left MTG, involved in language processing [ 211 ]), also showed significant BOLD signal decreases. Additionally, functional connectivity declined within PCC/precuneus after ayahuasca intake. These findings suggest that experienced ayahuasca users achieve a brain state that occurs with decreased mind-wandering, allowing them to observe their thoughts and feelings without judgment, similar to experienced meditators [ 212 ].
In a follow-up analysis of the same rs-fMRI data increases of global entropy (Shannon entropy, expressing the uncertainty or variability in stochastic variables) were identified. Increases of local integration and decreases of global integration in various brain networks [ 213 ] imply that ayahuasca altered the modular structures of resting state networks. These results align with the entropic brain hypothesis , which proposes that psychedelic states entail higher entropy than ordinary waking consciousness [ 214 ].
A proton magnetic resonance spectroscopy ([ 1 H]-MRS) and rs-fMRI study with baseline and post-acute measurements one day after ayahuasca ingestion showed decreased glutamate + glutamine, creatinine + phosphocreatinine, and N -acetylaspartate + N -acetylaspartylglutamate signals in the PCC [ 215 ]. These lower metabolite levels indicate higher neuronal activity during acute ayahuasca intake [ 215 ]. Indeed, other psychedelics evoked decreased inhibitory alpha-waves in similar brain regions as in ayahuasca studies [ 141 , 216 , 217 ], and similar MRS changes occur in in patients successfully treated for depression with cognitive behavioral therapy (CBT) or SSRIs [ 218 ]. Complementary rs-fMRI measurements revealed enhanced crosstalk between the ACC (associated with executive and cognitive-emotional processing) and the PCC and limbic structures (highly relevant for emotion and memory processing), which may relate to the antidepressant effects of ayahuasca [ 215 ]. Parts of the salience (SAL; ACC) and the DMN (PCC) networks are habitually anti-correlated in normal waking consciousness [ 219 ], but enhanced coupling may occur during ayahuasca and other psychedelic experiences [ 220 ]. A later study replicated those findings of post-acute increased connectivity between the SAL and the DMN one day after administration of ayahuasca to healthy volunteers [ 221 ]. In accordance with previous reports, increased ACC connectivity within the salience network and decreased connectivity in the PCC within the DMN were identified [ 221 ]. A novel approach was adopted in a rs-fMRI study in a group setting with members of the Santo Daime church presenting “connectome fingerprints” for each participant, based on the idea that functional connectivity is more consistent within the same person across repeated scans than between different subjects [ 222 ]. Participants showed greater alignment between connectomes during the acute ayahuasca phase than during the placebo scans. After ayahuasca treatment, network stability decreased in the SAL, and increased in the dorsal attention network (DAN). Between-network stability mostly decreased from the SAL and visual network (VIS), extending to the other five large-scale brain networks defined by Yeo and colleagues [ 223 ].
Similarly, i.v. DMT administration decreased within-network integrity in five (VIS, somatomotor network (SM), DAN, fronto-parietal network (FP) and DMN) of the seven Yeo networks, and increased within-network functional connectivity in the SAL, FP and DMN [ 224 ]. An increased between-network functional connectivity between the FP, DMN, and SAL networks, and the other Yeo networks, suggest that DMT mainly affects networks integrating and processing higher cognitive functions. Additionally, DMT flattened the principal cortical gradient acutely [ 224 ] (which ranges from areas for processing sensory and motor information to regions subserving higher cognitive processing [ 225 ]). These findings suggest that DMT transiently dysregulates functional hierarchies, enabling greater cross-communication between brain regions and networks as compared to ordinary consciousness.
Another task-based fMRI study testing implicit aversive stimulation showed longer reaction times to aversive compared to neutral images at baseline, whereas during the ayahuasca scan reaction times did not differ according to emotional valence of the visual stimulus [ 226 ]. Furthermore, in the ayahuasca condition, there was decreased activation of the bilateral amygdala and increased activation of bilateral insula and right dorsolateral PFC upon exposure to aversive images. These findings align with previous ayahuasca studies, showing activation of regions involved in emotion processing, such as the amygdala, ACC, and insula, possibly related to the intensified emotional experience [ 29 , 198 ].
EEG studies with ayahuasca and DMT
The first open-label EEG study during the ayahuasca ritual among healthy members of the Santo Daime church reported increases in gamma power in the left posterior temporal cortex and the left occipital lobe with close eyes and increased gamma power in the central, parietal, and occipital lobes with open eyes compared to baseline [ 227 ]. Gamma is a high frequency (30–80 Hz) band modulated by external sensory inputs and internal processes such as working memory and attention; as such, their EEG findings bear some relation to fMRI findings of increased activity (e.g., in visual cortex, fusiform gyrus or prefrontal cortex) during a mental imagery task after ayahuasca administration [ 210 ]. A later study found a dose-dependent reduction in EEG power across all frequency bands, peaking between 90 and 120 min after ayahuasca administration [ 228 ]. Additional EEG analyses focussing on peak effects at 60 and 90 min after high doses [ 229 ] showed widespread bilateral decreases in alpha and delta power in somatosensory, auditory, and visual association cortices. At 90 min even greater reductions in beta, delta, and theta power occurred in cortical regions relevant for emotion and memory processing. Similar decreases in lower frequency (delta and theta) power have been observed after treatment with other psychedelics, or psychostimulants [ 230 , 231 ].
Delta waves usually increase during deep sleep, or in meditative and relaxed states, so decreased delta power might suggest an excitatory effect of ayahuasca [ 229 ]. This would be in accordance with animal studies showing excitatory postsynaptic potential and currents after psychedelics administration [ 232 ]. Although delta and theta power in EEG recordings was unchanged in a later study up to two hours after ayahuasca intake [ 137 ], alpha power declined in parieto-occipital regions at 50 min. Some cortical regions showed increased slow-gamma power between 75 and 125 min, while fast-gamma power had decreased in four clusters during the same time window. DMT and β -carboline plasma levels showed positive correlations with EEG power in the beta, gamma and delta bands, and a negative correlation with alpha power. Specifically, DMT and harmine levels correlated more strongly with early phase alpha power decreases, while the harmaline and THH concentrations correlated more strongly with the late phase gamma band increases. These changes in β -carboline profiles matched earlier pharmacokinetics findings [ 10 , 11 ].
In an EEG study using transfer entropy (TE) to measure directed information transfer ayahuasca administration resulted in decreased information flow from frontal to posterior brain regions and increased flow from posterior to frontal regions [ 233 ]. These changes, observed at various time points after administration, suggest that ayahuasca disrupts the usual neural hierarchies between higher order frontal regions and more sensory-related posterior regions, aligning with similar findings from fMRI studies with i.v. DMT [ 224 ].
An EEG study that tested the effects of ayahuasca and ketanserin in a 2 × 2 design found decreases in alpha, delta, and theta frequency bands after 90 min [ 141 ], much as in the above-mentioned earlier studies [ 137 , 228 , 229 ]. Ketanserin alone had opposite effects, with unchanged alpha power but increased delta and theta powers compared to placebo. When combined, ketanserin and ayahuasca led to stronger increases in delta and theta power, counteracting ayahuasca’s effects. Ketanserin before ayahuasca reduced, but did not completely block all subjective effects, possibly related to changes in EEG bands.
Performance of a cognitive mismatch negativity (MMN, a brain response to violations of a rule) EEG task decreased dose-dependently during i.v. DMT administrations compared to baseline [ 234 ]. After the low DMT dose, there was diminished N1 peak amplitude (~ 150 ms after stimulus), indicating decreased attention to visual stimuli [ 235 ], and attenuated MMN signal in the right hemisphere. Similarly, psilocybin treatment also reduced N1 peak activity, albeit with stronger effects on MMN [ 236 , 237 ].
A more recent EEG study with i.v. DMT showed significantly increased signal diversity and delta and gamma powers, while decreasing alpha and posterior beta powers, correlating with intensity ratings and DMT plasma levels [ 238 ]. A cortical travelling wave analysis revealed increased forward waves (FW) and decreased backward waves (BW) [ 239 ]. After DMT administration, the frequency of the travelling waves decreased for alpha and beta and increased for delta and theta, matching previously reported frequency band power changes. These changes resembled those seen during visual stimulation [ 240 ], suggesting a mechanism for DMT-induced visual hallucinations [ 8 , 241 ]. Another analysis modelled the relationship between alpha and beta power, signal complexity and simulated DMT plasma levels, identifying specific concentrations evoking half-maximal (IC 50 ) band reductions in alpha (71 nM) and beta power (137 nM), and the EC 50 for signal complexity (54 nM). These results constitute the first dose–response relationship for EEG signal strength with DMT.
EEG recordings after self-administration of DMT by smoking in a naturalistic setting recapitulated findings [ 238 ] of a widespread reduction in alpha power lasting several minutes, along with reduced delta and gamma power in occipital, parietal, temporal and antero-central regions during the same time window [ 242 ]. In a separate reanalysis of these data, the same pattern of power changes was found alongside a negative correlation with subjective effects only with theta power changes [ 243 ].
An additional analysis of the study presented above [ 224 ] focused on the relationships between EEG and simultaneous fMRI findings after i.v. DMT administration. EEG data showed reduced alpha and beta power, decreased fractal spectral power below 30 Hz, and increased signal complexity. Significant negative correlations were found between intensity ratings and plasma DMT concentrations with alpha- and beta-power and positive correlations with delta- and theta-power, much as reported in [ 238 ]. The cross-model analysis showed positive correlations between frontal delta power and negative correlations between parietal alpha-power with GFC in most RSNs, along with positive correlations between gamma power and signal diversity in a few RSNs. This study reinforced preceding EEG findings with additional fMRI data, demonstrating the benefits of multimodal neuroimaging.
In reviewing EEG studies on ayahuasca and DMT, two main findings consistently appear: (1) a reduction in alpha frequency power, and (2) an increase in signal complexity. These effects occur 60–120 min after ayahuasca administration and shortly after i.v. or inhaled DMT [ 137 , 141 , 224 , 228 , 229 , 238 , 242 , 243 ]. Reduced alpha power has been linked to increased brain metabolism [ 244 , 245 , 246 ], which could explain the increased BOLD signal in the visual cortex [ 210 ], and the vivid visual effects often reported with these substances. The alpha band is the most prominent feature of resting-state EEG recordings in adults [ 247 ], and is linked to high-level psychological functioning [ 248 , 249 ] and top-down brain regulation [ 250 , 251 ], both of which are generally modified by psychedelics [ 224 , 233 , 252 , 253 ]. While changes in other frequency bands are less consistent, the increase in signal complexity supports the idea of decreased top-down regulation and hierarchical processing of neural information during the psychedelic state [ 214 , 252 ].
Neuroimaging and EEG studies on DMT and ayahuasca vary widely in their designs, dosages, administration routes, and settings, which can make comparisons difficult. However, many studies focused on resting-state EEG or fMRI, which are useful for examining brain activity without specific tasks and can be easily compared. Despite these caveats, these studies have informed several models of psychedelic action emerging over the past few years. These models include the entropic brain hypotheses as noted above [ 214 ] and its generalization, the REBUS (relaxed beliefs under psychedelics and the anarchic brain) model [ 252 ], the cortico-striato-thalamocortical (CSTC) model [ 254 ], the strong priors (SP) model [ 255 ], and the cortico-claustro-cortical (CCC) model [ 256 ]. The CSTC and the CCC model mainly rely on the assumption that 5-HT 2A receptor agonism is the key driver for psychedelic effects, which is less than certain for the case of DMT/harmine. The REBUS model proposes that psychedelics reduce the influence of top-down processes (like expectations or prior beliefs) and thereby enhance bottom-up sensory and emotional information flow potentially facilitating therapeutic change processes. We prefer the REBUS model because it explains several observed effects such as the reduction of a cortical gradient (fMRI), modulations of RSNs (especially the DMN), increased signal complexity (EEG) or altered direction of cortical traveling waves in the alpha band [ 257 ].
For a comprehensive integration of these models into general neuroscientific research on psychedelics, see [ 258 ]. Several systematic reviews have examined neuroimaging studies with various psychedelic substances, e.g., Gattuso et al. [ 259 ] and McCulloch et al. [ 260 ]. These reviews highlight the modulation of the DMN and resting-state brain activity under the influence of psychedelics, using various imaging techniques (e.g. fMRI, EGG, MEG). However, there is a notable lack of molecular imaging studies specifically examining the actions of DMT and ayahuasca.
Long-term psychological and neuroanatomical changes after ayahuasca use
In a cross-sectional study, Bouso et al. [ 261 ] compared long-term ayahuasca users (n = 127) of various ayahuasca churches in Brazil with a religious control group (n = 115) that abstains from substance consumption. Psychometric assessments were conducted at study inclusion (T1) and one year later (T2). The ayahuasca group showed significantly lower Harm Avoidance and Self-Directedness, higher Self-Transcendence, and lower general subjective symptoms, which suggests that consumption in religious contexts is beneficial for mental and physical health. Additionally, ayahuasca users scored higher on all subscales of the Spiritual Orientation Inventory [ 262 ] at both time-points, indicating a reinforcement of spiritual beliefs and attitudes. They also performed better in neuropsychological tests of conflict monitoring, executive function, and working memory at both time-points.
Structural MRI provides quantitative measures of brain volume and cortical thickness, which can indicate structural changes due to aging, neurotoxicity, or neuroplasticity. Bouso et al. [ 263 ] reported on cortical thickness in experienced ayahuasca users from the Santo Daime with a matched control group. The habitual ayahuasca users showed significant cortical thinning in middle and inferior frontal gyrus, precuneus, superior frontal gyrus, PCC, and superior occipital gyrus, along with cortical thickening in the precentral gyrus and ACC. Cortical thinning in the PCC negatively correlated with lifetime and years of ayahuasca use. Neuropsychological tests revealed the same differences as the cross-sectional study mentioned above. The cortical thinning in key nodes of the DMN might imply long-term downregulation of DMN activity, although no direct evidence links this to reduced within-DMN connectivity [ 43 , 224 ]. The negative correlation of PCC thickness and self-transcendence might imply an anatomical basis for the increased religiosity often reported by ayahuasca users. Overall, Bouso’s studies suggest that regular, long-term ayahuasca use in religious contexts benefits brain health, though these findings may not necessarily apply to a secular or psychiatric use. The general abstinence from other drugs among ayahuasca church members may support the cognitive benefits attributed to ritual use.
Another analysis of the same MRI study tested the hypothesis that regular ayahuasca use would lead to thickening of fiber tracts in the corpus callosum, the bundle connecting the cerebral hemispheres [ 264 ]. Results showed thickening in the isthmus of the corpus callosum, correlating with ayahuasca use frequency, although these findings did not hold after multiple testing corrections. The implicated callosal regions are positioned to mediate increased interhemispheric connectivity between motor and somatosensory regions [ 265 ]. Obtaining such an effect might be beneficial for motor function, various neurodegenerative disorders, e.g. amyotrophic lateral sclerosis (ALS), and for stroke rehabilitation [ 265 , 266 ].
A more recent cross-sectional structural MRI study assessed morphometric similarity (MS), an approach whereby anatomical connectivity is analyzed by considering multiple brain structural features (e.g. grey matter volume, and cortical curvature and thickness) [ 267 ], in 24 frequent ayahuasca users from the Santo Daime church and 24 matched controls [ 268 ]. The ayahuasca group showed overall reduced MS compared to controls, with lower MS in sensorimotor cortices (inferior frontal gyrus, precuneus, pre and post central gyrus) and higher MS in the orbitofrontal, entorhinal, cingulate, and anterior insular cortices. Lower MS indicates decreased anatomical connectivity between a region and the rest of the cortex [ 268 ]. The findings of increased MS in the ACC align with an earlier MRI study showing thinning [ 263 ]. MS analysis with the seven RSNs defined by Yeo and colleagues [ 223 ] revealed reduced MS in the sensorimotor, dorsal attention, and default mode networks for the ayahuasca group, with increased MS in the limbic network. Additional correlations with gene expression maps in the ayahuasca group revealed 18 genes relevant to DMT or ayahuasca effects (with either positive or negative weightings) on MS findings. Notably, 5-HT 2A receptor gene downregulation in sensorimotor cortices correlated with lower MS, suggesting that repeated ayahuasca use may lead to sustained downregulation and desensitization, similar to LSD tolerance [ 269 ]. Since ayahuasca or DMT do not seem to evoke rapid tolerance [ 62 ], it is questionable if such 5-HT 2A receptor downregulation could mediate tolerance. Earlier neuropsychology studies showed that regular ayahuasca users had better integrity of executive functions than less experienced users [ 270 ], which might relate to 5-HT 2A receptor desensitization or downregulation, a matter for future PET studies.
Pharmacological models alone may not fully explain the anatomic/functional associations observed in ayahuasca studies. For example, religiosity in Christian church members showed associations with a widespread pattern of greater cortical thickness [ 271 ], compared to the more diverse findings of cortical thickness changes in ayahuasca users. The cross-sectional studies of Santo Daime church members, who abstain from other drugs, provide a unique opportunity to study repeated ayahuasca use. However, these cross-sectional studies cannot infer causality. Larger, longitudinal studies are needed to confirm the structural and functional brain changes linked to ayahuasca use.
Conclusions and future directions
With this narrative review and synthesis, we summarize the current state of research with DMT, β -carbolines, and ayahuasca. While DMT is the main psychedelic constituent, the diverse β -carboline alkaloids in ayahuasca contribute to its unique (adverse) effects, creating an entourage effect that distinguishes it from synthetic formulations. The combination of DMT with MAO inhibitors enhances its bioavailability and duration and offers alternatives to inhaled or injectable routes of administration, which lead to short but intense DMT experiences. We emphasize the need to distinguish between a reductionist view of ayahuasca as a mixture of chemical substances and its full context as a cultural practice, often affiliated with traditional and syncretic religions. The findings presented herein mostly fall within the broad field of neurobiology, and do not adequately accommodate the cultural and botanical knowledge associated with indigenous usage of ayahuasca for therapeutic and ritualistic purposes.
Current understanding does not definitively implicate a singular molecular target that could explain the subjective effects of DMT or ayahuasca. Key candidates include several serotonin receptor subtypes (5-HT 1A/2A/2C and potentially others), an indirect influence on dopamine transmission due to β- carbolines, and potential roles of TrkB and sigma-1 receptors. Better qualifying the importance of 5-HT 2A receptor activation by DMT (alone or in combination with MAOIs) shall call for dedicated pre-clinical and clinical molecular imaging studies.
Neuroimaging and EEG studies have consistently shown reductions in alpha frequency power and increased signal complexity after ayahuasca or DMT administration. These findings are in line with brain models of decreased top–down regulation and enhanced neural communication during the psychedelic state. Functional neuroimaging studies have revealed changes in brain network dynamics, such as increased connectivity between the salience and default mode networks, and activations of brain areas associated with processing of emotions and autobiographical memories. Understanding these mechanisms is crucial for developing targeted therapeutic applications. The preponderance of imaging studies and clinical studies have been exploratory with open-label designs. There is a pressing need for larger-scale, controlled clinical trials to establish the dose-dependence and persistence of long-term therapeutic benefits and neurobiological effects induced by ayahuasca or DMT. Such studies should integrate clinical scoring with advanced imaging methods. We also see a need for comparative studies with other classical psychedelics, aiming to understand better the neurobiological basis of their differing phenomenology. Promising findings that DMT and ayahuasca evoke neuroplastic effects call for consolidation with comparable results seen with other psychedelic compounds. The bulk of such research has hitherto entailed studies in vitro and in preclinical research, without translation to the human clinical context. Multimodal neuroimaging techniques such as diffusion tensor imaging (DTI) could serve to investigate changes in white matter tracts in conjunction with MRS to follow changes in specific neurometabolites acutely or over time [ 272 ]. Recent advances in neuroimaging data processing, e.g. the development of a modality-overarching neuroimaging data structure [ 273 ], standardization of fMRI preprocessing pipelines [ 274 ], and the development of sophisticated computational approaches should enable streamlining and standardization of neuroimaging results to facilitate easier interpretation between studies.
Additionally, molecular imaging studies, including PET, are essential to further explore receptor occupancy and neuroplasticity mechanisms in vivo. Neuroplasticity in response to ayahuasca or its constituents might be amenable to investigation by PET with a ligand for synaptic vesicle protein 2A (SV2A), as shown autoradiographically for the case of psilocybin in experimental animals [ 275 ]. PET studies with the serotonin 5-HT 2A/2C receptor agonist radioligand [ 11 C]Cimbi-36 [ 276 ] (i.e., the psychedelic phenylethylamine generally known as 25B-NBOMe [ 277 ]) may be better suited than antagonist radioligands for establishing competition from the exogenous agonist DMT in vivo, as is the case for dopamine D 2/3 receptors [ 278 ]. Similarly, an agonist PET ligand for 5-HT 1A receptors might serve to detect occupancy by DMT at this receptor in human brain. As noted above, the complex alkaloid composition of ayahuasca calls for consideration of the entourage effect, a concept originally known from cannabis research [ 67 ], and indeed in consideration of the polypharmacology of tobacco smoke, which evokes inhibition of MAO-A in human organs to [ 11 C]clorgyline PET [ 279 ]. There were no effects in a pilot study of low dose harmine/DMT on energy metabolism in rat brain to [ 18 F]FDG PET [ 103 ], but we are currently undertaking human [ 18 F]FDG PET studies of pharmahuasca. Results of this ongoing neuroenergetics study could prove informative regarding the interpretation of the extensive fMRI/EEG literature on ayahuasca reviewed above.
In conclusion, the therapeutic potential of ayahuasca constituents to promote neuroplasticity and treat neuropsychiatric disorders, including depression, addiction, and PTSD, is gaining empirical support. Additionally, early evidence suggests a potential role of DMT in the treatment of acute brain injury such as ischemic stroke, which opens promising paths for future pharmacotherapeutic developments. Standardized formulations of DMT and harmala alkaloids present certain advantages for clinical investigations and basic research into the molecular pathways and mechanisms of action by offering more predictable pharmacokinetic and pharmacodynamic profiles, as well as better control of potential adverse effects, compared with botanical ayahuasca preparations. In addition to the molecular and neurophysiological perspective, we note the importance of processes of psychological change, alongside clinical and contextual factors such as supportive set and setting. While extending beyond this review’s original scope, we hold that such considerations are essential for obtaining a comprehensive understanding of the therapeutic potential of ayahuasca.
Data availability
Not applicable.
DMT is also present in a hallucinogenic snuff (known as yopo) derived from seeds of the South American trees Anadenanthera peregrina or A. columbina , along with the psychoactive tryptamines 5-methoxy-DMT (5-MeO-DMT) and 5-hydroxy-DMT (bufotenin) [ 280 ].
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Egger, K., Aicher, H.D., Cumming, P. et al. Neurobiological research on N,N -dimethyltryptamine (DMT) and its potentiation by monoamine oxidase (MAO) inhibition: from ayahuasca to synthetic combinations of DMT and MAO inhibitors. Cell. Mol. Life Sci. 81 , 395 (2024). https://doi.org/10.1007/s00018-024-05353-6
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