Does neurogenesis continue throughout life? New studies suggest yes – and it may play a key role in memory

The topic of adult neurogenesis has been controversial over the past couple of decades due to a lack of strong evidence that new neurons are generated in humans after adolescence. However, the development of new technologies and experimental techniques – as well as an alarming rise in Alzheimer’s disease and other dementias^1,2 – has brought adult neurogenesis back into the limelight.

There is a prevailing belief that neurogenesis – i.e. the growth and development of new neurons – halts once we reach adulthood. Indeed, most neurons are generated in the embryo, before birth. 

Adult neurogenesis, however, refers to the continued generation of neurons from neural stem cells in the adult brain. These newborn cells eventually become indistinguishable from those born during embryonic development³. 

Determining whether new neurons are continuously generated in the adult brain in humans, and how this process may be altered in both normal, ‘healthy’ aging and in neurodegenerative diseases such as Alzheimer’s, is an important question with potentially game-changing therapeutic potential.

In animal models, reductions in adult neurogenesis have been associated with a number of cognitive deficits including impairments in spatial memory, long-term memory and fear conditioning. Impaired neurogenesis has also been associated with a number of psychiatric disorders including depression, anxiety, addiction and schizophrenia. For example, patients with major depression have shown reduced levels of neurogenesis in the hippocampus, while antidepressants are known to increase neurogenesis in this region – an action which may be important in their therapeutic action^4,5. 

The hippocampus is involved in the consolidation of memories to other brain regions as well as in memory retrieval, and is one of the most affected areas in Alzheimer’s disease⁶. The dentate gyrus – a subsection of the hippocampus – plays a key role in memory retrieval, and is one of only two regions where the addition of new neurons has been observed throughout life in mammals. The other is the subventricular zone of the lateral ventricles, where the differentiation of new neurons plays a role in the sense of smell – although the latter is unlikely have any functional significance in humans^7,8. Although adult neurogenesis in these two regions has been observed rodents and monkeys⁹, neither has been reliably observed in humans. 

A seminal study by Eriksson et al. in 1998¹⁰ provided the first direct evidence of adult neurogenesis in the hippocampus of humans. The researchers were not, however, able to quantify the number of new neurons in the samples, nor did it provide any insights into the dynamics of adult neurogenesis. 

More recently, a study in 2013¹¹ built upon research in the field by devising a method to retrospectively determine the birth date of cells in the hippocampus. They achieved this by measuring the concentration of ¹⁴C in the DNA. The theory behind this approach was that, due to above-ground nuclear bomb testing during the Cold War, atmospheric ¹⁴C levels were elevated during the time period from 1955-1963; since then, levels of ¹⁴C in the atmosphere have steadily declined. Much of that ¹⁴C has reacted with oxygen to form CO₂ which has in turn been taken up by plants through photosynthesis before passing through the food chain into animals and humans. As a result, atmospheric ¹⁴C levels are mirrored in human genomic DNA, as the ¹⁴C is incorporated into chromosomes during cell division at a concentration corresponding to that in the atmosphere at the time – thus providing a method of determining the cells’ date of birth. Effectively, a radioactive timestamp. 

By measuring concentrations of ¹⁴C in human post-mortem hippocampal cells from subjects aged 19-92, the researchers could devise a model to calculate the rate of cell turnover which suggested that neurogenesis may indeed persist throughout adulthood. However, this was only a model – actual evidence of immature or newborn neurons being incorporated into adult brains in humans was still lacking. 

Last year, a study led by Sorrells et al.¹² attracted a lot of attention in the neuroscience community after publishing findings in which the authors failed to show any evidence of new neurons in post-mortem brain samples from adult humans. The research looked at the numbers of neural precursor cells and immature neurons in human port-mortem samples and concluded that neurogenesis in the hippocampus was most significant within the first year of life, before declining rapidly throughout childhood until eventually halting entirely in the brains of adults. 

A paper published in Nature earlier this year, however, found quite the contrary. 

The research¹³, led by Moreno-Jiménez et al. at the Department of Molecular Neuropathology, Universidad Autónoma de Madrid, Spain, aimed to investigate the extent of adult neurogenesis in the human hippocampus using post-mortem brain samples obtained from both healthy individuals and Alzheimer’s disease patients. 

Previous studies have shown both increases¹⁴ and decreases¹⁵ in neurogenesis in post-mortem tissue derived from patients with Alzheimer’s disease. Moreno-Jiménez and her team, however, sought to achieve more definitive results by improving upon the tissue-processing methods used in previous studies; proposing that previous failures to show direct evidence of adult neurogenesis in humans may actually be down to the experimental methods used in those studies. 

Thus, by using state-of-the-art methods to tightly control the conditions by which the brain samples were obtained and prepared, the team achieved a greater sensitivity allowing them to identify thousands of immature neurons in the dentate gyrus of hippocampi from 13 neurologically healthy human subjects and 45 subjects with Alzheimer’s disease. While the numbers of new neurons declined throughout life in both cohorts – suggesting a natural age-related decline in neurogenesis – immature neurons were identified right through to the ninth decade of life. 

The researchers identified newborn neurons using fluorescent antibodies, allowing them to visualise a specific marker of neuroblasts (neuronal precursor cells which will later develop into neurons) called doublecortin (DCX) (Figure 1). Moreno-Jiménez et al. reported a several-fold higher density of these types of immature cells in the dentate gyrus than has been reported in previous studies – most likely owing to the enhanced tissue preparation methods. The team also demonstrated the co-existence of several other neuroblast-associated markers, confirming that the cells identified were in fact immature neurons.

Figure 1: Confocal microscopy images showing (1) the entire hippocampus, (2) the dentate gyrus (DG) showing the abundant presence of DCX+ immature neurons (yellow triangles) and (3) a high-power-magnification image of one of these cells. Moreno-Jiménez et al. (2019)

Figure 2: The density of DCX+ neural precursor cells
is lower in Alzheimer’s disease patients compared with
controls and declines with age, with counts dropping
further as patients progress through the six Braak stages
of Alzheimer’s disease. Moreno-Jiménez et al. (2019)

As you may have guessed, the number of DCX-positive cells was significantly lower in the hippocampi of Alzheimer’s disease patients compared with neurologically healthy controls (Figure 2). Moreover, neurogenesis was even further reduced in the later stages of the disease. 

Even more interesting is that the reductions in adult neurogenesis were also detected in the early stages of the disease – before the presence of neurofibrillary tangles or senile plaques thought to underlie the pathophysiology of Alzheimer’s. 

It is possible therefore that detection of impairments in adult hippocampal neurogenesis using non-invasive methods may serve as an early biomarker for the disease, and that therapeutic targeting of cellular pathways underlying neurogenesis in the hippocampus could potentially mitigate the memory deficits characteristic of Alzheimer’s disease and other dementias. 

A new study published in Cell Stem Cell this week¹⁶ by researchers at the University of Illinois in Chicago reported similar findings in post-mortem samples taken from a cohort of 18 patients with Alzheimer’s disease and other mild cognitive impairments, aged between 79 and 99 years old. 

Similarly, the researchers investigated the levels of DCX-positive neuroblasts in the samples, finding that these neural precursor cells, among other markers of developing neurons, were present in the hippocampus of brain tissue taken from patients well into their 90’s. 

As well as supporting Moreno-Jiménez et al.’s conclusions that a decline in neurogenesis may be an important underlying feature of Alzheimer’s – potentially driving the decline in cognitive ability from the early stages of the disease – the study goes further by showing that higher counts of DCX-positive neuroblasts are associated with higher scores in measures of cognitive ability and an overall better clinical diagnosis. 

It is worth noting, however, that while the results of these studies strongly support the general consensus among neuroscientists that neurogenesis does indeed persist throughout life in the hippocampus of humans, the existence of these neuroblast markers does not necessarily prove that these precursor cells all develop into fully mature neurons – studies have shown that newborn neurons that do not complete cell maturation and integration processes are eliminated during adult neurogenesis in mice¹⁶. Nonetheless, the results are in stark contrast to previous research which has generally found a decline in neuroblast numbers in the adult hippocampus throughout life¹¹. These findings therefore provide crucial new evidence – reigniting the age-old debate about the relevance of adult neurogenesis in humans. 

Since adult-born neurons have been found to contribute to learning and memory in animal models, it is quite feasible that this may also be true in humans. Adult neurogenesis may indeed be a fundamental part of learning and memory, with impairments in the addition, maturation or survival of newborn neurons potentially leading to memory deficits such as those seen in Alzheimer’s disease and other forms of dementia. 

While these findings are the first to present direct evidence suggesting that neurogenesis does indeed continue throughout life in humans, research in the field is still in its infancy. Nevertheless, the results raise a host of questions regarding their potential to pave the way for new treatments for neurodegenerative diseases. What if we could isolate and therapeutically target a particular pathway or pathways involved in the regulation of adult neurogenesis in the hippocampus? Could this lead to improvements in memory in those suffering from Alzheimer’s and other dementias, potentially slowing or preventing the progression of the disease – or perhaps even offer a way of staving off the natural decline in memory due to ageing in healthy individuals? Future research will inevitably seek to answer these questions. 

On a final note – numerous studies have shown that both exercise and sleep can significantly increase neurogenesis in mice, as well as stave off the natural decline due to aging^17–20. Yet another reason to get more of both! 

References:

1. Winblad, B. et al. Defeating Alzheimer’s disease and other dementias: a priority for European science and society. The Lancet Neurology 15, 455–532 (2016).

2. Chan, K. Y. et al. Epidemiology of Alzheimer’s disease and other forms of dementia in China, 1990–2010: a systematic review and analysis. The Lancet 381, 2016–2023 (2013).

3. Laplagne, D. A. et al. Functional Convergence of Neurons Generated in the Developing and Adult Hippocampus. PLOS Biology 4, e409 (2006).

4. Gonçalves, J. T., Schafer, S. T. & Gage, F. H. Adult Neurogenesis in the Hippocampus: From Stem Cells to Behavior. Cell 167, 897–914 (2016).

5. Miller, B. R. & Hen, R. The current state of the neurogenic theory of depression and anxiety. Current Opinion in Neurobiology 30, 51–58 (2015).

6. Braak, H. & Braak, E. [Morphology of Alzheimer disease]. Fortschr Med 108, 621–624 (1990).

7. Bergmann, O. et al. The Age of Olfactory Bulb Neurons in Humans. Neuron 74, 634–639 (2012).

8. Wang, C. et al. Identification and characterization of neuroblasts in the subventricular zone and rostral migratory stream of the adult human brain. Cell Research 21, 1534–1550 (2011).

9. Kornack, D. R. & Rakic, P. Continuation of neurogenesis in the hippocampus of the adult macaque monkey. PNAS 96, 5768–5773 (1999).

10. Eriksson, P. S. et al. Neurogenesis in the adult human hippocampus. Nature Medicine 4, 1313–1317 (1998).

11. Spalding, K. L. et al. Dynamics of Hippocampal Neurogenesis in Adult Humans. Cell 153, 1219–1227 (2013).

12. Sorrells, S. F. et al. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature 555, 377–381 (2018).

13. Moreno-Jiménez, E. P. et al. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nature Medicine 25, 554 (2019).

14. Jin, K. et al. Increased hippocampal neurogenesis in Alzheimer’s disease. PNAS 101, 343–347 (2004).

15. Li, B. et al. Failure of Neuronal Maturation in Alzheimer Disease Dentate Gyrus. J Neuropathol Exp Neurol 67, 78–84 (2008).

16. Tobin, M. K. et al. Human Hippocampal Neurogenesis Persists in Aged Adults and Alzheimer’s Disease Patients. Cell Stem Cell (2019). doi:10.1016/j.stem.2019.05.003

17. Sierra, A. et al. Microglia Shape Adult Hippocampal Neurogenesis through Apoptosis-Coupled Phagocytosis. Cell Stem Cell 7, 483–495 (2010).

18. Kreutzmann, J. C., Havekes, R., Abel, T. & Meerlo, P. Sleep deprivation and hippocampal vulnerability: changes in neuronal plasticity, neurogenesis and cognitive function. Neuroscience 309, 173–190 (2015).

19. Lucassen, P. J. et al. Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: Implications for depression and antidepressant action. European Neuropsychopharmacology 20, 1–17 (2010).

20. Vukovic, J., Colditz, M. J., Blackmore, D. G., Ruitenberg, M. J. & Bartlett, P. F. Microglia Modulate Hippocampal Neural Precursor Activity in Response to Exercise and Aging. J. Neurosci. 32, 6435–6443 (2012).

21. Clemenson, G. D. et al. Enrichment rescues contextual discrimination deficit associated with immediate shock. Hippocampus 25, 385–392 (2015).

Twitter image by Jason Snyder. 

Major Advances in Alzheimer's Disease – Restoring Cognitive Ability and the Role of Chronic Gum Disease

Alzheimer's disease (AD) continues to be a leading cause of dementia and ultimately death, with over 44 million estimated to be suffering from the disease worldwide, and only 1-in-4 receiving an official diagnosis. 

Drug therapies have proved largely unsuccessful. Last year, a promising BACE1 inhibitor – a class of drugs which prevent the formation of toxic amyloid-β plaques – was dropped due to safety concerns. Another was found to reduce levels of amyloid-β, but without any significant improvements in cognition. Another type of drug – an antibody which seeks out and breaks down amyloid-β – was able to reduce levels of amyloid-β, but only at the highest dose and with significant side effects. The search for effective drug treatments continues. 

The role of epigenetics – i.e. environmentally-dependent and heritable changes in DNA structure which regulate the expression of genes without altering the nucleotide sequence itself – is being increasingly recognised in the disease pathology of psychiatric, neurodegenerative and mood disorders across the board, including in Alzheimer's.

A paper [1] last week found significant elevations of the histone methyltransferases EHMT1/2, which catalyse repressive histone H3 methylation (linked to gene silencing) in the prefrontal cortex of mice representing a late-stage familial Alzheimer's disease (FAD) mouse model, ultimately leading to a decreased expression and function of glutamatergic AMPA and NMDA receptors in the prefrontal cortex. Such epigenetic changes have also been observed [2] in human post-mortem tissue of human AD patients and are thought to, at least in part, underlie the progressive cognitive decline seen in the later stages of the disease. When the mice were treated with an EHMT1/2 inhibitor (BIX-01294 or UNC0642 [3,4]) or virally-mediated EHMT1/2 gene knockdown, these changes were reversed and glutamate receptor expression and function was restored in the prefrontal cortex and hippocampus. Significantly, the cognitive impairments in object-recognition, working memory and spatial memory usually exhibited in late-stage FAD mice were consistently (albeit temporarily) restored to that of wild-type controls in a T-Maze delayed-alternation task, novel object recognition task and the Barnes maze, respectively – suggesting a potential new therapeutic target in the treatment of Alzheimer's disease, independent of the amyloid-β deposits and tauopathy thought to underlie the disease pathology. Future research will look at whether treatment with EHMT1/2 inhibitors could restore cognitive function and memory deficits in Alzheimer's patients.

Back to the amyloid-β hypothesis – which may be a contributing factor to the aforementioned epigenetic changes – a separate research paper [5] last week showed that the bacterium porphyromonas gingivalis (P. gingivalis) may play a central role in the pathogenesis of Alzheimer's disease.

Gingipains (red) bind to amyloid-β

S. Dominy et al., Science Advances 5, 2019.

The bacterium – commonly associated with chronic periodontitis (gum disease) – has previously been identified as a risk factor in the development of AD and has been directly correlated with a greater accumulation of amyloid-β plaques [6] in humans. In the current study the bacterium was identified in the cerebrospinal fluid of 10 suspected AD patients. P. gingivalis produces toxic proteases known as gingipains, which have been shown to drive the host colonisation and pathogenesis [7] of the bacterium. Oral infection with P. gingivalis in mice consistently increased production of Aβ1–42, a key component of the toxic amyloid plaques known to underlie neurotoxicity and neuroinflammation in AD. Furthermore, when the researchers injected gingipains into mice, the mice consistently developed the hallmark tau and ubiquitin pathology assosciated with AD, and showed significantly greater neurodegeneration than saline-injected mice. The researchers therefore administered selective, small-molecule gingipain inhibitors in vivo, and found that not only was the host Aβ1–42 response to P. gingivalis infection significantly decreased, but the associated neurodegeneration was successfully blocked. Future research will continue to investigate whether selective gingipain inhibitors able to cross the blood-brain-barrier may represent a potential new mode of treatment for Alzheimer's disease, as well as the link between P. gingivalis infection and apolipoprotein E4 (APOE4). An orally bioavailable, brain-penetrant gingipain inhibitor is already being tested in human clinical trials.

The research supports the recently emerging hypothesis that amyloid-β may act as an antimicrobial peptide [8,9], with mutations contributing to its dysfunction leading to a more robust response to infection with P. gingivalis (amongst other microbes) and thus an increased risk of neurotoxicity. The authors further propose that genetic polymorphisms of innate immune system genes may result in defective clearance of P. gingivalis and its associated gingipains from the brain, resulting in chronic, low-level infection and neuroinflammation in susceptible individuals. Neuroinflammation has long been known to be a significant causal factor in AD pathology.

Exciting advances – both a new target to reduce aberrant amyloid-β production and subseqeunt neurodegeneration in Alzheimer's before it occurs, and a novel target to potentially restore cognitive function in the later stages of the disease.


References:
[1] Zheng, Y., Liu, A., Wang, Z.-J., Cao, Q., Wang, W., Lin, L., Ma, K., Zhang, F., Wei, J., Matas, E., et al. Inhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer’s disease. Brain. Available at: https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awy354/5298257 [Accessed January 28, 2019].

[2] Narayan, P., and Dragunow, M. (2017). Alzheimer’s Disease and Histone Code Alterations. In Neuroepigenomics in Aging and Disease Advances in Experimental Medicine and Biology., R. Delgado-Morales, ed. (Cham: Springer International Publishing), pp. 321–336. Available at: https://doi.org/10.1007/978-3-319-53889-1_17.

[3] Kubicek, S., O’Sullivan, R.J., August, E.M., Hickey, E.R., Zhang, Q., Teodoro, M.L., Rea, S., Mechtler, K., Kowalski, J.A., Homon, C.A., et al. (2007). Reversal of H3K9me2 by a Small-Molecule Inhibitor for the G9a Histone Methyltransferase. Molecular Cell 25, 473–481.

[4] Liu, F., Barsyte-Lovejoy, D., Li, F., Xiong, Y., Korboukh, V., Huang, X.-P., Allali-Hassani, A., Janzen, W.P., Roth, B.L., Frye, S.V., et al. (2013). Discovery of an in vivo Chemical Probe of the Lysine Methyltransferases G9a and GLP. J Med Chem 56. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880643/.

[5] Dominy, S.S., Lynch, C., Ermini, F., Benedyk, M., Marczyk, A., Konradi, A., Nguyen, M., Haditsch, U., Raha, D., Griffin, C., et al. (2019). Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Science Advances 5, eaau3333.

[6] Kamer, A.R., Pirraglia, E., Tsui, W., Rusinek, H., Vallabhajosula, S., Mosconi, L., Yi, L., McHugh, P., Craig, R.G., Svetcov, S., et al. (2015). Periodontal disease associates with higher brain amyloid load in normal elderly. Neurobiology of Aging 36, 627–633.

[7] Stathopoulou, P.G., Galicia, J.C., Benakanakere, M.R., Garcia, C.A., Potempa, J., and Kinane, D.F. (2009). Porphyromonas gingivalis induce apoptosis in human gingival epithelial cells through a gingipain-dependent mechanism. BMC Microbiol 9, 107.

[8] Soscia, S.J., Kirby, J.E., Washicosky, K.J., Tucker, S.M., Ingelsson, M., Hyman, B., Burton, M.A., Goldstein, L.E., Duong, S., Tanzi, R.E., et al. (2010). The Alzheimer’s Disease-Associated Amyloid β-Protein Is an Antimicrobial Peptide. PLOS ONE 5, e9505.

[9] Kumar, D.K.V., Choi, S.H., Washicosky, K.J., Eimer, W.A., Tucker, S., Ghofrani, J., Lefkowitz, A., McColl, G., Goldstein, L.E., Tanzi, R.E., et al. (2016). Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Science Translational Medicine 8, 340ra72-340ra72.

The Future of Neuroscience

In the current animal model of depression, a mouse is placed in a jar of water and struggles to swim to avoid drowning, in the aptly named “forced-swim” test(1). After a few minutes, the mouse stops trying to escape, instead choosing to float immobile in the water. At this point, the mouse is said to experience “behavioural despair” (the mouse loses hope to escape the stressful environment) and the mouse is then classified as suffering from “depression”. This is the standard model used to test antidepressant drugs – the time spent immobile versus swimming in mice given the drug is compared to that of controls. Clearly, this is a simplistic model with very little resemblance to the highly complex, multi-faceted disorder of clinical depression in humans. Yet, although its efficacy has long been contested(2), this is still the most common mouse model used in the majority of research into “depression”. 

This is not just the case for depression. Many psychiatric disorders are still studied using simplistic animal models which – though important – essentially bear little resemblance to the experiences of those suffering from the disease on a daily basis. 

On top of this there, is a pervasive disconnect between psychology and neuroscience. It is fundamentally impossible to study affective or cognitive phenomena such as emotion or foresight using animal models, since mice, rats and monkeys are all unable to communicate what they are feeling with humans. Instead, researchers study behaviours as a proxy – for instance, what a mouse does before it gets a reward, which is largely a matter of interpretation. But we lack a way to study actual emotions in mice – which, besides, are likely vastly different subjective experiences to those of humans. While mouse models have their uses, they are generally an insufficient representation of brain disease or even normal brain function in humans. 

It is without surprise then, that over the past 40 years there has been little improvements in the outcomes of patients with the most common brain diseases. Some pharmaceutical companies are abandoning research into drugs for psychiatric diseases altogether due to the high cost and low success rate. For example for Alzheimer’s, every time we think we have a promising new drug in development to break down the toxic amyloid plaques, we find that it fails in clinical trials, and moreover, we find that we were coming at the problem from the wrong angle altogether(3). We now know that we need to intervene long before amyloid deposits are prevalent, and long before symptoms are seen. Some research shows a portion of patients diagnosed with Alzheimer’s do not even have significantly more amyloid-β plaques in their brains than healthy controls, and amyloid pathology has been observed in cognitively healthy elderly individuals, suggesting that amyloid-driven tauopathy may at best only be part of the problem. Thus, we currently lack even an effective diagnostic criteria for neurodegenerative disorders. Treatment for Alzheimer’s is largely symptomatic; we are a long way off from understanding the root causes of the disease. Progress is slow, but we are learning. 

There is also the problem of brain scanning. The most prevalent form of brain imaging in neuroscience and psychology is undoubtedly functional magnetic resonance imaging (fMRI). However, again, this is a proxy – fMRI measures blood flow across the brain while the subject is engaged in a particular task or activity; it does not directly measure neuronal activity(4). One unpublished study from 2009 found apparent cognitive activity in the brain of a dead salmon(5), highlighting the risk of false positives in fMRI studies. Similarly, electroencephalography (EEG) measures electrical activity at the brain surface – however it lacks specificity in that it does not measure the activity of specific neurons or sets of neurons, but rather of a crude combination of electrical currents across a particular brain area. Unfortunately, it is not yet possible to measure the activity of a specific set of neurons in living, human brain tissue. 

However, a small minority of forward-thinking neuroengineers are currently working on measuring real-time electrical brain activity in vivo, in humans. This is already possible in the brains of mice and in monkeys, but not yet in humans. Thus, hopefully in the not-too-distant future, we will be able to record activity from specific sub-sets of neurons and correlate this with not only behaviour, but with thought, emotion and, of course, depression. 

With a little imagination, let’s fast forward 100, or perhaps only 50 years. We now understand the root causes of Alzheimer’s, Parkinson’s, depression, schizophrenia etc., and are able to deliver targeted genetic or drug therapies, custom-made for each patient, to treat brain disease both symptomatically, and more importantly, prophylactically. Furthermore, we now understand that these disorders which we considered one disease, were in fact different diseases with similar symptoms but vastly different biological causes, each requiring a different treatment. We will look back to the primitive days of neuroscience – the early 21st century – and be amazed that the majority of brain diseases were being treated with the wrong drugs, which were more often than not completely ineffective, or even counter-productive(6,7).

In order to achieve this, we first had to figure out how to get electrodes through the skull and into the brains of healthy, living humans, without causing any risk to the subject. Rather than drilling holes through the skull, we use microelectrodes so small that they can be inserted without rupturing any blood vessels, thus avoiding the risk of stroke. We might even use lasers. As technology progresses, we will be able to record from thousands of electrodes at once using smart, robotic, microscopic implantations which work their way around blood vessels and through the brain tissue. Eventually, this will be possible using wearable devices which the subject can implant into their brain and go about their day, while the device is constantly collecting and uploading high-resolution neuronal activity directly from their brain to the computer of a researcher, or their doctor, for analysis. Combined with powerful yet harmless lasers able to pass through the skull and produce images of neurons and synapses with sub-cellular precision, we are able to decipher not only the connectome, but the precise patterns of activity between specific neurons during a particular function, on an individual level, for each patient. By collecting masses of data from millions of patients, we can mathematically calculate – with the aid of superfast computers – what exactly is going wrong in neurological diseases such as Alzheimer’s. Furthermore, we have finally managed to bridge the gap between psychology and neuroscience, by being able to ask the patients about their emotional, subjective experiences, and correlate this with their neuronal activity at that exact point in time. 

At some point, these wearable devices will become commercialised by the likes of Google, Amazon and Apple, offering free services to customers in exchange for their private data – their thoughts. Having learned from our mistakes in the early 21st century regarding privacy and data harvesting, customers will demand rights and legislation to decide how their personal brain activity is used by multinational corporations. However, this will prove ineffective, and customers will willingly sacrifice their privacy anyway, by updating to the latest version of Apple iBrain® without reading the terms and conditions. This will open up a whole Pandora’s box of neuro-hacking and neuro-spyware, as well as further driving inequality and elitism – since only those in first-world countries can access the devices, and only the wealthiest of those can afford the latest and greatest bio-upgrades. The societal, political and economic ramifications of this could fill an entire book in and of itself. But from a neuroscientific perspective, this will be a turning-point; a revolution in neuroscience research, allowing for not only the enhancement of normal brain function – or biohacking – but also significant advances in the treatment of brain diseases. Alzheimer’s, schizophrenia, autism, ADHD, addiction, depression and anxiety disorders will all be things of the past. 

So too will smartphones. Generation Y will tell their kids, “I remember when we had to type our text messages with our thumbs, or ask Alexa to add vegan meat to the shopping list. We never had Google Think® in my day”, or “I remember when we had to go to college to study for years, we had to sit down and read books to learn things. We never had Amazon HiveMind® in my day”. Meanwhile their kids seamlessly communicate via Apple iThought®, video chat via Skype Hologram®, and instantaneously download entire textbooks and literature via an ultra-fast 100Gb/s subscription to Amazon’s entire library for only $19.99 per month. Fake news will become a thing of the past, as every news article you download is instantly verified against thousands of peer-reviewed sources – reviewed both by humans and by sophisticated AI technology. You will never forget anything ever again, as any memory you choose to remember will be uploaded to the cloud, ready to be accessed and relived at will. Alternatively, should you choose, you can delete a traumatic or stressful memory, like it never happened. Without delving too far into the realm of science fiction, the possibilities are Limitless®. Anything is possible, so long as we can dream it – or Google DeepDream® it. 

Our knowledge of neuroscience is only in its infancy. Our understanding the human brain in all its complexity is only a mere few steps away from exponential growth. As technology combines with neuroscience, we become ever closer to understanding ourselves, and to an entirely interconnected consciousness. Societies working together as a collective intelligence are capable of amazing things – just look at bees and ants. Times are changing, for better or for worse.

Now, back to those mice...

References: 

1. Can, Adem, Dao, David T., Arad, Michal, Terrillion, Chantelle E., et al. (2012) ‘The Mouse Forced Swim Test’. Journal of Visualized Experiments : JoVE, (59). [online] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3353513/

2. Borsini, Franco, Volterra, Giovanna and Meli, Alberto (1986) ‘Does the behavioral “despair” test measure “despair”?’ Physiology & Behavior, 38(3), pp. 385–386.

3. Castello, Michael A., Jeppson, John David and Soriano, Salvador (2014) ‘Moving beyond anti-amyloid therapy for the prevention and treatment of Alzheimer’s disease’. BMC Neurology, 14, p. 169.

4. Ekstrom, Arne (2010) ‘How and when the fMRI BOLD signal relates to underlying neural activity: The danger in dissociation’. Brain Research Reviews, 62(2), pp. 233–244.

5. Scicurious (2012) ‘IgNobel Prize in Neuroscience: The dead salmon study’. Scientific American Blog Network. [online] Available from: http://blogs.scientificamerican.com/scicurious-brain/ignobel-prize-in-neuroscience-the-dead-salmon-study/ (Accessed 27 April 2016)

6. Anon (2016) ‘Most antidepressant drugs ineffective for children and teens, study finds’. University of Oxford. [online] Available from: http://www.ox.ac.uk/news/2016-06-08-most-antidepressant-drugs-ineffective-children-and-teens-study-finds (Accessed 6 July 2018)
7. Cipriani, Andrea, Zhou, Xinyu, Giovane, Cinzia Del, Hetrick, Sarah E., et al. (2016) ‘Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis’. The Lancet, 388(10047), pp. 881–890. 

Antioxidants Appear No Help for Alzheimer's

Antioxidant supplements don't appear to have an impact on cerebrospinal fluid (CSF) biomarkers related to Alzheimer's disease, a clinical trial determined.

The combination of vitamin E, vitamin C, and alpha-lipoic acid did not lower levels of the amyloid and tau proteins that make up the plaques and tangles seen in the brain with Alzheimer's disease, Douglas R. Galasko, MD, of the University of California San Diego, and colleagues found.

The combination did reduce CSF levels of the oxidative stress biomarker F2-isoprostane by 19% but raised a safety concern with faster decline in cognitive scores, they reported online in the Archives of Neurology.

The popular antioxidant coenzyme Q (CoQ) had no significant impact on any CSF measures in the Alzheimer's Disease Cooperative Study antioxidant biomarker trial.

Oxidative damage is widespread in the brain in Alzheimer's disease and contributes to neuronal damage, Galasko's group explained.

Some prior observational evidence has pointed to lower Alzheimer's risk with an antioxidant-rich diet, although prevention trials with supplements have had mixed results, they noted.

Their study included 78 adults with mild to moderate Alzheimer's randomly assigned to double-blind treatment over 16 weeks with the combination of 800 IU vitamin E, 500 mg vitamin C, and 900 mg of alpha-lipoic acid once a day; CoQ alone at a dose of 400 mg three times a day; or placebo.

Vitamins C and E act as antioxidants by controlling dangerous free radicals produced when oxygen reacts with certain molecules, while alpha-lipoic acid spurs production of many antioxidant enzymes in the body. CoQ is an antioxidant that helps protect mitochondria from oxidation.

Serial CSF specimens collected from 66 of the participants showed only small changes from baseline.

Beta-amyloid 42, which accumulates to forms plaques in the Alzheimer's brain, declined by 8 pg/mL from a baseline of 190 pg/mL with the antioxidant combination and by 15 pg/mL from a baseline of 185 in the CoQ group, but neither was a significant difference from placebo.

Tau protein, which forms neurofibrillary tangles in the brain with Alzheimer's, fell by 23 pg/mL with the antioxidant combination from a baseline of 123 and by 9 pg/mL from a baseline of 109 in the CoQ group, but again neither differed from changes with placebo.

Levels of tau phosphorylated at a specific site (P-tau181) likewise declined slightly over the study period for the two antioxidant groups but without a significant difference from placebo.

The one significant change was in CSF levels of the oxidative marker F2-isoprostane, which is stable oxidized arachidonic acid.

The vitamin C and E plus alpha-lipoic acid group saw a 7 pg/mL reduction in F2-isoprostane from a baseline of 38 over the 16 weeks of treatment (P=0.04). The other groups showed no change.

"It is unclear whether the relatively small reduction in CSF F2-isoprostane level seen in this study may lead to clinical benefits in Alzheimer disease," the group cautioned.

Cognition, measured with the Mini-Mental State Examination, didn't improve in any of the groups. In fact, the decline in scores appeared accelerated in the antioxidant combination group, with a change of -4.6 points over the 16 weeks compared with -2.3 to -2.4 in the other two groups.

The researchers highlighted that as a potential safety concern that needs further careful assessment if longer-term trials are considered. The antioxidants were otherwise well tolerated.

Function, as measured on the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale, didn't change in any group.


http://www.medpagetoday.com/Neurology/AlzheimersDisease/31721

Galasko D, et al "Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures" Arch Neurol 2012; DOI:10.1001/archneurol.2012.85.