Brain Rhythms from the speed of thought to Alzheimer’s and Novichok
Professor of Neuropharmacology
University of Bath
The brain is our most complex organ consisting of 84 billion cells, many cognitive (neurones) with supportive cells to maintain the former in tip-top condition (e.g. astrocytes, microglia, oligodendrocytes etc). Each neurone consists of a cell body, an axon conducting impulses, and many dendrites, branching extensions that transmit/receive messages from adjoining neurones. Each nerve cell (see Fig.1) has approximately 10,000 connections with other cells, giving around 15 x 109 connections in the average human brain. Connectivity, rather than number of cells, is the key to the extraordinary capabilities of the brain.
Fig.1. Schematic diagram of various brain cells and the synapse
Mechanically, interconnections between nerve cells are moderated not by a direct electrical connection, as might be found in a wiring junction box, but by a synapse, a definitive gap between neuronal processes across which an impulse is chemically transmitted. The synapse is sufficiently small for the impulse to travel, via a chemical mediator (transmitter), to receptor sites on the receiving side without significant delay. Having been utilised to transmit a nerve impulse, the transmitter substance is immediately deactivated by an appropriate enzyme to prevent an unnecessary prolonging of its action.
There are different categories of nerves within the brain which use different chemical intermediaries. Many use acetycholine (ACh). Other neurotransmitters include dopamine and nitric oxide, to name but two. This gives different categories of nerves specific susceptibility to chemicals or drugs that may be ingested or absorbed by the body.
Of notable importance are cholinergic nerves which (as noted above) use acetylcholine (ACh) as the transmitter substance. In the case of cholinergic nervous transmission, ACh mediates the transmission, it is neutralised having crossed the synapse by the enzyme cholinesterase (AChE). Anti-cholinesterase drugs (or AChE inhibitors) will decrease or eliminate the effect of cholinesterase enzyme thereby enhancing cholinergic activity.
Besides the anatomical marvel of the brain, Roland made reference to the importance of rhythms (synchronicity), not only in biological systems, but also in the environment generally. Whole biological systems are rhythmic, for example, in heart activity and circadian rhythms. Even a single cell possesses its own rhythm. Hibernation, a big sleep over Winter, is a long-term rhythm. A round of applause, seemingly constituted of the random claps of individuals quickly develops into a rhythmic beat. Another classic example is where three (or more) metronomes, placed on a plank, quickly, through connectivity via the plank, gradually converge their beats until they are beating in synchronicity1.
Since 1875, scientists have been intrigued by electrical activity in various parts of the brain. The development of the electroencephalogram (EEG) in 1924, allowed researchers to investigate in greater detail.
Fig. 2 Characteristic wave forms detectable and their relevance to brain activity
Distinct categories of wave patterns have been discovered (see Fig. 2). These include alpha, beta, delta, theta waves and most recently discovered are gamma waves, with a frequency of 25-100hz (40hz is typical). For Roland, these are considered the most important of brain rhythms in unifying brain activity. They are important for memory recall and their gradual loss is correlated with cognitive decline.
An intriguing observation of brain activity is that brain function seems to occur much faster than would be imagined from an examination of the speed of an impulse by considering each component in the impulse pathway individually. Roland flashed several images very briefly on a screen demonstrating how quickly we detect them. Gamma waves are considered to represent the binding together of different populations of nerves together into a network for carrying out certain cognitive and motor functions. Rhythm between different populations seems to speed up brain processes. Some researchers go as far as to suggest they are responsible for unity of consciousness- a very big claim!
How do cells generate rhythm? There are certain key cells within the brain, Rhythm Drivers (RD’s), which originate rhythm. The connectivity of nerve cells transmits this rhythm through the brain. Essentially, through connections, cells ‘listen’ to each other. Individual cells will switch off where there is danger of the rhythm becoming unstable.
Rhythm Drivers are found primarily in the thalamus, a structure which lies above the brain stem. The thalamus modulates sleep, alertness and consciousness and acts as a hub regulating motor and sensory signals to the cerebral cortex. If nerve cells in the thalamus (many are cholinergic) are compromised the cognitive action of the brain will be detrimentally affected. Cholinergic nerves are also found in many connecting pathways within the brain. Their degeneration is also heavily implicated in Alzheimer’s and other neurodegenerative diseases such as Parkinson’s and Huntington’s.
Alzheimer’s Disease (AD)
Alzheimer’s is a loss of memory and cognitive process, mild cognitive impairment being an intermediate stage. Loss of gamma wave function is frequently a very early sign followed by later loss of cognitive ability. Susceptibility factors are various: environmental causes (e.g. pollution) have been implicated whilst genetics are regarded as a weak connection. Conversely, there is evidence that using cognitive processes (e.g. learning a foreign language, sudoku) are possibly protective (‘use-it-or-lose-it’ approach). In AD, older memories tend to be more secure than newer ones. Recall forges stronger memories and older ones are likely to have been recalled more frequently and are therefore better retained.
Fig. 3 Brain atrophy in Alzheimer’s Disease
Why are Alzheimer’s patients gamma impaired? In the brain, cholinergic nerves are particular susceptible to damage by amyloid plaques which form during (and are hallmarks of) AD’s. The so-called Cholinergic Theory of AD suggests that it is these plaques of B-amyloid protein which cause degeneration and death of cholinergic nerve cells and loss of cholinergic neurotransmission (see Fig.3).
Interestingly, in healthy individuals, administering Scopolamine, an anticholinergic drug, blocks cholinergic activity and produces memory impairments similar to AD. These impairments are reversed if treated with Physostigmine (AChE inhibitor) which prevents the breakdown of ACh ensuring that even a small amount of ACH present will have an enhanced effect. Similarly, Curare, beloved by poison dart firing Indians of South America, blocks cholinergic processes inducing pseudo-AD, requiring an AChE inhibitor as an antidote.
Ideally, the best strategy would be to stop degeneration of these nerves. Stem cell therapy has been tried. It is not good for neurodegenerative disorders where the nervous network has been physically disrupted and in consequence has not proved to be beneficial. The alternative is to increase ACh activity by making more ACh available by exogenous application or preventing its breakdown by administering AChE inhibitors.
Various AChE inhibitor drugs have been approved: donepezil (Aricept), rivastigmine (Exelon) and galantamine (Reminyl). AChE inhibitors do increase gamma wave activity. However, they have a range of side effects, including affecting motor control, increased salivation and sweating, which makes its use for practical purposes somewhat challenging.
Memantine, another medication for AD (but not an AChE inhibitor), acts on the glutamatergic system, blocking NMDA activity, suggesting an alternative methodology in attacking AD.
Treatments and strategies for tackling AD suggest two particularly interesting leads. Novichok, a potent nerve agent weapon, notorious for its use by assassins from the Russian state, is an AChE inhibitor and could therefore be considered a treatment for AD. It is extremely potent, as the Salisbury attack showed, and would need to be used in very small, controlled doses.
Another possible treatment of note comes not from secret laboratories of Putin’s Russian, but from the fungus family, a family that has brought to our attention several notable drugs2. Territrem B, a mycotoxin, derived from Aspergillus terreus is an AChE inhibitor and when administered, produces a significant increase in amplitude of gamma activity, mitigating, to some degree, the effects of AD.
Clearly, AD and its elimination, is high on the medical research agenda and Roland’s work is but one important strand of this complex area, which may ultimately provide a satisfactory and much desired breakthrough in this far too common and debilitating disease.
1 Three metronomes developing synchronicity
2 See presentation on fungii and drugs see: ‘Fungi Will Save The World!’ by Lee Davies, March 2018 https://drive.google.com/open?id=1lshtCrZ4NdGPrpSsIucRjyjlE72rEre8