Schizophrenia—Evolution of Humanness

Is schizophrenia bound to human evolution? Schizophrenia is a neuro-developmental disorder characterised by delusions, hallucinations, and bizarre behaviours. No other animal displays these symptoms. Depression, addiction, anxiety are all found in other animal species, but not schizophrenia. Schizophrenia is not even found in chimpanzees our most recent evolutionary ancestors. It is inheritable, and highly disadvantageous to survival of the affected person. Given this, schizophrenia should be almost non-existent. Yet it continues to affect a massive 1% of the global population. Something is pushing for the persistence of this disorder and its spontaneous manifestation in humans.

Human evolution separated from the chimpanzees 5.5 million years ago when we walked upright and then acquired language abilities. Language ability developed after 'lateralisation', the separation of brain functions into the left (sequential) and right (parallel processing) hemispheres. The peculiar delusions and hallucinations of schizophrenia can be understood as failure of the complex brain mechanism that enables the speaker to distinguish his thoughts from his speech or that of others. This brain mechanism evolved with lateralisation of brain functions. Loss of brain laterality in schizophrenia has been demonstrated.

Comparison of the gene sequences of early humans and their close evolutionary relatives, the Neanderthals have shown that regions of the human genome that underwent positive selection are enriched by association with schizophrenia. This suggests that schizophrenia susceptibility factors may be a "side effect" of human achievements like language and creative thinking. 

Recent evolutionary modifications in brain wiring and connections may have played a role in the development of schizophrenia in humans. Compared to our closest living relative the chimpanzee, brain connections present only in humans show a higher involvement in schizophrenia. Evolutionary changes in the human brain related to supporting more complex brain functions are paralleled with a higher risk for brain dysfunctions that can manifest as schizophrenia.

However, this genetic susceptibility is actually reducing. A study comparing modern-human-specific gene sites with archaic ones has shown that schizophrenia-risk related genes in modern humans are much less than those in Neanderthals and Denisovans (archaic humans). So negative selection of schizophrenia risk-related genes are probably being gradually removed from the modern human genome.

References

1. https://en.wikipedia.org/wiki/Human_evolution
2. Crow TJ. Is schizophrenia the price that Homo sapiens pays for language? Schizophr Res. 1997;28(2-3):127–141. doi:10.1016/s0920-9964(97)00110-2
3. Crow TJ. Schizophrenia as the price that homo sapiens pays for language: a resolution of the central paradox in the origin of the species. Brain Res Brain Res Rev. 2000;31(2-3):118–129. doi:10.1016/s0165-0173(99)00029-6
4. Srinivasan S, Bettella F, Mattingsdal M, et al. Genetic Markers of Human Evolution Are Enriched in Schizophrenia. Biol Psychiatry. 2016;80(4):284–292. doi:10.1016/j.biopsych.2015.10.009
5. van den Heuvel MP, Scholtens LH, de Lange SC, et al. Evolutionary modifications in human brain connectivity associated with schizophrenia. Brain. 2019;142(12):3991–4002. doi:10.1093/brain/awz330
6. Liu C, Everall I, Pantelis C, Bousman C. Interrogating the Evolutionary Paradox of Schizophrenia: A Novel Framework and Evidence Supporting Recent Negative Selection of Schizophrenia Risk Alleles. Front Genet. 2019;10:389. Published 2019 Apr 30. doi:10.3389/fgene.2019.00389

Alzheimers disease - mild cognitive impairment countdown

Alzheimers dementia is usually diagnosed when memory loss and behavioural symptoms are readily apparent to their caregivers. At this stage the primary concern is to slow further deterioration. Caregivers at the clinic have often wished they could have looked into the future. Many have a history of Alzheimers disease in their elderly and wondered whether there was an earlier way of knowing. New knowledge gives us hope in this direction.

Alzheimers disease before memory loss

We now have the beginnings of a time line in the countdown to dementia. It is now possible to trace the beginnings of Alzheimers Dementia up to 20 years before its manifestation with memory loss and impaired function.

20

Beta-amyloid levels in the cerebrospinal fluid (CSF)  begin to drop 20 years before the onset of dementia. Alzheimer's Disease is characterized by toxic deposition of specific beta-amyloid (Aβ1-42) plaques around the brain cells. In normal aging beta-amyloid continues to increase in the brain fluid. However, in Alzheimers Dementia brain fluid beta-amyloid is markedly reduced.This is due to reduce clearance of beta-amyloid from the brain to the blood and CSF, as well as increased beta-amyloid plaque deposition in the brain.

15

15 years before dementia onset, beta-amyloid deposits can be detected by amyloid imaging PET scans. The best known amyloid PET tracer is Pittsburgh Compound-B (PIB). PIB retention is found in over 90% clinically diagnosed AD patients.
Tau protein accumulation inside the brain cells (neurons) is the second hallmark of Alzheimer's disease.  Microtuble associated protein tau (MAPT) in the brain fluid (CSF) increases with age. In Alzheimer's disease tau levels are markedly increased and reflects damage to the neurons and axons (brain cells). High CSF tau level differentiates mild cognitive impairment (MCI) from that which progresses to Alzheimer's disease.
Shrinkage or atrophy of the brain becomes detectable by MRI. This atrophy is visible in brain structures that are essential for the conscious memory of facts and events. These areas are located in the brain’s medial temporal lobe. This shrinkage is apparent on using a visual rating system which also measures its severity. The more extensive the brain atrophy, the more advanced the clinical stage of Alzheimer’s disease.

10

PET Scan (FDG-PET) changes in the way the brain uses glucose are apparent 10 years before dementia. These PET scan changes correlate with progression of Alzheimers disease.
Episodic memory loss begins at this stage. Episodic memory loss is the inability to learn new information or to recall previously learned information. It manifests as forgetting of recent events and conversations, repetitive questions, repetitive retelling of stories, forgetting the date, forgetting appointments, misplacing objects, losing valuables, and forgetting that food is cooking on the stove. The formation of new episodic memories requires intact medial temporal lobes of the brain; these are progressively destroyed in Alzheimers disease.

5

Mild cognitive impairment (MCI) deveelops 5 years before dementia. People with mild cognitive impairment have problems with thinking and memory loss. Mild cognitive impairment does not interfere with everyday activities. Persons with mild cognitive impairment are often aware of their forgetfulness.
Preventive therapies for Alzheimers disease (AD) require the development of biomarkers that are sensitive to subtle brain changes occurring in the preclinical stage of the disease. Early diagnostics is necessary to identify and treat at risk individuals before irreversible neuronal loss occurs.
Sources

1. Bateman R. The dominantly inherited Alzheimer's network trials: an opportunity to prevent Alzheimer's disease. Program and abstracts of the Alzheimer's Association International Conference 2012; July 14-19, 2012; Vancouver, British Columbia, Canada. Featured research session F3-04
2. Christian Humpel. Identifying and validating biomarkers for Alzheimer's disease. Trends Biotechnol. 2011 January; 29(1): 26–32. doi: 10.1016/j.tibtech.2010.09.007
3. Duara R, Loewenstein DA, Potter E, Appel J, Greig MT, Urs R, Shen Q, Raj A, Small B, Barker W, Schofield E, Wu Y, Potter H. Medial temporal lobe atrophy on MRI scans and the diagnosis of Alzheimer disease. Neurology. 2008 Dec 9;71(24):1986-92.
4. Mosconi L, Berti V, Glodzik L, Pupi A, De Santi S, de Leon MJ. Pre-clinical detection of Alzheimers disease using FDG-PET, with or without amyloid imaging. J Alzheimers Dis. 2010;20(3):843-54.

Brain effects of cellular phone use

Mobile phone induced EEG changes

Cellular phones affect the brain to cause injury and death through inattention and reaction time delays. Cellular phone radiations also induce abnormal changes in brainwaves. Here we are not concerned with the potential for death due to the cancer generating properties of GSM radiation. We are concerned with the direct and immediate adverse effects of cellular phone conversations.

Cellphones continue to kill their users in Pune. At least two people died crossing the Hadapsar railway tracks while engrossed in conversation. One of them was oblivious to shouting onlookers warning him of the oncoming train. Another cell-bewitched user fell off his eighth-floor balcony while conversing. And of course cellphone use while driving continues to kill despite the ban. All this is besides the cancer risk that the WHO (2011) is unable to disregard.

How distracting is a cellphone conversation?

Any extraneous demand on attention will distract from performance on an ongoing task. If the task itself is critical, as in driving, distractions can be lethal. Even hands-free cellphone conversations while driving cause attention lapses and slow down reaction time (McCartt 2006). These effects are seen in drivers across gender and age groups. The surest way to verify that a crash occurred during mobile phone use is to check billing records. Using this method crashes leading to personal or property damage are found to be four times more common during mobile phone use. When there is a higher mental load in the mobile phone conversation problems with attention and reaction time are magnified (Lin 2006).

The stream of media reported mobile phone related deaths during the performance of everyday tasks highlights the much neglected aspect of non-driving related mobile phone injuries. Pedestrians conversing on a mobile phone cross the road more slowly, are less likely to look for traffic, and take more risks in the face of oncoming traffic (Neider 2010). Pedestrians are less likely to cross a road successfully while using a mobile phone than while listening to music on an iPod. These effects are more pronounced in adolescents.

The risk of injury is related to the need to shift the focus attention from the task on hand to the conversation. Conversing on a mobile phone takes up a significant amount of mental processing ability. Mobile phone conversations increase reaction times and reduce accuracy on task performance. These impairments increase with increasing complexity of the task being interrupted. One can only imagine the effect of a mobile phone interruption on the outcome of an ongoing medical procedure.

Do cellular phone generated electromagnetic waves interfere with brainwaves?

Intriguingly, GSM microwave radiation interacts with and distorts brainwaves. This effect can be directly measured and recorded on an electro-encephalogram (EEG). Electromagnetic fields emitted by cellular phones cause a slowing of brain waves (delta waves) that is not seen in healthy adults during normal wakefulness. These changes persist for up to ten of minutes after the mobile phone is switched off. Children are more vulnerable to these effects as microwave absorption is greatest in an object the size of a child’s head. This radiation also penetrates the thinner skull of an infant with greater ease (Kramarenko 2003).

Brainwaves normally discharge asynchronously when attention is drawn to an event in the environment. This event related de-synchronisation is altered by mobile phone electromagnetic fields. This affects tasks involving memory, especially in children (Krause 2000, 2006). Cellphone radiofrequency waves have a dose dependent effect on tasks attention, concentration and short term memory. Reaction speed decelerates with increasing GSM field intensity. These effects are more pronounced when the responding hand and side of radiation exposure are taken into account (Luria 2009).

These dose dependent radiation effects are also seen when cellular phone use also alters brainwave patterns (spindle activity) during slow-wave sleep. These effects are long lasting, and indicate a non-thermal effect. The thalamus, a part of the brain that processes sensation, is responsible for generating sleep spindle activity and may be especially susceptible to cellphone radiation (Regel 2007).

Walk and talk is a bad idea

References

1. Robert Baan, Yann Grosse, Béatrice Lauby-Secretan, Fatiha El Ghissassi, Véronique Bouvard, Lamia Benbrahim-Tallaa, Neela Guha, Farhad Islami, Laurent Galichet, Kurt Straif, on behalf of the WHO International Agency for Research on Cancer Monograph Working Group. Carcinogenicity of radiofrequency electromagnetic fields. The Lancet Oncology, Volume 12, Issue 7, Pages 624 - 626, July 2011 doi:10.1016/S1470-2045(11)70147-4
2. Kemker BE, Stierwalt JA, LaPointe LL, Heald GR. Effects of a cell phone conversation on cognitive processing performances. J Am Acad Audiol. 2009 Oct;20(9):582-8.
3. Kramarenko AV, Tan U. Effects of high-frequency electromagnetic fields on human EEG: A brain mapping study. Intern. J. Neuroscience, 113:1007–1019, 2003 DOI: 10.1080/00207450390220330
4. Krause CM, Sillanmäki L, Koivisto M, Häggqvist A, Saarela C, Revonsuo A, Laine M, Hämäläinen H.  Effects of electromagnetic fields emitted by cellular phones on the electroencephalogram during a visual working memory task. Int J Radiat Biol. 2000 Dec;76(12):1659-67.
5. Krause CM, Björnberg CH, Pesonen M, Hulten A, Liesivuori T, Koivisto M, Revonsuo A, Laine M, Hämäläinen H. Mobile phone effects on children's event-related oscillatory EEG during an auditory memory task. Int J Radiat Biol. 2006 Jun;82(6):443-50.
6. Lin CJ, Chen HJ. Verbal and cognitive distractors in driving performance while using hands-free phones. Percept Mot Skills. 2006 Dec;103(3):803-10.
7. Luria R, Eliyahu I, Hareuveny R, Margaliot M, Meiran N. Cognitive effects of radiation emitted by cellular phones: the influence of exposure side and time. Bioelectromagnetics. 2009 Apr;30(3):198-204.
8. McCartt AT, Hellinga LA, Bratiman KA. Cell phones and driving: review of research. Traffic Inj Prev. 2006 Jun;7(2):89-106.
9. Mark B. Neider, Jason S. McCarley, James A. Crowell, Henry Kaczmarski, Arthur F. Kramer. Pedestrians, vehicles, and cell phones. Accident Analysis and Prevention 42 (2010) 589–594
10. Regel SJ, Tinguely G, Schuderer J, Adam M, Kuster N, Landolt HP, Achermann P. Pulsed radio-frequency electromagnetic fields: dose-dependent effects on sleep, the sleep EEG and cognitive performance. J Sleep Res. 2007 Sep;16(3):253-8.

Neurotoxic effects of alcohol on the adolescent and young adult brain

(or why the 25 year age-bar on alcohol consumption could be reasonable)

Does alcohol have specific neurotoxic effects on the adolescent or young adult brain? This question is the only important one for deciding whether the 25 year age-bar on alcohol consumption in Maharashtra is justifiable. While the debate rages two students from the premier medical college of India drowned in an alcohol fuelled swimming pool misadventure, and in an unrelated incident on the same night five inebriated youths were arrested for disturbing the peace in a residential area. We have seen how to recognise problem alcohol drinking in teenagers, and how to refuse alcohol. This article probes the specific effects of alcohol on the maturing brain.

Infancy

Alcohol is a neurotoxin. It distorts the normal architecture of the developing brain. This distortion starts during pregnancy when imbibed maternal alcohol crosses the placenta into the foetus. In the foetus alcohol acts on the specially vulnerable immature insulating cells (oligodendroglia) of the brain. The child is born with Fetal Alcohol Syndrome, characterised by irreversible mental retardation, a small head, small stature and facial abnormalities. Because the exact amount of alcohol required and the most vulnerable periods of pregnancy have not been definitively established all pregnant women are advised to abstain from any use of alcohol.

Childhood

By the second year of life the number of connections between brain cells (synapses) are at a maximum. These synapses are gradually reduced to the adult number (synaptic pruning). This process is controlled by immature excitatory (glutamate) receptors in the synapses. These receptors differ from adult ones by allowing quicker and longer excitation. Immature glutamate receptors are vulnerable to the effects of alcohol. Their over-stimulation distorts synaptic pruning (Johnston 1995).

Adolescence

In adolescence there is a rapid growth of gray matter and the formation of new connections (proliferation) in the brain. Elimination of some synaptic connections (pruning) enables the adolescent or young adult brain to change in response to environmental demands. Stability of these connections is enhanced through insulation of neuronal fibres (myelination). Myelination increases the overall speed of information processing within the brain. These maturational processes are critical for cognitive development. They are all adversely affected by alcohol (Guerri 2010).
These adverse effects specifically impact the frontal lobes of the brain and are highly associated with level of intelligence. In addition the brain area essential for working memory (hippocampus) is preferentially damaged by alcohol (De Bellis 2000). Gender effects render female adolescents more vulnerable than males to these alcohol effects.
The reward system of the brain is responsible for motivation and learning. The immature reward system has an adolescent-specific vulnerability for alcohol and drug addiction. Early exposure to alcohol sensitises the brain regions involved in drug addiction and alters gene expression in the brain reward regions (nucleus accumbens).
The pattern of brain electrical activity changes during the transition from adolescence to adulthood. Alcohol also has a premature aging effect on brain electrical activity during wakefulness and sleep. Animal models have shown that even brief exposure to alcohol in adolescence can cause long lasting changes in brain electrical activity. These changes place the adolescent at a high risk for later substance abuse and addiction (Ehlers 2010).

Youth

Alcohol differentially impairs the young persons judgement and motor skills. The evidence for this is so robust that some administrations have placed a lower legal blood alcohol level limit on drivers less than 21 years old (Hingson 1994). This differential susceptibility to alcohol has been shown to persist up to 30 years of age when a specific impact is seen on frontal lobe functions related to driving skills (Domniques 2009).

Whether the authorities considered the neurotoxic effects of alcohol while imposing the 25 year age-ban on alcohol consumption is a moot point. However, educating adolescents and youth regarding these adverse alcohol effects should be the duty of every parent.

References

1. De Bellis MD, Clark DB, Beers SR, Soloff PH, Boring AM, Hall J, Kersh A, Keshavan MS. Hippocampal volume in adolescent-onset alcohol use disorders. Am J Psychiatry. 2000 May;157(5):737-44.
2. Domingues SC, Mendonça JB, Laranjeira R, Nakamura-Palacios EM. Drinking and driving: a decrease in executive frontal functions in young drivers with high blood alcohol concentration. Alcohol. 2009 Dec;43(8):657-64.
3. Ehlers CL, Criado JR. Adolescent ethanol exposure: does it produce long-lasting electrophysiological effects? Alcohol. 2010 Feb;44(1):27-37.
4. Guerri C, Pascual M. Mechanisms involved in the neurotoxic, cognitive, and neurobehavioral effects of alcohol consumption during adolescence. Alcohol. 2010 Feb;44(1):15-26.
5. R Hingson, T Heeren, and M Winter. Lower legal blood alcohol limits for young drivers. Public Health Rep. 1994 Nov-Dec; 109(6): 738–744.
6. Johnston MV. Neurotransmitters and vulnerability of the developing brain. Brain Dev. 1995 Sep-Oct;17(5):301-6.