Monthly Archives: November 2010

The Electrical Nature of Being

The picture above illustrates the discredited phrenological model. Crudely speaking the idea was that the mind correlated with the brain and that inferences about the brain could be made from measurements of the skull. In this manner, higher mental functions could be mapped to certain parts of the skull. We now know that this is simply wrong. While very broad functions can indeed be mapped to certain brain regions, more complex mental functions need a more sophisticated understanding. At a certain level though there is truth in some of the assumptions in this model. We know that some functions can indeed be mapped to certain regions of the brain. The correlation of visual perceptions to the occipital cortex is a simple case in point. However if we talk more specifically about visual perceptions of a cup then we will get lost in semantics. A simple object might be represented in one part of the visual cortex. The same object might also be represented in the temporal lobe. Stimulation therefore of the temporal lobe might reproduce this visual experience. We don’t have a one to one correlation between experience and brain location. There are many further subtle arguments to complicate matters…

However there is a gem of a paper by two neurologists who being rather intrigued by over a century of electrical brain stimulation have decided to summarise the findings in a paper. Electrical stimulation of the brain typically happens when somebody undergoes certain types of neurosurgical procedure. For instance, some people with chronic epilepsy that hasn’t responded well to medication might undergo surgery to remove part of the brain which causes the seizures – the so-called seizure focus. Needless to say this is a very delicate procedure as the neurosurgeon will need to remove the maximum amount of dysfunctional brain tissue and the minimum amount of functioning brain tissue. In order to do this, surgeons and neurophysiologists have developed a remarkable procedure which is known as intraoperative electrode recording. The patient will remain awake while their brain is exposed and stimulated with electrodes. In this manner, the surgeon will stimulate brain tissue around the area which will be operated on. The patient will then be able to describe their experiences while the brain is being stimulated in this way. This gives the surgeon an idea of the ‘boundaries’ of the viable tissue.

Aslihan Selimbeyoglu and Josef Parvizi have gone to considerable lengths to identify the relevant literature in a paper which is freely available here. They have searched through the medical literature using the medline database in combination with relevant search terms. They identified 9272 reports and read through all of the abstracts. After completing this search they were left with 93 papers. They gathered additional papers from handsearching the reference sections of the papers they had retrieved. They then document the corresponding experiences and observations of patients when certain areas of the brain are stimulated. The essence of the paper is contained in Table 1. Many of the findings will be unsurprising to those with a background in neuropsychology, psychiatry, neurology or neurosurgery. However a number of findings will be surprising.

I will give a few examples of the types of associations that were found

Anterior Cingulate Cortex – ‘sensation of whole body swaying or rocking’

Insular – ‘Feeling like “out of this world” ‘

Dorsomedial Parietal and Precuneus – ‘Feeling of levitation’

Temporooccipital Junction – ‘Seeing people’

Hippocampus – ‘Hearing water dripping’

Internal Capsule – ‘Crying uncontrollably without sadness’

Orbitofrontal and Ventromedial Frontal Cortex – ‘Twitching’

There are some general conclusions that the authors have made. Roughly half of the stimulations produced no corresponding experiences or observations that the researchers were aware of. There are explanations for this and developments in tests have allowed for insights in this regards. Simple experiences are easier to elicit than complex experiences while some of the areas have not readily been mapped due to the difficulty in safely recording activity. I think that this type of data is not easy to summarise or to use in making generalisations. There are many regions that have been stimulated and each offers us esoteric insights. The brain remains complex and whole realms of functioning remain distant. The results may not relate to the area directly stimulated but instead to a modulation of the activity from neurons synapsing on this area – afferent neurons.

Nevertheless Selimbeyoglu and Parvizi have ‘quietly’ produced a masterpiece. They have taken over 100 years of electrical stimulation data and put it into a single table that can be easily accessed. This table allows us to ask fascinating questions about the brain. The results are able to fill us with awe and humility as we realise how little and how much we know about the brain and how the journey began by Galvani in clarifying the biological importance of electrical impulses continues with further deep insights over 200 years later. The recognition that electrical impulses causes us to experience our innermost feelings, our most nostalgic memories, our very perception of the outside world which changes from moment to moment is nowhere more clearly demonstrated than in the findings of these two authors.

Index: An index of the site can be found here. The page contains links to all of the articles in the blog in chronological order. Twitter: You can follow ‘The Amazing World of Psychiatry’ Twitter by clicking on this link. Podcast: You can listen to this post on Odiogo by clicking on this link (there may be a small delay between publishing of the blog article and the availability of the podcast). It is available for a limited period. TAWOP Channel: You can follow the TAWOP Channel on YouTube by clicking on this link. Responses: If you have any comments, you can leave them below or alternatively e-mail justinmarley17@yahoo.co.uk. Disclaimer: The comments made here represent the opinions of the author and do not represent the profession or any body/organisation. The comments made here are not meant as a source of medical advice and those seeking medical advice are advised to consult with their own doctor. The author is not responsible for the contents of any external sites that are linked to in this blog.

Spontaneous Cerebral Amyloid Angiopathy and Screening

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There is a study by Alessandro Biffi and colleagues titled ‘Screening for Familial APP Mutations in Sporadic Cerebral Amyloid Angiopathy’ and which is freely available here. The researchers are interested in answering the question ‘Should we be screening for familial Cerebral Amyloid Angiopathy gene mutations or novel mutations in sporadic Cerebral Amyloid Angiopathy’. This condition has relevance to vascular dementia. The Boston criteria the researchers use for the diagnosis are given in Table 1 and based on these criteria they divide up cases into probable or definite Cerebral Amyloid Angiopathy (CAA). They identified 58 subjects, 35 having probable CAA and 23 having confirmed CAA. They examined the APP gene and four flanking genes and found no evidence of the novel or familial mutations in their sample. They from this study they found no evidence to support the screening of this population with the stated markers. The researchers note that they have restricted screening to currently identified mutations. They also suggest that mutations in exons 16 and 17 will be of low frequency and corresponding low risk (at the population level). They recommend larger replications studies to further investigate the relationship between APP variants and spontaneous CAA. One of the neat features of this paper is that a practical question is given an explicit evidence based response in the discussion.

November 2010 4th Edition: A New Understanding of a Dementia Gene And A Controversial Take on Happiness

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There has been some positive news in Frontotemporal Lobar Degeneration (FTLD) research with two groups independently identifying the role of an FTLD related gene – progranulin in binding to a cell surface protein – Sortilin.

There has been a recent PNAS study involving researchers from several institutions looking at the effects of Metformin on Alzheimer’s Disease associated neurofibrillary tangles in mice. The researchers found some evidence that Metformin interfered with tau phosphorylation and that it might have a prophylactic effect against the development of tangles. However it will be interesting to see the results of clinical trials.

Ed Yong has another edition of ‘Missing Links‘ which includes a link to an intriguing piece on the pathologisation of happiness. The article in question quotes from the abstract of an article in the Journal of Medical Ethics. This seems like a curious suggestion as achieving happiness is one of the approaches (eudonic) in the positive psychology movement and is associated with wellbeing.

There is another edition of Spike Activity which includes a link to a short piece on synaesthesia.

There is an edition of ‘Quick Links‘ at Blog Around the Clock which includes a link to an article on the evolution of the social brain which includes a discussion of Dunbar’s number as well as cranial capacity in the late pleicostene.

Anatomy of the Hippocampus

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There’s a nice video by Dr Robert Droual on the anatomy of the hippocampus over at YouTube. Since the hippocampal volume is a very important biomarker for conversion from mild cognitive impairment to Alzheimer’s Disease, knowing the local anatomical connections has many potential benefits. In this video, Droual emphasises the fornix and its relation to both the hippocampus and the hypothalamus.

Having a Purpose in Life and the Risk of Cognitive Decline

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There’s a very interesting paper by Boyle and colleagues from the March edition of the Archives of General Psychiatry titled ‘Effect of a purpose in life on risk of incident Alzheimer’s Disease and Mild Cognitive Impairment in community dwelling older persons’ and which is freely available here. I think that there is some really good data in this paper and although coming to the paper a little sceptical at first, the researchers have put some strong arguments together. Firstly they have used a longitudinal design. Patients are broadly divided into those without cognitive impairment, those with mild cognitive impairment and those with Alzheimer’s Disease (AD). A battery of neuropsychological tests have been administered and a clinical team have made the diagnoses. Furthermore in those that developed AD a large percentage were confirmed at autopsy. Superficial examination of the purpose in life scale reveals a ten-item questionnaire which however has been validated in previous research and which has also been associated with an increase in life-expectancy. In this paper the researchers demonstrate the relationship between Mild Cognitive Impairment(MCI)/AD and purpose in life using three statistical approaches. The first is simply a comparison of those who developed AD with those that did not (and similarly for MCI). Although there are significant difference in the expected difference, the magnitude of the differences aren’t particularly large.

The second approach is a proportional hazards model. This produces some interesting results. Thus those with a high score on the purpose in life test were 1.5 x and ~~2.5~~ 2.4 x more likely to remain free of MCI and AD respectively than those with a low score. Thirdly the researchers have also demonstrated that the rate of decline is slower in the group with higher score on the purpose in life test. What’s also interesting is that the researchers controlled for depressive symptoms in their analysis thus reasonbly excluding one obvious confounder. With a good sample size, thorough workup and confidence in caseness, the support of previous research for their purpose in life measure – the researchers have produced some very significant results and it will be very interesting to see further work in this area considering the potential implications. This also relates well to the emerging discipline of positive psychology (see here, here and here).

The Fox, the Pigeon and the Cognitive Test

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Yamaguchi and colleagues have devised a simple test for screening for dementia and report their results in a paper which is freely available here. They recruit 160 older adults from outpatient clinics (presumably neurology clinics) and exclude people with delirium as well as specific neurological conditions. They then present them with a test. The examiner fold their hands into two shapes – one resembling a fox and the other a pigeon. The researchers intend that these are meaningless and that they place a demand on the parietal lobe. They further argue that in the prodromal phase of Alzheimer’s Disease, parietal lobe dysfunction can precede the symptomatic phase of the illness. Within their group they have both subjects with dementia and mild cognitive impairment and use the Clinical Dementia Rating to stratify according to severity. The fox shape is easier to reproduce than the pigeon shape. More than 50% of subjects with a CDR of greater than 0.5 failed to reproduce the pigeon shape.

Overall the specificity of the test was 94% with the following sensitivities

– 58% in CDR 0.5

– 77% in CDR 1

– 75% in CDR 2

– 90% in CDR 3 correlating with severe dementia

While these initial test results are promising it would be useful to have replication studies to examine the interaction with different variables, norming results amongst the population and correlating results with progression to dementia subtypes. Subsequent integration into clinical practice would require careful consideration, contingent upon local protocols as well as an understanding of expectations from the test.

The Insular Cortex and Frontotemporal Dementia

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Figure showing the insular cortex (circled) in a coronal section indicated by the blue line in the inset*

Neurologist Dr William Seeley has a review article on the relationship between the anterior insula and frontotemporal dementia which is freely available here and which is written under a creative commons license**. I found this really interesting as it ties together a diverse amount of material on both frontotemporal dementia and the insular cortex at the same time as generating a number of profound hypotheses. Damasio and later Craig have generated a lot of interest in the insular cortex and its possible relation to how we feel. Seeley makes a lot of links in this review and this perspective opens up a number of avenues for further research into frontotemporal dementia. The main focus in his review however is on behavioural variant frontotemporal dementia (bvFTD) (although he also examines semantic dementia and progressive non-fluent aphasia) and in the first few sections he sets the scene for more detailed hypotheses about the relationship between the insular cortex and bvFTD.

‘bvFTD is associated with dramatic changes in social–emotional processing which result from targeted medial frontal and frontoinsular degeneration‘

Furthermore in frontotemporal dementia, Seeley cites seminal research showing that in the early stages of the disease process at post-mortem that

‘Stage 1 showed atrophy limited to dorsomedial frontal cortex (including ACC) and posterior orbitofrontal cortex where it meets the frontoinsula‘

He then introduces the reader to the ‘salience network’ – a functional network in the brain and cites research showing that bvFTD involves this network initially before affecting other networks as the disease progresses. He makes interesting points about Von Economo neurons and points to interesting research suggesting involvement of these specialised neurons in FTD rather than Alzheimer’s Disease. He suggests the extremely interesting hypothesis that the Von Economo neurons might in some way be related to the disease process itself. I think the Von Economo neurons have been considered to be a rather mysterious class of neurons given that they have massively widespread connections. Indeed authors such as Craig have suggested that they together with the insular cortex might represent the anatomical correlate of ‘self-awareness’. Certainly if researchers such as Sebastian Seung are interested in clarifying the role of networks, or connectomes – those featuring the Von Economo neurons might present a fascinating starting point.

Seeley cites other research providing even more specific hypotheses

‘Strikingly, bvFTD clinical severity correlated with connectivity disruption in only one Salience Network region: the right frontoinsula‘

For those interested in Frontotemporal Dementia research, such very specific hypotheses give very useful insights and one has only to think of the Amyloid hypothesis to think of how useful this can be in offering a framework for developing further insights through hypothesis-driven research initiatives (e.g the Alzheimer’s Disease Neuroimaging Initiative).

Acknowledgements

*Modified from Original Image by John Beal PhD, Dep’t. of Cellular Biology & Anatomy, Louisiana State University Health Sciences Center Shreveport

** Creative Commons Non-Commercial Attribution License

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The Amazing World of Psychiatry: A Psychiatry Blog

by Dr Justin Marley

Monthly Archives: November 2010

The Electrical Nature of Being

Spontaneous Cerebral Amyloid Angiopathy and Screening

November 2010 4th Edition: A New Understanding of a Dementia Gene And A Controversial Take on Happiness

Anatomy of the Hippocampus

The Fox, the Pigeon and the Cognitive Test

The Insular Cortex and Frontotemporal Dementia

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