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Aims

  • Understand the basis and utility of different forms of assessing the brain including anatomical imaging, functional imaging and EEG.
  • Explore the biological basis of "self" and the effect of neurological diseases on the "self” as well as obtaining insight into cortical specialisation.

Key concepts

  • No tool provides a uniformly reliable view of the brain for diagnosing brain disorders, although each technique has its own strengths.
  • Specialisation and localisation of function in the brain.
  • Patients with brain damage can provide us with important insights into the functioning of the healthy brain.
  • Present an overview of different techniques for non-invasive examination of the brain

CT (Computer Tomography) scan

  • The principle of operation of the technique
    • Produce rapid 2D images of organ, bones and tissues
    • Multiple X ray beams at different angles to produce many cross-sectional to create 3D image of internal structures
    • Detect exact shape and size of various organs and tissues
  • The parameters of the nervous system that can actually be measured
    • Bone and vascular irregularities
    • Brain tumors and cysts
    • Herniated discs
    • Epilepsy
    • Encephalitis
    • Spinal stenosis
    • A blood clot or intracranial hemorrhage in patients with stroke
    • Brain damage from head injury
  • The benefits and disadvantages compared with the other techniques
    • Most detailed imaging procedure available
    • Wide field of view
    • Shows many planes of imagery - advantage over 2D medical radiography
    • Detection of even subtle differences between body tissues
    • Very quick (e.g. lungs can be scanned in a minute)
    • Accurate
  • The cost and availability of the technique
    • Expensive instrument
    • May produce artefacts due to high accuracy
    • Tissue non-specificity
      • Can’t highlight different organs or tissues
    • Requires contrast media for enhanced soft tissue contrast

PET (Positron Emission Tomography)

  • The principle of operation of the technique
    • Radionuclide introduced into body
      • On biologically active molecule e.g. Oxygen-15
    • System detects paris of gamma rays emitted in the area of tissue molecule is caused indirectly by action of radionuclide beta decay
    • Appears as burst of light which is detected
    • Concentrations of luminescence are used to construct an image by a computer
  • The parameters of the nervous system that can actually be measured
    • Measures flow of blood to different parts of brain
    • Biological or metabolic activity of the brain
      • Observe blood flow, oxygen, and glucose metabolism
      • Shows diseases that cause changes in metabolism
    • Brain tumors, strokes, Alzheimer’s, multiple sclerosis
    • Molecular interactions and pathways
      • Neurotransmitter receptor binding sites and metabolic substrate and transport
  • The benefits and disadvantages compared with the other techniques
    • Low radiation dose due to short half-life radionuclides
    • Able to see details of molecular biology prior to anatomic changes
      • Useful in locating cancers
    • Expanding role in assessing response to radiotherapy
  • The cost and availability of the technique
    • High cost and logistical difficulties in preparing short life radionuclides
      • Production, transport and recalibration of dose, careful patient scheduling

MRI (not fMRI) (Magnetic Resonance Imaging)

  • The principle of operation of the technique
    • Electromagnets surrounding the hollow centre is utilized to create a magnetic field.
    • The magnetic field fixes the position of protons in the body, and aligns them in a specific direction.
    • Radio waves are transmitted through the tube, to excite the protons.
    • This causes a deflection of the protons.
    • When protons return to original position, they emit an energy that is absorbed by a scanner, which shows up as the MRI image.
  • The parameters of the nervous system that can actually be measured
    • Sinuses
      • Thickening of sinus tissue, presence of fluid
    • Orbits
      • Tumors, bleeds, inflammation
    • Bones
      • Bone tumors, infection, large fractures
    • Epidural/sub-dural bleeds
    • Brain matter
    • Ventricles
      • Hemorrhage
  • The benefits and disadvantages compared with the other techniques
    • Very detailed
      • More accurate than CT scan in showing hemorrhagic areas
      • Effective at imaging areas with huge difference in water content.
      • Therefore able to effectively show areas of hemorrhage.
    • Painless
    • Does not use radiation
    • The cost and availability of the technique
    • Patient required to lay totally still
    • Takes a long time
      • 35 to 45 minutes
    • A huge person can’t fit into MRI
    • Metal objects are not allowed
      • Implants
    • Expensive

EEG (ElectroEncephaloGraphy)

  • The principle of operation of the technique
    • Recording of brain’s spontaneous electrical activity over short period of time.
      • Firing of neurons in brain
    • Provides evidence of how brain functions
    • Electrodes are attached to different parts of the head
  • The parameters of the nervous system that can actually be measured
    • Evaluates brain disorders
      • Shows type and location of activity in brain during a seizure
      • Determine brain death for those on life support
  • The benefits compared with the other techniques
    • Hardware costs are lower
    • EEG sensors can be deployed into a wider variety of environments (less bulky)
    • Fast
    • Tolerant of subject movement
    • Silent, allows better study of the responses to auditory stimuli
    • Does not aggravate claustrophobia
    • Can measure rapid changes in brain activity
    • Measures electrical activity directly
  • The disadvantages compared with other techniques
    • Not exact. Can only measure activity in general areas
    • Significantly lower spatial resolution
    • EEGs of babies doesn’t mean anything.
    • A normal EEG doesn’t rule out epilepsy
    • Person with epilepsy may experience a seizure, triggered by the flashing lights of the EEG device.
  • Cost and availability of the device
    • Cheap
    • Widely available
      • Patients can buy cheap devices ($100) and take it home for sleep tests
  • View the five case videos, breaking after each to explore what these cases help us learn about the relationship between the idea of “self’ and the brain using the guided discussion questions

Motor neuron disease

Motor neuron disease is a group of neurodegenerative disorders that can affect both upper and lower motor neurons, located in motor cortex and spinal cord respectively. A common form is amyotrophic lateral sclerosis (often called Lou Gehrig’s disease in the U.S.). Most motor neuron disease causes the death of the sufferer within 5 years of diagnosis, though Stephen Hawking has been going for more than 40 years. Philip Simmons, the subject of the video, is a writer who lived with the disease for 10 years. He died, at age 45, within 12 months of this video footage.

  • What function has the subject lost/had modified?
    • The subject is almost completely paralysed. Face still shows expression, unlike a Parkinsonian mask. The disease usually affects control of peripheral muscles first.
  • Which of the imaging techniques you have examined would be the best to diagnose this disease (if any)?
    • None are useful to positively diagnose the disease though a CT or MRI scan can be used to rule out a tumour or multiple sclerosis.
  • How else would you diagnose these conditions? Are there specific tests you would administer?
    • Clinical diagnosis: observation and case history. Test muscle strength with nerve stimulation compared with voluntary contraction to rule out muscle problems.
  • Is the condition likely to improve, stay stable, or continue to deteriorate?
    • It is a progressive condition, though the rate is different for each patient, and we expect the subject’s condition to deteriorate.
  • What is the consequence of the condition for person’s sense of self? If you knew the subject, would you say they were still the same person that you knew before they had the condition?
    • The sufferer’s personality and humour seem intact. The anecdote is well structured and obviously rehearsed – future planning and “finesse” of social interaction are very evident. However the physical disability makes him completely reliant on others for most daily tasks. The “self” seems intact but trapped by physical disability.

Alzheimer's disease

Alzheimer’s disease is a progressive neurodegenerative disorder with diffuse cortical effects that are usually most pronounced in temporal and parietal lobes. Sufferers usually first exhibit short-term memory loss, but as the disease progresses the dementia becomes increasingly severe and patients become bed-ridden and unable to feed themselves.

  • What function has the subject lost/had modified?
    • The first subject, Mr Johnson, has memory and sleeping problems. The second subject, in a more advanced stage of the disease, can not perform the basic tasks of living or communicate effectively.
  • Which of the imaging techniques you have examined would be the best to diagnose this disease (if any)?
    • None are useful to positively diagnose the disease.
  • How else would you diagnose these conditions? Are there specific tests you would administer?
    • Clinical diagnosis: observation and case history. Mini-mental state test.
  • Is the condition likely to improve, stay stable, or continue to deteriorate?
    • It is a progressive condition, though the rate is different for each patient.
  • What is the consequence of the condition for person’s sense of self? If you knew the subject, would you say they were still the same person that you knew before they had the condition?
    • Mr Johnson still has a sense of humour, but cannot recollect events from his life. In the more advanced patient, there is a loss of “higher” abilities – adult traits are not in evidence. Human relationships are maintained despite the absence of coherent personality – one-sided relationships of care and love. The “self” is progressively compromised, absent in late stages.

Aphasia

Dr Talley has suffered a stroke, which has profoundly impaired his ability to interpret and produce speech. Wernicke’s area, near the border of the temporal and parietal lobes, is part of the brain associated with the comprehension of speech. In most people, this function is located only in the relevant part of cortex in the left hemisphere, which is why it is said that language is localised to the left hemisphere. (Note Wernicke's = in a cursory way, they seem to make sense, but when you concentrate on it, they don't). Broca's aphasia = expressive, Wernicke's = receptive

  • What function has the subject lost/had modified?
    • The subject has great difficulty with understanding spoken or written language and cannot produce coherent spoken or written language.
  • Which of the imaging techniques you have examined would be the best to diagnose this disease (if any)?
    • MRI or a CT scan would give the highest resolution image of the lesion. PET, fMRI and maybe MEG may indicate new areas assuming the role of language areas.
  • How else would you diagnose these conditions? Are there specific tests you would administer?
    • Clinical diagnosis: observation and case history. Test ability to reproduce spoken and written word lists in both reading and writing.
  • Is the condition likely to improve, stay stable, or continue to deteriorate?
    • The condition may show some improvement as the brain is retrained to use new areas for this task. Full function is unlikely to be restored given the level of speech 12 months after the stroke.
  • What is the consequence of the condition for person’s sense of self? If you knew the subject, would you say they were still the same person that you knew before they had the condition?
    • Clearly speech and language, and comprehension, have been specifically damaged, but he is able to perform complex tasks such as driving (but can he read road signs?). Understands the change in himself and is clearly frustrated by the loss of these abilities. In this sense the changes are external to his “self”.
    • Furthermore, he can also use other areas of the brain to interpret language. He constantly tries to use nonverbal cues to understand what is going on around him: expressions, gestures, intonation. He gives the impression of understanding everything, but when we use a controlled environment, we can determine he has a profound language defect. But there is a broad network of brain area with specific aspects of language
      • Various different parts of the complex process that is language are mapped to different specific structures in the brain
      • Unfortunately, we rarely see complete recovery
      • Remaining brain areas try to take on the functions of language, but they're not as good at these functions

Prosopagnosia

The patient, Mrs Maxwell, has a rare and specific deficit called prosopagnosia. Her vision is normal but she is unable to recognize faces. She has probably suffered damage to a cortical area called the fusiform face area (FFA) which is in the temporal lobe, and is part of a region known as visual association cortex. The FFA has been defined in healthy subjects using fMRI and seems to vary slightly in anatomical location between subjects. (Bilateral injury to the temporo-occipital area of the brain due to anoxic brain damage, secondary to cardiac arrest; unable to recognise faces - it's specific to faces only, not other objects). Uses other cues to determine gender etc.) Purely on the face = fail at recognising people.

  • What function has the subject lost/had modified?
    • Mrs Maxwell is completely unable to recognize faces, but can otherwise see normally and is able to read, recognize objects and so on.
  • Which of the imaging techniques you have examined would be the best to diagnose this disease (if any)?
    • A CT or MRI scan would give the highest resolution image of the lesion, though the damage may be small. PET or fMRI might demonstrate the absence of a specific area in the temporal lobe associated with faces. None of these are as convincing as the clinical diagnosis, but could rule out tumours etc.
  • How else would you diagnose these conditions? Are there specific tests you would administer?
    • Clinical diagnosis: observation and case history. Test ability to recognize buildings, animals and compare this with the ability to recognize faces.
  • Is the condition likely to improve, stay stable, or continue to deteriorate?
    • The condition will most likely be stable, though it is possible there might be some improvement as the brain is retrained to use new areas for this task. However this is a specialised function and it is very unlikely that full function will be restored.
  • What is the consequence of the condition for person’s sense of self? If you knew the subject, would you say they were still the same person that you knew before they had the condition?
    • Highly specific loss of function, despite apparently normal perception of visual world. Loss of ability also involves loss of any memory that she could do these things previously – hence, Mrs Maxwell is not distressed by the problem; hence the “self’s” integrity has been damaged.

Frontal lobe damage

The subject, Mr Ricker, had an accident and the trauma has damaged his frontal lobes.

  • What function has the subject lost/had modified?
    • Mr Ricker has had a change in personality, and seems less “responsible” than before. Note that frontal lobe controls inhibition.
  • Which of the imaging techniques you have examined would be the best to diagnose this disease (if any)?
    • A CT or MRI scan would give the highest resolution image of the lesion. PET or fMRI might demonstrate the abnormal activity related to impulse control or motivation.
  • How else would you diagnose these conditions? Are there specific tests you would administer?
    • Clinical diagnosis: observation and case history. May be difficult to assess without evidence from family, or records (written, film etc.) of the patient before the accident.
  • Is the condition likely to improve, stay stable, or continue to deteriorate?
    • The condition will most likely be stable.
  • What is the consequence of the condition for person’s sense of self? If you knew the subject, would you say they were still the same person that you knew before they had the condition?
    • Doesn’t affect functions commonly used in navigating the world – for instance, he was able to drive across town in the immediate aftermath of the injury. Injury is equivalent to a frontal lobotomy, from the era when mental illness was routinely treated surgically. Says he would like to be back to “how he was” but isn’t actually bothered by his current state, in fact seems to enjoy it. “Self” is clearly compromised.
  • Using brain lesions to study specialisation of cortical function
    • Much of our insight into brain function comes from people who have suffered brain damage. What potential complications are there in using data from brain-damaged patients to elucidate brain function?
  • The damage is rarely restricted to just one region of the brain, and may affect axons originating from a remote region but passing through the damaged region. After brain damage there is often brain plasticity which leads to a partial recovery of function, perhaps by reassigning functions within the remaining healthy regions of the brain. This plasticity means that the patient's brain is not the direct equivalent of a healthy brain missing just the damaged regions. The brain damage is not usually reversible, so it is not possible to have "before and after" data to do precise and careful comparisons across all functions.

  • What techniques could we use to study these functions in a healthy brain, and what caveats should be associated with interpreting the results of these techniques?
    • Brain damage usually decreases or abolishes neuronal activity in the affected tissue. Decreasing the neuronal activity of particular regions in the healthy brain is difficult. Some drugs may target particular brain regions and reduce activity. Alcohol appears to act mainly on a particular sub-unit of the inhibitory receptor for the neurotransmitter GABA, and this sub-unit is localised to particular brain regions including cerebellum and hippocampus. Increasing the inhibitory effect of GABA causes an overall decrease in neuronal output from the affected region. Problems with this technique usually relate the specificity of the drug, and the precision of localization of the target. Another approach may be trans-cranial magnetic stimulation (TMS), which uses a powerful magnetic pulse to cross scalp and skull and generate electric currents in the brain. These currents may temporarily inactivate the brain region subject to stimulation. With TMS it is difficult to be confident of the spatial extent of inactivation, the effect is short-lived, and might be heterogeneous and stimulate certain neurons while inhibiting others.

Other approaches that could be used are observation or stimulation. In observation, the subject is given a task to perform which is expected to make full use of the function under study. The activity of the subject's brain is then studied by imaging (functional magnetic resonance imaging - fMRI, positron emission tomography - PET) or by recording brain electrical activity, usually as an electroencephalogram – EEG. This may have the problem that it is impossible to find a task with the increase in activity limited to just the one brain region of interest. The temporal and spatial resolution of imaging and recording techniques is limited, so that it is difficult to be confident about the exact sub-population affected by an increase in activity. Stimulation of the brain using electrical pulses or TMS restricts the initial activation to small brain areas, but cannot easily stimulate deeper brain areas, and does not replicate an increase of normal activity.

  • Many of these patients are not aware of their condition. How do you know that you are not suffering from some brain lesions? How could you check this? Would use of recreational drugs increase the frequency of brain lesions?
    • Age-related prevalence of asymptomatic MRI infarctions. Consistent age-related increases in prevalence is seen for both men and women through the 5th and 9th decades of life where sufficient data are available for interpretation. From DeCarli, C. et al. (2005), Neurobiology of Aging, 26:491-510. Measures of brain morphology and infarction in the Framingham heart study: establishing what is normal.

However, other studies have shown that MRI underestimates the true incidence of infarcts, and that 80% of people aged 52-72 have brain lesions (Kirkpatrick, JB and Hayman, LA (1987). Radiology, 162: 509-511. White-matter lesions in MR imaging of clinically healthy brains of elderly subjects: possible pathologic basis).

    • As we age, some of our neurons die. Because the functions of our brain are distributed across multiple neurons and often multiple brain regions, the gradual death of neurons does not cause any pronounced change. High resolution MRI might reveal small lesions; carefully controlled functional tests repeated at intervals should eventually reveal declining performance. Drugs that might cause excitotoxicity, raise blood pressure, or that are taken in toxic concentration may all increase the risk of damaging neurons, and IV drug use may increase the risk of infections affecting the brain.

Some neuroscientists have accused functional magnetic resonance imaging (fMRI) of being modern day phrenology, which is a now discredited field of study that related brain function to particular bumps on the skull. The basis of this argument is that there is massive inter-connection of the regions of the brain, so that to try and localize functions to a particular area is extremely suspect. How would you counter this argument on the basis of the cases you have seen and your knowledge of the brain? It is true that most brain regions send output to, and receive input from, a very large number of other regions. Presumably these connections are a basis for some of the plasticity that occurs after brain injury. However the fact that these regions can be mapped and have specific input and output pathways argues that they perform a specialised function. The loss of particular functions related to brain lesions is strong evidence for functional specialization of brain regions. Brain regions are perhaps best thought of as intersections between various networks subserving different functions. The precise nature of their inputs determines the role of the brain region, which may be crucial to a particular brain function without being the sole seat of that function. It is also likely that the fine detail of functional localization is different for every person.

  • What brain-related abilities are central to the idea of the self? All of the following are recognised syndromes from specific brain lesions. Do you believe that you are still the same person if:
    • You can't name objects you see?
    • You don't recognise loved ones and believe them to be impostors?
    • You can't remember the events of your life?
    • You can't form new memories?
    • You lose the concept of "left" and ignore anything to the left of you, including the left side of your own body?
    • You lose your social judgement and your ability to interact appropriately with other people?
    • You lose control of your emotions and become easily angered or frustrated by simple things?
    • You have a "split brain" and only your left hemisphere is able to express itself?

Consider how a court might rule in cases involving someone suffering from one of these conditions: for example, a crime committed by the left arm of a split-brain patient to the horror of the left hemisphere which pleads its own innocence in court.

Neurological lesion studies

  • Neuroplasticity
  • Variability in anatomical locations of functions
  • Note: transcranial magnetic stimulation etc can be used to temporarily inactivate brain regions subject to stimulation, to determine the effects of "lesions" in otherwise healthy individuals
    • Lesions in autopsy etc can be used to identify regions associated with various functions

Soon's notes

  • MRI:
    • Body tissue contains hydrogen atoms
    • MRI involves a large, strong magnet which a patient lie within
      • When a pulse of energy is applied at a specific wave length, this imposes electric and magnetic fields
      • The hydrogen atoms align at different speeds depending on the density if tissue
    • Thus a computer can generate a visual image of the tissue
    • MRI examines the density of tissue
      • This can be used to create a visual image of the specific area
      • Thus we can identify abnormal tissue as compared to normal tissue
    • Advantages:
      • Painless and relatively safe (no radiation)
      • Detailed images and good contrast between the different soft tissues of the body
    • Much better than X-rays, ultrasounds and CT 􏰂 Disadvantages
      • Metallic implants and ferromagnetic foreign objects inside a patient’s body can interact with the magnetic field causing damage
      • Expensive ($US 2-2.3 million) and the unit cost of scans is higher than for X-rays and ultrasounds
      • Difficult to administer for obese patients
      • Patients suffering from severe claustrophobia may require sedatives
      • More time consuming (30 – 60 minutes) than X-rays.
      • The false positive rate is relatively high
  • CT
    • Computed tomography
    • X-rays + computers
    • Internal structures: BVs, bones, soft tissues
    • X-rays pass through/are absorbed/are scattered etc
    • Circle around and take cross-sections that are converted into 3D using computer
    • Detects:

***Bleeding, brain injuries, aneurysms, injuries, tumours etc

    • Benefits
      • Cheap, short duration, detect fractures etc, first line imaging in emergency departments, low radiation risk, no allergic reactions, not always appropriate, poor resolution
  • PET
    • Radioisotope
      • Decays and emits positrons
    • Concentrates in areas depending on tracer
    • Reacts with tissue cand camma rays are released by annihilation of the positron with an electron
      • Use to examine blood flow etc,
    • Advantages
      • Functional assessment of organs
      • Standardised
    • Disadvantages
      • Cost
      • Distance to production
    • Radiation

Cases

  • Motor neuron disease
    • Lost motor control of peripheral limbs
    • Speech slower
    • Imaging – rule out tumour, MS with MRI, CT
      • Clinical exam/diagnosis, muscle strength assessment o Degenerates
      • Feel useless, physical changes etc. Alzheimer’s
    • subject loses memory/high functions o no useful scans
    • diagnosing – history, mini-mental
    • degenerative
    • sense of self – brain function decline, self awareness decreases
      • effects family and friends significantly
  • Hippocampal damage
    • viral infection destroyed parts of the hippocampus
      • loss of short term memory, ability to make new memories is lost
    • diagnosis: MRI, CT, PET functionality
      • tests: mini-mental, memories
    • prognosis – stay the same
      • improve?
    • Unaware of changes
  • Aphasia – due to stroke
    • Haemorrhage to Wernicke’s area
      • Language centre that allows understanding of reading/speaking and formation of words/language
    • Can improve as other parts of the brain adapt to perform the functions of the areas lost
      • Communication can adapt to use other forms of information
    • Diagnosis: CT, MRI
  • Face recognition lost – prosopagnosia
    • uses other features: facial hair etc to recognise
    • scans: CT, MRI
      • recognition tests
    • sense of self – can’t recognise self/friends/family

Brain lesions

  • Insight into brain function comes from lesions
    • problems:
      • Individuals, variable
      • Can’t choose patients/lesions
      • No before/after view of function
    • Plasticity – regain of function despite loss
  • Technologies used to study function in healthy brains
    • PET
    • Q and A + both
    • Transcranial magnetic stimulation
      • Generates electric currents that stimulate parts of the brain
  • 10% of 50 year olds have brain lesions
    • Framinghamstudy