This is a version of a piece of coursework relating to my recent stint at the National Hospital for Neurology and Neurosurgery. It’s an interesting breed of hospital, seeing an array of highly rare and specialised cases. Whereas the Grand Round presentation cases at a regular hospital may be of an odd quirk of a case, or citing an area for improvement, at NHNN they’re of bizarre presentations involving 1 in a million gene mutations and investigations most clinicians haven’t heard of.

Origins of Neuroimaging

The Human Circulation Balance

The title of grandfather of neuroimaging goes to Angelo Mosso, a 19th Century Italian physician from Turin. Mosso devoted a large portion of his career to the study human physiology, eventually turning to neurology. He was highly successful throughout his career, not restricted to medicine, earning him many plaudits and rising to Senator of the Kingdom of Italy shortly before he died 1.

Writing four major works on brain circulation, he was a firm proponent that areas of brain activity induce changes in cerebral blood flow to support the activity of the local neurons, an idea at the foundation of modern functional neuroimaging. Although his techniques and devices were not of clinical significance during his time, he laid the groundwork for future efforts, touching on several important concepts such as the signal-to-noise ratio 2.

He started by investigating patients with skull defects, allowing easy access to monitor the state of the brain underneath. He developed his practices into the Mosso Method, monitoring the pulse volume and pressure using a plethysmograph. His experiments showed local increase in blood flow when confronted with a variety of stimuli, such as calling the patients name repeatedly or simple mathematics 3.

One of the main limitations of the Mosso Method was that it only functioned for patients with skull breeches. In an effort to overcome this he developed the Human Circulation Balance (Figure 1), effectively a finely tuned set of scales with the participant placed evenly over the fulcrum.

Figure 1: The Human Circulation Balance.
Figure 1: The Human Circulation Balance.

The conclusions of Mosso’s actual experiments with the Balance are unknown, and it’s doubtful how clinically significant results with this apparatus could be. There have been several attempts to recreate Mosso’s work, including an attempt in 1936 at Kings College London 4, and a modern reinterpretation using a set of electronic scales and signal processing techniques. They were able to successfully identify the effects of cognitive activity in the readings from their scales 5. Both sets of experimenters commented on the difficulty of acquiring noise-free data and interference due to regular bodily processes, such as breathing.

Mosso may not have used his instruments to inform the treatment of patients, but he laid the groundwork for a number of areas of neurology and his remarks regarding confounding factors and methodology reflect similar issues in the beginnings of functional MRI 2.

Beginnings of Radiography

The medical applications of Röntgen’s rays were immediately apparent, in part due to the now famous image of his wife’s hand (Figure 2) taken in 1895. On seeing the image she is reported to have said the ominous words “I have seen my death” 6. These words were to be prophetic as within months of Röntgen’s original announcement there were reports of radiation burns in many early engineers. Clarence Dally is thought to be the first fatality due to xrays, dying in 1904 of metastatic cancer at the age of 39 7.

Figure 2: The first xray image of Anna Bertha Rontgen's hand.
Figure 2: The first xray image of Anna Bertha Rontgen's hand.

Despite the early dangers, there were many who pressed the medical uses of xrays. Of these, Arthur Schüller is considered a key figure in brain imaging, even coining the term "neuroradiology". Schüller’s work with skull radiographs, first published in 1912, was the first concerted effort to chart intracranial disease using xrays 8.

There were several problems with early skull radiographs in the application of neurology. The brain, being composed of soft tissue, has poor contrast on plain radiographs. Therefore early attempts to identify and localise lesions and tumours were limited to identifying areas of calcification or disruption of surrounding bone. Dandy and Heuer, two neurosurgeons with an interest in neuroradiology, published a review in 1916 of 100 cases of brain tumours, finding xray changes in approximately 45% of cases 9.

They were well aware of the limits of plain radiography, theorising the need for a contrast agent to highlight the contours of the brain and ventricles. Dandy, noting how air in the sinuses contrasted with the signal of the skull, applied this to the brain in what would become Pneumoencephalography.

Publishing his first results in 1918, he drained a portion of CSF from 20 paediatric patients via open fontanelles or drilled burr holes, replacing a portion of it with air 10. This technique was able to increase the diagnostic rate of neurological tumours and became the mainstay of neuroimaging for the next 50 years.

Pneumoencephalography and its cousin Ventriculography were not without their issues. Firstly they are both deeply invasive techniques, often requiring sedation or anaesthesia, and even then would often cause patients pain for many hours after the procedure. They also did not offer significant soft tissue differentiation and originally there was no control over where the air settled, offering only limited views of the brain. Finally, for a non-therapeutic investigation, it had significant associated mortality. A review in 1957, at which time the technique had been in use for 40 years, found a mortality rate ranging between 0.2 and 1.6% 11.

These limitations spurred Egas Moniz to develop cerebral angiography. Originally experimenting in cadavers, he used strontium bromide and sodium iodide to successfully visualise the internal carotid artery 12. Although this afforded entirely new views of the brain, the necessity for an arterial cutdown and significant complication rate caused only slow adoption.

Refinement

The subsequent decades saw only refinements of pre-existing techniques. A key milestone was the recommendation of multiple views in a standard sequence. This was fronted by Erik Lysholm and Georg Schönander’s development of the skull table, which allowed for reproducible angles at which to take films, aiding in the precision of diagnosis.

Then the addition of a chair rotating on multiple axes (Figure 3) allowed using smaller amounts of air to visualise a larger portion of the brain. By altering the orientation of the patient, the air displaced the CSF in a different region of the brain, highlighting the soft tissue. As well as increasing diagnosis, it reduced the complication rate, allowing for worldwide uptake of pneumoencephalography.

Figure 3: A somersaulting chair for pneumoencephalography.
Figure 3: A somersaulting chair for pneumoencephalography.

The field of cerebral angiography also saw advancements during this period. In its infancy, visualisation of cerebral vasculature was achieved through direct punctures of the common carotid, vertebral, and brachial arteries. A complete mapping required multiple punctures, often leaving multiple scars on the neck, and carrying a risk of exsanguination.

In 1953 Seldinger described the use of catheters in percutaneous angiography 13. He proposed several key advantages of this new technique, including the allowing for contrast injection at any level, flexibility in patient positioning, and the ability to leave the catheter in situ in order to repeat tests. Lindgren then publicised a technique of vertebral artery catheterisation via the femoral artery in 1954.

Despite these two developments being able to perform a complete study through only a singular puncture, trans-femoral cerebral angiography did not see widespread adoption until the middle of the 1960s 12.

Modern Neuroimaging

Computed Tomography

The origins of CT lie with William Oldendorf, a physician in the United States, who became disaffected with the invasive and dangerous nature of contemporary methods of imaging the brain. Using household objects as his test subjects, he developed a coupled source and detector which could revolve 360around the target. He also posited some of the more recent enhancements in CT, including helical scans 14.

However, he lacked the capital to fully realise his ideas, and on requesting backing was met with the now blindingly short sighted reply that "Even if it could be made to work as you suggest, we cannot imagine a significant market for such an expensive apparatus, which could do nothing but make a radiographic cross-section of a head." 15

Therefore it was left to Godfrey Hounsfield, operating out of EMI Laboratories, to fully realise computed tomography. For his efforts he, along with Alan Cormack a physicist who described methods of mathematical reconstruction used in CT, earned the 1979 Nobel Prize in Medicine, controversially leaving out Oldendorf 12 14.

Function

Traditional CT functions in a similar way to plain radiography in that the fundamental unit is the xray source and detector pair. These are revolved and translated, building up a corpus of data of xray transmittance around the subject. The raw data can be represented in a sinogram (Figure 4).

Figure 4: A CT Sinogram of a Human Jaw.
Figure 4: A CT Sinogram of a Human Jaw.

After the raw data has been acquired, mathematical methods of tomographic reconstruction are applied, turning the sinogram into a radiographic cross-section. The radiographic attenuation at a pixel is typically measured in Hounsfield Units, a scale named after Sir Godfrey Hounsfield based around the attenuation of water.

There have been many advancements in the field of CT scanning including the introduction of contrast agents, methods of reducing radiation exposure and scan time, and improving resolution. These have largely involved new arrangements of source and detectors, as well as the introduction of helical scan protocols.

Clinical Significance

CT has become ubiquitous as one of the cheapest and fastest modalities of 3D imaging. Its speed places it in a good position for rapid evaluation of intracranial bleeds and trauma situations. Due to the need for differing attenuation of xray radiation it is primarily useful in pathologies involving gross anatomical change, such as large neoplasms, or bony abnormality, such as skull fracture 16. The availability of intravascular radio-contrast agents, such as iodine, has also made CT invaluable in the area of angiography.

CT is not without disadvantages, primarily in the form of radiation exposure. As the technique necessitates full angular coverage of the subject, the radiation dose is significantly high than in plain radiography. This is thought to be of special importance to vulnerable groups such as children and pregnant women, and so the modality is limited in these populations [@brenner_estimated_2001]. Finally, there is poor differentiation in soft tissues, where radio-attenuation is relatively homogenise, although contrast agents can compensate in this area.

Magnetic Resonance Imaging

The groundwork for MRI was laid by chemists in 1946, where Nuclear Magnetic Resonance Spectroscopy was applied to analytical chemistry 17. However it was several decades before the principles behind NMR were turned towards biomedical imaging. This points towards the significant mathematical, computational, and engineering challenges that MRI provided.

In 1971 Nuclear Magnetic Resonance Imaging was used to distinguish fibroadenomas in laboratory mice 18, and even then it was another decade before becoming commercially available. Around this time NMR was renamed MRI to avoid public worry about the term ‘nuclear’.

Although gadolinium contrast agents were first posited at the beginning of the 1980s, they were only approved for human use at the end of the decade, where they proved especially useful in the identification of head and neck lesions 19.

Function

Magnetic Resonance Imaging utilises a combination of strong magnetic fields and radio frequency pulses to give information about the location and state of protons in the body.

The magnetic field aligns the protons, which are then excited using specifically tuned radio frequency pulses. As they relax they give of their own radio signals, which are then measured and interpreted into images.

The timing of the excitatory pulses and magnetic fields can be varied in order to provide specialised MRI sequences. These sequences have different properties, offering new views, such as suppressing the signal from fluids in the case of the FLAIR modality.

Much research effort has gone into the development of new sequences, such that MRI is much more versatile than when originally introduced. As well as increases in spatial and temporal resolution, functional information can be acquired through modalities like Diffusion Weighted Imaging. DWI gives information about the net movement of water in the body. This can prove particularly useful in conditions such as stroke, where cellular diffusion and transport is affected.

Clinical Significance

The superior soft tissue differentiation MRI affords, resulted in it becoming the imaging modality of choice for investigating many neurological conditions (Figure 5). The combination of structural and functional information makes it ideal for visualising the extent of lesions as well as areas of damage than may be invisible to CT 20. It is also one of the few imaging modalities not to expose the patient to radiation, making it safer in patients with long term follow up.

Figure 5: A comparison of a CT and MRI of a Human Head.
Figure 5: A comparison of a CT and MRI of a Human Head.

Despite recent advancements in speed, MRI takes significantly longer than CT, with scan times often around 20 minutes. Functional sequences sacrifice spatial for temporal resolution, and often combined with longer structural sequences to provide a canvas on which to apply the functional data.

The other disadvantages lie in nature of the magnetic fields. Understandably, all ferromagnetic equipment must not be used near the field. This includes devices such as pacemakers and implants the patient may have. MRI sequences require rapid switching of the magnetic fields, causing physical stresses and the characteristic banging noise, which coupled with the long scanning durations can make them unsuitable for children or patients with claustrophobia 16.

Radioisotope Imaging

Parallel to the rise of CT and MRI, was the invention of Positron Emission Tomography and Single Photon Computed Tomography. These modalities both utilise tracers which give off characteristic radiation.

These tracers are either dealt with in certain ways, or tag existing body molecules, and accumulate in prescribed ways. Disruptions to these processes, such as tumours, may either increase or decrease the uptake of the tracer causing an region of altered signal in the image. Because these methods are dependent on processes occurring in the body, they give functional information about the imaging site.

A form of SPECT using a tracer with a high affinity for pre-synaptic dopamine transporters, called a DaTScan, has proved useful in the diagnosis and differentiation of Parkinson’s Disease. The tracer accumulates selectively accumulates in the striatum, giving functional information about the presence of dopaminergic neuron destruction in that area. Several studies have shown DaTScans to have a role in patients where there is diagnostic uncertainty in their parkinsonism 21 22.

Because these methods both require radioactive material, they are both contraindicated in radiation-sensitive groups, and carry a financial burden through correct procurement and storage of the tracers. They also provide limited spacial resolution, and so it is becoming increasingly common for them to be paired with a high resolution structural technique.

Conclusion

Despite the long history of neurology, originating near the ancient Greeks before picking up steam in the 17th and 18th Centuries 23, methods of imaging the brain are young. Although pneumoencephalography began to provide useful clinical information, it was not until the 1970s when neuroimaging took off 12.

Since then it has had a similar trajectory to the rest of modern medicine, becoming considerably safer, less invasive, while at the same time becoming of more use and ubiquity to physicians.

As clinical neurology becomes more reliant on imaging modalities, it is difficult to prophesy their decline in significance. All that can be reliably said is that future methods will likely seem to our current ways as CT seems to injecting air into peoples’ heads.

References

  1. Sandrone S, Bacigaluppi M, Galloni MR, Martino G. Angelo Mosso (1846–1910). J Neurol. 2012 Nov 1;259(11):2513–4. 

  2. Sandrone S, Bacigaluppi M, Galloni MR, Cappa SF, Moro A, Catani M, et al. Weighing brain activity with the balance: Angelo Mosso’s original manuscripts come to light. Brain. 2014 Feb 1;137(2):621–33.  2

  3. Zago S, Ferrucci R, Marceglia S, Priori A. The Mosso method for recording brain pulsation: The forerunner of functional neuroimaging. NeuroImage. 2009 Dec 1;48(4):652–6. 

  4. Lowe MF. THE APPLICATION OF THE BALANCE TO THE STUDY OF THE BODILY CHANGES OCCURRING DURING PERIODS OF VOLITIONAL ACTIVITY. British Journal of Psychology General Section. 1936 Jan;26(3):245–62. 

  5. Field DT, Inman LA. Weighing brain activity with the balance: a contemporary replication of Angelo Mosso’s historical experiment. Brain. 2014 Feb 1;137(2):634–9. 

  6. X-Ray Anniversary [Internet]. Wellcome Library. [cited 2018 Dec 14]. Available from: http://blog.wellcomelibrary.org/2010/11/x-ray-anniversary/ 

  7. Sansare K, Khanna V, Karjodkar F. Early victims of X-rays: a tribute and current perception. Dentomaxillofac Radiol. 2011 Feb;40(2):123–5. 

  8. Schindler E. Arthur Schüller: pioneer of neuroradiology. American Journal of Neuroradiology. 1997 Aug 1;18(7):1297–302. 

  9. Heuer GJ, Dandy WE. Roentgenography in the localization of brain tumor, based upon a series of one hundred consecutive cases. Johns Hopkins Hospital; 1916. 

  10. Dandy WE. VENTRICULOGRAPHY FOLLOWING THE INJECTION OF AIR INTO THE CEREBRAL VENTRICLES. Ann Surg. 1918 Jul;68(1):5–11. 

  11. Solomon S, Barron KD. Complications of Pneumoencephalography Associated with Internal Carotid Thrombosis. Neurology. 1957 Jun 1;7(6):373–373. 

  12. Hoeffner EG, Mukherji SK, Srinivasan A, Quint DJ. Neuroradiology Back to the Future: Brain Imaging. American Journal of Neuroradiology. 2012 Jan;33(1):5–11.  2 3 4

  13. Seldinger SI. Catheter Replacement of the Needle in Percutaneous Arteriography: A new technique. Acta Radiologica. 1953 May 1;39(5):368–76. 

  14. Mishra SK, Singh P. History of Neuroimaging: The Legacy of William Oldendorf. Journal of Child Neurology. 2010 Apr;25(4):508–17.  2

  15. Wolpert SM. Neuroradiology Classics. American Journal of Neuroradiology. 1999 Oct 1;20(9):1752–3. 

  16. Chadwick D, Compston A, Donaghy M, Fletcher N, Grant R, Hilton-Jones D, et al. Investigations [Internet]. Oxford University Press; [cited 2018 Dec 13]. Available from: http://oxfordmedicine.com/view/10.1093/med/9780198569381.001.0001/med-9780198569381-chapter-003  2

  17. Purcell EM, Torrey HC, Pound RV. Resonance Absorption by Nuclear Magnetic Moments in a Solid. Phys Rev. 1946 Jan 1;69(1–2):37–8. 

  18. Damadian R. Tumor Detection by Nuclear Magnetic Resonance. Science. 1971 Mar 19;171(3976):1151–3. 

  19. Runge VM, Carollo BR, Wolf CR, Nelson KL, Gelblum DY. Gd DTPA: a review of clinical indications in central nervous system magnetic resonance imaging. RadioGraphics. 1989 Sep 1;9(5):929–58. 

  20. Kidwell CS, Chalela JA, Saver JL, Starkman S, Hill MD, Demchuk AM, et al. Comparison of MRI and CT for Detection of Acute Intracerebral Hemorrhage. JAMA. 2004 Oct 20;292(15):1823–30. 

  21. de la Fuente-Fernandez R. Role of DaTSCAN and clinical diagnosis in Parkinson disease. Neurology. 2012 Mar 6;78(10):696–701. 

  22. Tolosa E, Borght TV, Moreno E. Accuracy of DaTSCAN (123I-ioflupane) SPECT in diagnosis of patients with clinically uncertain parkinsonism: 2-Year follow-up of an open-label study. Movement Disorders. 2007;22(16):2346–51. 

  23. Compston A. A short history of clinical neurology [Internet]. Oxford University Press; [cited 2018 Dec 13]. Available from: http://oxfordmedicine.com/view/10.1093/med/9780198569381.001.0001/med-9780198569381-chapter-001