On Neuroimaging, Alzheimers and Stress

An old essay of mine, I dug out:

Humans have been curious about what the structure of the Brain is for hundreds of years. Galen (200-300 AD) instructed his students that they should not make drawings of these “internal embodiments” without physical evidence. Galen’s students had already been making rudimentary drawings of pig’s brains by this time and made some very primitive assessments of what the various areas of the brain were for (Clarke & Dewhurst, 1995). In the years following Wundt’s founding of the empirical paradigm of experimental psychology, the discipline has grown to encompass many new areas and the boundaries between Neuroscience, psychology and Medicine in areas such as brain imaging are now blurred.

The last ten years have seen the “explosion in scope and scale” (Thompson, 2002) of neuroimaging techniques. Major diseases of the brain can now be studied in a way that would have been impossible until recently. Neuroimaging has two distinct fields. Structural – revealing the physical structure of the brain and functional – revealing the physiological processes within the brain. Structural imaging techniques are comprised of Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). “CT is widely available and relatively inexpensive. It is also fast. A whole head scan can be performed in less than 30 seconds.” (O’Brien & Barber, 2000) As a mechanism for elucidating structure, it is excellent and most useful for determining space-occupying brain lesions such as tumours and subdural haematomas (O’Brien & Barber, 2000). CT is now almost universally available in the UK National Health Service as the first modality of imaging available to Doctors. (CT Scanning in the NHS, 2007)

SPECT is a form of functional computed tomography widely used in clinical neuroscience and neuropsychology. Godfrey Hounsfield of EMI laboratories and Allan McCormick of Tufts University, USA invented computed tomography independently. They shared the Nobel Prize for Medicine in recognition of their work and the substantial medical benefits brought to bear by this new technology. SPECT is also a type of nuclear medicine, it is functional and like other functional imaging methods does not directly measure the neural activity of the brain, but a correlate of this; blood flow. Other neuroimaging techniques measure physiological features such as oxygenation and other metabolic pathways. Prior to SPECT scanning, the researcher injects a radioactive isotope into the patient. The process is very quick and significant amounts of the isotope get in the brain within 2 – 5 minutes of the injection (O’Brien & Barber, 2000). This is mostly, but not always, Technetium-99, attached to the compound HexaMethylPropylene Amine Oxime to become 99m-HMPAO.
99m-HMPAO is a radioligand. Ligand is a term from the chemical sciences and refers to the organic molecule used to contain the radioactive isotope.

The machine measures the gamma ray (photonic) activity from the decaying radioactive isotope. The specific way the images are generated in the scan is the tomography in SPECT. The word tomography comes from the Greek word for slice; since the SPECT machine can gather images sliced through the brain in the three standard planes – Coronal, Sagittal and Axial. These represent the view through the brain from the front, side and top. The tomographic representations depict each pixel. These are approximately 1mm square. These squares then stack together in 3 or 4mm lengths to form a three dimensional shape. This is the smallest unit of brain imaging, which we call a voxel. The changes in the counts of gamma activity, which are correlated to the relative regional cerebral blood flow (rCBF) in the cerebellum that form the dataset for further analysis. The scanner is able to measure the concentration of the radioactivity in the cells in the brain and hence determine the amount of blood flow reaching each part of the brain. The SPECT scanner “mathematically manipulates these two dimensional pictures to form a full three-dimensional image of the brain by creating these voxels. (Bremner, 2005)

Where blood flow is significantly insufficient, areas of the brain may have started to die. We are able to determine specifically those affected areas of the brain, by comparing the differences in the SPECT images. Baseline images of the brain are made and these are compared to activation images (where the patient is performing a task) and a statistical filter is applied to the mathematical models of the images. These filters create a third image that is a picture of the brain showing only the active/non-active areas. Medical professionals can then interpret the images and progress the diagnosis of the patient. This form of brain imaging is particularly useful in the differential diagnosis of brain disorders. Due to the specific temporal and spatial resolutions of SPECT scanning it can reveal details of the differing physiological states in the geography of the brain, which are used to distinguish between types of dementing illness. (Hart & Semple, 1994) There are disadvantages to SPECT: the scanning is not performed in real-time; the radioligand is fixed in the brain following the injections, so the images are essentially a snapshot of the brain a few moments after the injection has taken place. Compared to MRI the resolution of the images is actually quite poor (10 – 15mm) and, of course, there is a need for exposure to radiation – which is always a risk to be balanced against the benefits of getting good images of the patient. Scanning of the patient in SPECT can take 30 minutes and “so may not be appropriate for the very restless or disturbed” (Thompson, 2002)

We can use other neuroimaging techniques to elucidate structures in the brain to assist in making the differential diagnoses referred to earlier. The (O’Brien & Barber, 2000) paper describes the major differences between the imaging modalities. In cases of Alzheimer’s disease, Structural CT and MRI show white matter lesions (Neurofibrilliary tangles and neuritic plaques) and Ventricular enlargement. SPECT imaging shows “hyper perfusion” (reduced blood flow to the cerebral cortex) (Hart & Semple, 1994) – this is in contrast to cases of Vascular dementia when structural neuroimaging shows infarcts and deep lesions whereas SPECT only shows “patchy” patterns of hyper perfusion (O’Brien & Barber, 2000). It is worth describing here a third method of imaging, which is in some senses, superior to SPECT – particularly in relation to temporal and spatial resolution. Positron Emission Tomography (PET) imaging uses quantum mechanical properties of the fundamental particles to generate image maps of the brain. Positrons (anti-matter electrons) are emitted in the radioactive decay of atoms which are neutron deficient e.g. 15O. When released these positrons collide with and mutually annihilate electrons they meet. Discharge of measurable gamma radiation occurs. We measure these gamma patterns in a PET scanner.
PET images are created in real-time and have spatial and temporal resolutions that give highly detailed pictures of the brain. PET scanning though is still very limited in its availability and application. This is because the radioisotopes used in the procedure have very short half-lives and as such, most PET scanners are located near the facilities that produce those isotopes.

Neuropsychology is now starting to look at functional mental illness. Traditionally imaging has focussed mostly on the organic illnesses, but new techniques mean this is an area of great contemporary relevance. Post-mortem examinations of the brains in patients with Schizophrenia often show “subtle morphological differences” to normal brains. Myelin sheathing in axons may also be damaged. (Jalili, et al., 2007) studied the disconnective topography of live subjects using Electroencephalography (EEG). They found reduced clustering of neurons, decreased cortical thickness and increased cell-packing density. They hypothesised that this disconnectivity gives rise to the pathophysiological mechanisms underlying some of the presentation in schizophrenia patients. They go further to say they are “confident” that that these changes to the morphology of the brain are the underlying reasons for Schizophrenia. Other functional illnesses have also been considered.

Borderline Personality disorder (BPD) is characterised by a pervasive pattern of emotional instability. It is a very severe risk factor for suicide in adolescents and young adults. There has been little research into the biological nature of this illness, though its “incidence in psychiatric settings has been assessed as high as 15-20%” (Lis, Greenfield, Henry, Guile, & Dougherty, 2007) Lis et al considered a number of research papers published over the period 1980 -2006 to review the information pertinent to BPD. They found consistent evidence of the reduction in volumes in the frontal and temporal lobes; volume loss in both the amygdala and the hippocampus in the patients studied. Co-morbid disorders (such as Post traumatic stress disorder or addictions) are shown to change the patterns of brain morphology also. Lis et al are seeking, along with many other researchers, to find the links between changes in brain morphology and the psychopathologies exhibited by the patients. Their review also points out the contrasts in brain images in patients who present with the same diagnosis but different on-going symptoms. This will make it difficult to form direct links between brain structures and those disorders – and as we might expect, the situation is more complex than cause and effect.

Alzheimers disease is characterised by “widespread cortical atrophy” and “ventricular enlargement.” (Hart & Semple, 1994) Diagnostic criteria include demonstrable evidence of short or long-term memory impairment, impairment in abstract thinking, impairment of judgement and interpersonal disturbances. As the disease progress, sufferers lose gross and fine motor control, orientation in space and time and eventually speech – leading to an inability to communicate even the most simple of thoughts. It is an extremely distressing illness for the patients and cause considerable stress on family members caring for those people. Seyle (1956) cited in (Bennett, 2000) created a threes stage model based on the physiological changes which occur in the Human body when we are experiencing a stressor which is beyond our normal control. Later Lazarus and Folkman (1984) also cited in (Bennett, 2000) created what is now the widely accepted cognitive model for stress; its function, mechanisms and associated problems; they also defined coping as “…constantly changing cognitive and behavioural efforts to manage specific external and internal demands…” Coping strategies have two main theories – the transactional approach and the trait approach. The first is the application of multiple strategies across and within different situations, whilst the trait theory describes how people bring their own personal models to situations to enable them to cope and move forward. Clearly coping strategies are going to be of great importance to the carer of the Alzheimer’s patient. However some people do not cope well in these circumstances and there are a very real problems for families coping with this disease as we will see. Alzheimer’s can be difficult to diagnose and (Barrett, Keller, Damagaard, & Swerdlow, 2006) have shown that up-to 28% patients are mis-diagnosed in the first instance. They report qualitatively, in their study, this, as causing “huge distress” to both families and patients. Improvements in neuroimaging will help to improve the lives of patients through arriving at the correct diagnosis and therefore embarking on the treatment plan sooner. Services can be put in place to assist families after the initial diagnosis when stress levels are extremely high. They conclude that further research is required on “educating those who disclose and those who receive dementia diagnoses”

In their paper (Braekhaus, Osksengard, Engedal, & Laake, 1998 ) describe symptoms of carer stress in the social and depressive dimensions as “frequent” and highlight the particular needs of this group in relation to information and intervention strategies, though they do not define what these strategies ought to be. We might hypothesise about the nature of these interventions being: Medication, Therapy and increased social activities.

In quite a remarkable paper (Perodeau, Lauzon, Levesque, & Lachance, 2001) describe how carers of dementing relatives who use or misuse psychotropic drugs are more likely to have a wide variety of coping and “emotion-reducing” strategies and are more likely to seek out effective alternative support from outside the family network. Oddly, participants’ who used psychotropic drugs also reported greater stress levels because of their relatives’ behaviours and more difficulty in the interpersonal relationship. They hypothesised that by lowering emotional reactivity with their drug use, these people are more able to cope than non-users. Based on the Lazarus and Folkman (1984) model of Stress-Appraisal-Coping, the researchers called for better use of the cognitive behavioural model to break the cycles associated with prescribed or illicit drug use in these circumstances. The control of “affective lability” may mean that risks are incorrectly appraised in this group of people. There are obvious dangers in this.

(Ford, Goode, Barrett, Harrell, & Haley, 1997) support the assertions of other researchers than gender differences in subjective stressors are nil. However, female caregivers report “increased burdens” that are likely associated with the “gender socialization process.” Some female caregivers report specific difficulties with behaviours (such as wandering) in the Alzheimers patient and the paper describes the benefits of having behavioural and supportive interventions in family groups where these stressors are most apparent. There are problems associated with the experimental methodologies here in as much as the there is a reliance on subjective reporting. One way to negate this effect is to create experiments where the reports of caregivers are corroborated by direct behavioural observation.

We have seen how effective neuroimaging can give dementia sufferers a chance of early diagnosis and that this is beneficial to both the patient and the patient’s relatives. Early diagnosis offers the opportunity to put in place effective interventions for both patient and carers and many researchers have highlighted good information as being a starting point. From the stress models we can see that information leads to options that may not have been present without it. It is empowering for both patient and carer. The carers are more able to make a robust appraisal of stressful behaviours and seek appropriate interventions.

Cognitive behavioural therapy (CBT) interventions are oft cited in the research as being a model for preventing stress overload in people with caring responsibilities (Balfour, 2006) From the Perodeau (2001) paper, CBT may also offer hope to those carers who use/misuse psychotropic drugs in order to deal with their day-to-day responsibilities. Current capacity in the CBT system is poor, however the Governments proposed expansion of this service (an extra ten thousand therapists within 10 years) should offer hope to carers and patients alike in carrying the burden of this isolating illness.


Bibliography

Balfour, A. (2006). Thinking about the experience of Dementia: The importance of the unconscious. Journal of Social Work Practice , 20 (3), 329-346.

Barrett, A. M., Keller, M., Damagaard, P., & Swerdlow, R. H. (2006). Short terms effects of Dementia disclosure – how families describe diagnosis. Journal of the American Geriatric Society , 54 (12), 1968-1970.

Bennett, P. (2000). Introduction to clinical health psychology. Maidenhead & Philadelphia: OUP.

Braekhaus, A., Osksengard, A. R., Engedal, K., & Laake, K. (1998). Social and Depressive stress suffered by spouses of patients with mild dementia. Scandinavian Journal of Primary Mental Health Care , 16, 242-246.

Bremner, D. J. (2005). Brain Imaging Handbook. London: W W Norton & Co Ltd.

Clarke, E., & Dewhurst, K. (1995, March 2). Imaging the Brain from Antiquity to the Present. http://books.google.co.uk/books?id=yz8YRf2sQDEC&dq=history+of+brain+imaging&lr=&source=gbs_summary_s&cad=0

CT Scanning in the NHS. (2007, August 17). Retrieved April 24, 2008, from NHS Direct: http://www.nhsdirect.nhs.uk/articles/article.aspx?articleId=554

Ford, G. R., Goode, K. T., Barrett, J. J., Harrell, L. E., & Haley, W. E. (1997). Gender. Roles and cergiving stress: An examination of subjective appraisals of specific primary stressors in Alzheimer’s caregivers , 1 (2), 158-165.

Hart, S., & Semple, J. M. (1994). Neuropsychology of the Dementias. Hove: Lawrence Erlbaum Associates Ltd.

Jalili, M., Lavoie, S., Deppen, P., Meuli, R., Do, K. Q., Cuenod, M., et al. (2007). Dysconnection Topography in Schizophrenia revealed with State Space analysis of EED. PLoS One (10), e1059.

Lis, E., Greenfield, B., Henry, M., Guile, J. M., & Dougherty, G. (2007). Neuroimaging and genetics of Borderline Personality Disorder – A Review. Journal of Psychiatry and Neuroscience , 32 (3), 162-173.

O’Brien, J., & Barber, B. (2000). Neuroimaging in Dementia and Depression. Advances in Psychiatric Treatment , 6, 109-119.

Perodeau, G., Lauzon, S., Levesque, L., & Lachance, L. (2001). Mental health stress correlates and psychotropic drug use among aged caregivers to elders with Dementia. Ageing and Mental Health , 5 (3), 225-234.

Thompson, P. M. (2002). Bioinformatics and Brain Imaging: Recent Advances and Neuroscience applications. UCLA School of Medicine, Laboratory of Neuroimaging, Brain Mapping Division and Brain Research Institute. Los Angeles: Society for Neuroscience.

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