Richard Caton in 1872 was first to publish a paper describing electrical activity of the brain. He found the surface of the brain showed negative voltage when activated. EEG is a modern technique used to represent electrical activation states by depicting variations in frequency and amplitude on a graph. The sleep-wake cycle provides a common depiction of different frequencies and amplitudes of signal dependent upon brain states of alertness.
Biological electricity is dictated by different concentrations of ions, ions that are disolved in solutions. It is a truism that if you separate differing ion solutions and have some sort of membrane separating them an electrical charge will be produced. Similarly, if you separate fresh water from salty sea water separated by a membrane has been used as a form of clean energy production. Within the brain, inside and outside the cell there are ion imbalances of sodium and potassium. Essentially if a neurone is excited, there is a current influx (usually of sodium) and an action potential is produced. Action potentials can be generated at very high rates. These rates are compatible with synchronous activity. Most of what EEG measures is excitatory post synaptic potentials rather than inhibitory post synaptic potentials.
Much of the scalp EEG is thought to reflect extracellular ionic changes associated with post synaptic potentials. The direct contribution of action potentials is much smaller and very short lived. What EEG really measures is much more to do with the direct consequence of the build up of ions in the extracellular space and this accounts for 15% of brain volume only. Thus activity within the brain cells influences ion concentrations in extracellelar space and this is why EEG more directly reflects brain activity than other imaging techniques that measure blood flow or metabolic activity.
Electrical activity essentially travels at the speed of light, therefore meaning the temporal resolution of EEG is effectively instantaneous. This means that EEG's best attribute allows for dividing cognitive processes into stages of very close temporal proximity (see strengths section later). This is particularly clinically useful in determing if bottom up processes are impeded, reflecting brain stem dysfunction in MS for example.
Voltage detection relies upon proximity; the inverse square law means that electrical activity decreases increasingly the further away the electrode is from the source. EEG measures voltage at regions of interest in comparison to neutral regions (for instance by placing an electrode on the ear lobe). The differential amplifier measures this discrepancy in voltage. EEG amplifiers have high and low frequency filters which act a little bit like treble and bass adjusters on a stereo. These filters help turn down the distractions from information of interest. Wavelet and fourier analysis provide further methods of understanding EEG data.
The neo cortex can be divided into six sections. Shallow layers tend to be cortico-cortical connections and alertness projections from the thalamus whilst deep layers tend to be associated with outputs from the cortex (eg cortico-subcortico projection). Neural activity is of course, both excitory and inhibitory. Pyradimal neurons straddle layers of the neo cortex. Pyramidal cells tend to orientate in the same direction and can be likened to trees in a wood. Pyramidal neurons of the cortex are thought to produce the most EEG signal because they are well-aligned and fire together.
One of the key drawbacks to EEG is not only the limiting factor of proximity in imaging subcortical activities, but also in measuring radial structures in the brain. Radial structures such as the hippocampus are structures that do not tend to have aligning neurones and therfore the electrical output tends to cancel itself out. Only consistent activity across populations of aligned neurons is recorded at the scalp. Random activity associated with randomly aligned dipoles cancels out and is not measured. This is why vertically aligned pyramidal neurons are thought to dominate scalp EEG. However, the brain is not flat and therefore this limits the spatial resolution potential of EEG. Accuracy of source localisation marginally improves with the increased amounts of electrodes on modern EEG equipment; nevertheless the bulk of EEG reflects cortical activity and only marginally reflects subcortical activity. That is not to dismiss that there is an indirect relationship to subcortical process when one considers the projections that go to the neocortex from the thalamus.
Signal averaging across event related potentials reduces noise and random artefact by using a technique that relies upon repeating stimuli over and over again and determining the signals of interest over random signals. The amounts of repeated trials is somewhat dependent upon the amplitude of the signal versus the amount of background noise, but this technique has been used effectively to divide previousely undividable cognitive process into stages.
One of the key limitations to EEG Is that the measurement is prone to both biological and environmental artefacts (factors that intefere with true signals). Mains electric supply, mobile phones and electrical devices such as computer monitors are particularly problematic environmental artefacts particularly as they are so common in hospitals and research laboratories.
Common biological artefacts include all types of muscle activity such as muscle tension, gritting teetch etc, sweat, blinks, when the tongue touches the roof of the mouth. Often biological artefacts results in high frequency artefacts, whilst environmental artefacts result in low frequency artefacts.
Best recordings should be obtained when partcipants are calm and relaxed, room temparature is comfortable and stable, no hair product is used and electrical shielding is available.
Closely related to EEG is Magneto-Encephalography (MEG). Whenever there is a difference in electrical potential, a magnetic field exists around such a difference. Magnetic north pole aligned is based upon the 'right hand rule' whereby the direction of the fingers represent the direction of current and the thumb (pointing upwards) represents the direction of the magnetic force. MEG is based upon the same principle within the brain and it is a technique that measures magnetic fields in the brain. Scalp electrical potentials that produce EEG are generally thought to be caused by the extracellular ionic currents, whereas MEG signals are more closely associated with intracellular ionic currents. EEG can be recorded at the same time as MEG so that data from these complementary high-time-resolution techniques can be combined.
Strengths of EEG and MEG:
Primarily reflects neuronal activity and associated glial activity (artefact aside)
Easy to record and relatively inexpensive
Very useful in clinical settings (identifying epilepsy and titrating treatment approaches, identifying slow function in MS and ascertain awareness/brainstem function in coma)
Very sensitive to minor changes in arousal and especially good at illustarting the sleep-wake cycle
Superb temporal resolution to millisecond level (essentially limitless)
-ability to fractionate components of cognitive activity (eg early brainstem v later cortical responses)
-ability to track brain changes which occur as a stimulus is processed in real time (perception, central processing, response preparation)
-thus EEG studies have clarified psyChodynamic models of unconcsious processes
-sensitivity to fluctuations in attention during stages of stimulus processing
-can use randomised designs as opposed to block designs
Can be analysed in real time but signal averaging removes artefact and adds great power by increasing signal to noise ratio of time-locked cognitive processing
Relatively good value in comparison to other techniques
Drawbacks of EEG and MEG:
Very poor spatial resolution.
2D representation of a 3D brain.
Largely limited to neocortical activity.
It is constantly susceptible to a number of biological and environmental artefacts, including muscle movements, seating, electrical activity nearby etc.
The inverse problem means that real electrical activity that is not aligned directionally in the tissue goes unmeasured and instead cancels itself out.
Source localisation algorithms are complex and problematic and have to make simplifying assumptions.
The meninges, cerebrospinal fluid and skull "smear" the EEG signal, obscuring its intracranial source. Furthermore the orientation of brain relative to scalp makes source localisation less reliable (although in MEG, MRI scans can be incorporated for computer analysis to compensate for size and shape of the brain in question).
This final point is perhaps a point to conclude on, that all imaging techniques have their pros and cons and that the future is perhaps about combining techniques for converging information in order to infer function of the brain.
Saturday, 11 February 2012
Saturday, 4 February 2012
How does Positron Emission Tomography (PET) work and has it had its day?
Tomography comes from the latin 'tomo-to slice' and 'graphy- to image'. The essence of PET is to create artificially radioactive substances and introduce this to the body to be studied through the process of metabolism. The key requirement is that this radioactive material permeates the 'blood-brain barrier'. Radioactive sugar fluorodeoxyglucose (FDG) is commonly used. However, radioactive forms of drugs, neurotransmitters, gabba, serotonin and dopamine amongst other things can be used and studied with PET and this illustrates a key advantage when compared to its closest rival fMRI.
The introduction of radioactive substances to the body is usually done intravenousely, but can be accomplished through inhalation. Once inside the body the radioactive substances undergo decay and emit radioaction. This radiation is detected by the scanner (essentially a complex set of cameras) and this allows metabolically active regions of either the body or the brain to be identified. But it is important to conceptualise this as activity rather than activation. For instance the inhibition of neural systems often requires energy.
PET is not a technique for providing adequete structure. You need another form of structural imaging such as MRI or CT to provide this and then overlay the PET image to indicate function. This introduce further costs and administrative complications. Partial rotating systems go some way to addressing this criticism by saving money and provide additional room for a CT scanner within the PET scanner.
A further drawback of PET scanning is that the costs are not limited to the machine itself. A synthesis device or cyclotron is the contraption used in the production of PET isotopes to be introduced to the brain or body to be studied. The machines work by using rapid magnetic field reversals that excite particles under high energy spinning. These essentially spin out of the device and bombard a non-radioactive element which in turn produces the isotope. Often these devices are very expensive (often more expensive than the scanner itself). Furthermore there is a cost implication to the human skills and security measures needed to run these devices safely.
To understand PET one must start at the level of atom. A positron is an anti matter electron; identical to an electron but with a positive charge rather than negative. In PET positrons are produced as a result of nuclear decay. Positrons are produced by positron emitting radioisotopes. If a nucleas is unstable with too many protons it has a positive charge. Decay occurs when a proton is converted into a neutron, making the nucleas stable again. Emitted positrons only travel a short distance until they meet an electron. The distance travelled is dependent on the energy of the positron. Emitted positrons have a brief life. When matter meets anti matter you get a mutual annhililation. At the point of mutual annhilation two gamma rays (aka photons) are discharged in an opposite direction at 180 degrees to each other. This opposite direction is virtually perfectly opposite and this is very important in understanding PET scanning. The rate of decay is often quantified by 'half-life'. Differing isotopes have different half lifes and the choice of which to use depends upon the purpose of the PET investigation.
The production of gamma rays can be analogised as being like bullets being fired from a gun. A bullet flies in a straight line. Imagine a bullet blasts through a door and comes to rest in a wall. One could trace the shooter of the bullet by tracing a line back from the bullet in the wall through the hole in the door. The scanners in a PET machine are advanced enough to determine a single annihilation event by detecting both opposing sides of the gamma ray emission. The scanner can then trace the source of the annihilation to a position in three dimensional space. This is essentially the process by which the camera detects and reconstructs the image to help image the function of the body or brain. The gamma ray detectors in the PET scanner uses scintillators that involve photomultipliers to amplify the weak light emitted. Computer modelling helps reconstruct the data into a visually meaningful form.
PET scanners work on the basis that gamma rays emit at 180 degress? However there is a small natural variation. This natural variation introduces another small factor affecting resolution accuracy. Additional interference comes from both the short distance and non-linear directions travelled by the proton and rare occassions where the scanner mistakes true event annihilations from various types of random, scattered or suprious gamma ray errors.
There are various ways of controlling for error. Firstly, 2D PET rather than 3D PET are scans that deploy 'blinkers' that are often made of lead and work to restrict the span of gamma rays available, therefore improving the percentage of true annihilations, therby reducing scatter and random coincidences.
There are also specific methods for controlling random annihilation interference. The delayed window procedure corrects by shifting the time of one side of the detector by a small amount of time. The data is reanalysed and in theory every coincidence should be random. So the amount of randoms can be superimposed, counted and compared to the original amount providing an estimate of the accuracy of the scan.
Another source of inaccuracy are the scanners themselves. The crystals in the scintillators are not identical in thickness for example. To control for this the scanners are regularly calibrated. The procedure to do this involve inserting a simple radioactive rod or similar. Furthermore, there is the factor of 'dead time' which is the very short lapse of time where the scintillator has detected a gamma ray and is ready to detect another independent gamma ray. The technique depends on as low as possible amounts of radiation to control for some of this limitation.
Scatter events, whereby a gamma ray deflects off of something unrelated to that under observation, are quite rare events in comparison to true events. In 2D scans there presence is even rarer. Scatter correction presents a control method whereby events are plotted and outliers are subtracted.
Attentuation correction is an important correction procedure and it compensates for the occassions where gamma rays lose energy through collisions with extraneous particles and are therefore failed to be detected. The procedure is a calibration procedure developed from inserting a radioactive rod inserted into dummy patient/deceased body. These corrections take place in the post hoc image period.
In summary the image reconstruction requires:
A data file for all response detected within time window
A normalisation file
Two attenuation correction files
And a CT scan
Advantages of PET:
Many different tracers can be used enabling analysis of glucose, oxygenation, neurotransmitters, peptides. They can target the effects of drugs.
There is no echon planar noise, making them suitable for auditory studies (fMRI is not suitable).
High magnetic fields in fMRI machines can produce internal heat and induce currents within tissue. They are therefore applicable to those with metal objects within their bodies such as pacemakers.
PET is a measure of neural tissue rather than vascular tissue. And therefore is a reliable way of imaging certain regions where fMRI is not as accurate.
There is the exciting potential to conduct dual tracer PET involving two tracers with differing half lifes. For example, this allows an image that can detect two neurotransmitters at once.
Radioactive Gene insertion therapy can be studied.
Can be used to detect early brain area dysfunction in dementia, before any structural changes emerge.
PET has been instrumental in researching and monitoring cancers in the body.
Disadvantages:
Very poor temporal resolution is its biggest weakness compared to fMRI and EEG (many minutes to acquire scan). Hence the need for block designs, whereby people repeat an intervention in order for the scan to detect the change.
Extremely costly (scanners, security, physicists, set up costs approximatelymtwice the cost of fMRI)
Poor spatial resolution (5-7mm although improving with modern scanner 2mm has been proposed)
Some parts of the brain pulse (brain stem especially) this again interfers with resolution (although can be controlled for taking images between heart beats)
Convincing participants to consent to treatment/research is often problematic.
Conclusion
In summary, like all neuroimaging techniques, PET has recently come under scrutiny for the statistical levels at which results and conclusions are founded (Savoy 2001). Like fMRI average data will often produce different arguments than individual data. Often the number of areas identified in research increase with average data and researchers in the past have been culpable of 'fishing for data' and making unjustified or speculative post hoc hypothese.
PET on its own has had a greater research history than clinical history. For example, PET has repeatedly been used in experimental designs to illustrate the activation of thalamus and primary somatosensory cortex areas in response to pain. It's directly clinical value is severely restricted by its costs.
No single neuroimaging technique is unanimousley superior and so PET has not had its day. In fact its use has experienced somewhat of a revival since the movement away from: 'do this task, this area lights up'. Neuropsychology has moved on from a 'modern phrenology' to something more interactional and system based. Perhaps a converge of techniques is the future?
The introduction of radioactive substances to the body is usually done intravenousely, but can be accomplished through inhalation. Once inside the body the radioactive substances undergo decay and emit radioaction. This radiation is detected by the scanner (essentially a complex set of cameras) and this allows metabolically active regions of either the body or the brain to be identified. But it is important to conceptualise this as activity rather than activation. For instance the inhibition of neural systems often requires energy.
PET is not a technique for providing adequete structure. You need another form of structural imaging such as MRI or CT to provide this and then overlay the PET image to indicate function. This introduce further costs and administrative complications. Partial rotating systems go some way to addressing this criticism by saving money and provide additional room for a CT scanner within the PET scanner.
A further drawback of PET scanning is that the costs are not limited to the machine itself. A synthesis device or cyclotron is the contraption used in the production of PET isotopes to be introduced to the brain or body to be studied. The machines work by using rapid magnetic field reversals that excite particles under high energy spinning. These essentially spin out of the device and bombard a non-radioactive element which in turn produces the isotope. Often these devices are very expensive (often more expensive than the scanner itself). Furthermore there is a cost implication to the human skills and security measures needed to run these devices safely.
To understand PET one must start at the level of atom. A positron is an anti matter electron; identical to an electron but with a positive charge rather than negative. In PET positrons are produced as a result of nuclear decay. Positrons are produced by positron emitting radioisotopes. If a nucleas is unstable with too many protons it has a positive charge. Decay occurs when a proton is converted into a neutron, making the nucleas stable again. Emitted positrons only travel a short distance until they meet an electron. The distance travelled is dependent on the energy of the positron. Emitted positrons have a brief life. When matter meets anti matter you get a mutual annhililation. At the point of mutual annhilation two gamma rays (aka photons) are discharged in an opposite direction at 180 degrees to each other. This opposite direction is virtually perfectly opposite and this is very important in understanding PET scanning. The rate of decay is often quantified by 'half-life'. Differing isotopes have different half lifes and the choice of which to use depends upon the purpose of the PET investigation.
The production of gamma rays can be analogised as being like bullets being fired from a gun. A bullet flies in a straight line. Imagine a bullet blasts through a door and comes to rest in a wall. One could trace the shooter of the bullet by tracing a line back from the bullet in the wall through the hole in the door. The scanners in a PET machine are advanced enough to determine a single annihilation event by detecting both opposing sides of the gamma ray emission. The scanner can then trace the source of the annihilation to a position in three dimensional space. This is essentially the process by which the camera detects and reconstructs the image to help image the function of the body or brain. The gamma ray detectors in the PET scanner uses scintillators that involve photomultipliers to amplify the weak light emitted. Computer modelling helps reconstruct the data into a visually meaningful form.
PET scanners work on the basis that gamma rays emit at 180 degress? However there is a small natural variation. This natural variation introduces another small factor affecting resolution accuracy. Additional interference comes from both the short distance and non-linear directions travelled by the proton and rare occassions where the scanner mistakes true event annihilations from various types of random, scattered or suprious gamma ray errors.
There are various ways of controlling for error. Firstly, 2D PET rather than 3D PET are scans that deploy 'blinkers' that are often made of lead and work to restrict the span of gamma rays available, therefore improving the percentage of true annihilations, therby reducing scatter and random coincidences.
There are also specific methods for controlling random annihilation interference. The delayed window procedure corrects by shifting the time of one side of the detector by a small amount of time. The data is reanalysed and in theory every coincidence should be random. So the amount of randoms can be superimposed, counted and compared to the original amount providing an estimate of the accuracy of the scan.
Another source of inaccuracy are the scanners themselves. The crystals in the scintillators are not identical in thickness for example. To control for this the scanners are regularly calibrated. The procedure to do this involve inserting a simple radioactive rod or similar. Furthermore, there is the factor of 'dead time' which is the very short lapse of time where the scintillator has detected a gamma ray and is ready to detect another independent gamma ray. The technique depends on as low as possible amounts of radiation to control for some of this limitation.
Scatter events, whereby a gamma ray deflects off of something unrelated to that under observation, are quite rare events in comparison to true events. In 2D scans there presence is even rarer. Scatter correction presents a control method whereby events are plotted and outliers are subtracted.
Attentuation correction is an important correction procedure and it compensates for the occassions where gamma rays lose energy through collisions with extraneous particles and are therefore failed to be detected. The procedure is a calibration procedure developed from inserting a radioactive rod inserted into dummy patient/deceased body. These corrections take place in the post hoc image period.
In summary the image reconstruction requires:
A data file for all response detected within time window
A normalisation file
Two attenuation correction files
And a CT scan
Advantages of PET:
Many different tracers can be used enabling analysis of glucose, oxygenation, neurotransmitters, peptides. They can target the effects of drugs.
There is no echon planar noise, making them suitable for auditory studies (fMRI is not suitable).
High magnetic fields in fMRI machines can produce internal heat and induce currents within tissue. They are therefore applicable to those with metal objects within their bodies such as pacemakers.
PET is a measure of neural tissue rather than vascular tissue. And therefore is a reliable way of imaging certain regions where fMRI is not as accurate.
There is the exciting potential to conduct dual tracer PET involving two tracers with differing half lifes. For example, this allows an image that can detect two neurotransmitters at once.
Radioactive Gene insertion therapy can be studied.
Can be used to detect early brain area dysfunction in dementia, before any structural changes emerge.
PET has been instrumental in researching and monitoring cancers in the body.
Disadvantages:
Very poor temporal resolution is its biggest weakness compared to fMRI and EEG (many minutes to acquire scan). Hence the need for block designs, whereby people repeat an intervention in order for the scan to detect the change.
Extremely costly (scanners, security, physicists, set up costs approximatelymtwice the cost of fMRI)
Poor spatial resolution (5-7mm although improving with modern scanner 2mm has been proposed)
Some parts of the brain pulse (brain stem especially) this again interfers with resolution (although can be controlled for taking images between heart beats)
Convincing participants to consent to treatment/research is often problematic.
Conclusion
In summary, like all neuroimaging techniques, PET has recently come under scrutiny for the statistical levels at which results and conclusions are founded (Savoy 2001). Like fMRI average data will often produce different arguments than individual data. Often the number of areas identified in research increase with average data and researchers in the past have been culpable of 'fishing for data' and making unjustified or speculative post hoc hypothese.
PET on its own has had a greater research history than clinical history. For example, PET has repeatedly been used in experimental designs to illustrate the activation of thalamus and primary somatosensory cortex areas in response to pain. It's directly clinical value is severely restricted by its costs.
No single neuroimaging technique is unanimousley superior and so PET has not had its day. In fact its use has experienced somewhat of a revival since the movement away from: 'do this task, this area lights up'. Neuropsychology has moved on from a 'modern phrenology' to something more interactional and system based. Perhaps a converge of techniques is the future?
Wednesday, 18 January 2012
The Principles of Psychopharmacology
Psychopharmacology is the study of the actions of drugs and their effects on mood, sensation, thinking, and behavior. It is the sometimes approximated as the study of drugs used in the treatment of psychiatric disorders. Psychoactive drugs in a recreational or a clinical context differ only in context, aims and ethics. They do not differ in their action.
A historical appreciation of drugs helps contextualise the long standing use of drugs in altering consciousness, extending thousands of years stemming back to the use of mushrooms in tribal rituals, for example. In a clinical context, drugs first came to be used in the mid twentieth century to treat psychiatric disorders such as depression and psychosis.
Pharmacokinetics refers to the movement and time course through the body. It is divided into several areas including the extent and rate of absorption, distribution, metabolism and excretion. This is commonly referred to as the ADME scheme:
• Absorption - the process of a substance entering the blood circulation.
• Distribution - the dispersion or dissemination of substances throughout the fluids and tissues of the body.
• Metabolism (or Biotransformation) - the irreversible transformation of parent compounds into daughter metabolites.
• Excretion (or Elimination) - the elimination of the substances from the body. In rare cases, some drugs irreversibly accumulate in body tissue.
Absorption can be done oral, rectal, transdermal, subcutaneuos, sublingual, lingual and intramuscular. The specifics of this are decided based on feasibility, absorption rate, tolerability, safety and invasiveness.
The 'blood-brain' barrier is there to protect us as a huge amount of blood needs to service the brain and a flood of something psychoactive or neurotoxic could be devastating without filter protection. Drugs therefore need to transpose the 'blood-brain barrier' and either need to be compatible with the transport system, lipid soluble, or they have to be small so that the drugs can pass successfully through it. Heroine and morphine provide a synonymous example once within the brain, but the way they are absorbed is very different, thus giving them different potencies.
Half life can be used in various domains. It usually refers to the ‘elimination’ half life. This means the half life for half of the drug to be completely metabolized. Half life is important to achieve steady state concentration. This allows for us to get to efficacious doses without reaching toxic levels or overdose.
The psychopharmacological industry have developed several mathmatical models to help determine doses and pharmacokinetic profiles of drugs. Dose-response relationships will differ across individuals, due to individual differences. Drugs will have a number of effects, each with their own dose-response relationship. Similar drugs, even with similar mechanism of action will differ. Drugs will have a phlethora of effects: Wanted effects and side effects. Sometimes the metabolites will have the effect you are interested in and it is this that dose-relationship needs to focus on.
Figure 1. Dose-Response Relationship
Two abbreviated terms are important in pharmacokinetics. ED50 refers to concept that 50 percent of the population experience efficacious doses at this level. LD50 refers to the concept that 50% of the population die at this dose (lethal). The larger the window between the two figures, the safer the drug. LD50 divided by ED50 gives therapeutic index- the ratio of safety in other words. Indexes of around 100 are considered safe.
Pharmacodynamics refers to the process by which drugs work and take effect, there mechanism of action. There are 7 main drug actions:
• stimulating action through direct receptor agonism and downstream effects
• depressing action through direct receptor agonism and downstream effects (ex.: inverse agonist)
• blocking/antagonizing action (as with silent antagonists), the drug binds the receptor but does not activate it
• stabilizing action, the drug seems to act neither as a stimulant or as a depressant (ex.: some drugs possess receptor activity that allows to stabilize general receptor activation, like buprenorphine in opioid dependent individuals or aripiprazole in schizophrenia, all depending on the dose and the recipient)
• exchanging/replacing substances or accumulating them to form a reserve (ex.: glycogen storage)
• direct beneficial chemical reaction as in free radical scavenging
• direct harmful chemical reaction which might result in damage or destruction of the cells, through induced toxic or lethal damage (cytotoxicity or irritation)
The clinical trials process is a thorough process, that is often completed over a number of years across multiple sites. They are often very specific, typically beginning with animal testing, and ending with human testing. In the human testing phase, there is often a group of subjects, one group is given a placebo, and the other is administered a carefully measured therapeutic dose of the drug in question. After all of the testing is completed, the drug is proposed to the concerned regulatory authority and is either commercially introduced to the public via prescription, or deemed safe enough for over the counter sale. Specifically, phases consist of:
Phase 1- small (20-80) test of experimental drug to determine safety, dosing and identify side effects.
Phase 2- larger (100-300) safety and efficacy
Phase 3- large scale (500+) efficacy within target population, monitor side effects and compare standard treatments.
Phase 4- Licence studies to provide further information and detail on risk and efficacy.
Figure 2. Drug Development Process
A historical appreciation of drugs helps contextualise the long standing use of drugs in altering consciousness, extending thousands of years stemming back to the use of mushrooms in tribal rituals, for example. In a clinical context, drugs first came to be used in the mid twentieth century to treat psychiatric disorders such as depression and psychosis.
Pharmacokinetics refers to the movement and time course through the body. It is divided into several areas including the extent and rate of absorption, distribution, metabolism and excretion. This is commonly referred to as the ADME scheme:
• Absorption - the process of a substance entering the blood circulation.
• Distribution - the dispersion or dissemination of substances throughout the fluids and tissues of the body.
• Metabolism (or Biotransformation) - the irreversible transformation of parent compounds into daughter metabolites.
• Excretion (or Elimination) - the elimination of the substances from the body. In rare cases, some drugs irreversibly accumulate in body tissue.
Absorption can be done oral, rectal, transdermal, subcutaneuos, sublingual, lingual and intramuscular. The specifics of this are decided based on feasibility, absorption rate, tolerability, safety and invasiveness.
The 'blood-brain' barrier is there to protect us as a huge amount of blood needs to service the brain and a flood of something psychoactive or neurotoxic could be devastating without filter protection. Drugs therefore need to transpose the 'blood-brain barrier' and either need to be compatible with the transport system, lipid soluble, or they have to be small so that the drugs can pass successfully through it. Heroine and morphine provide a synonymous example once within the brain, but the way they are absorbed is very different, thus giving them different potencies.
Half life can be used in various domains. It usually refers to the ‘elimination’ half life. This means the half life for half of the drug to be completely metabolized. Half life is important to achieve steady state concentration. This allows for us to get to efficacious doses without reaching toxic levels or overdose.
The psychopharmacological industry have developed several mathmatical models to help determine doses and pharmacokinetic profiles of drugs. Dose-response relationships will differ across individuals, due to individual differences. Drugs will have a number of effects, each with their own dose-response relationship. Similar drugs, even with similar mechanism of action will differ. Drugs will have a phlethora of effects: Wanted effects and side effects. Sometimes the metabolites will have the effect you are interested in and it is this that dose-relationship needs to focus on.
Figure 1. Dose-Response Relationship
Two abbreviated terms are important in pharmacokinetics. ED50 refers to concept that 50 percent of the population experience efficacious doses at this level. LD50 refers to the concept that 50% of the population die at this dose (lethal). The larger the window between the two figures, the safer the drug. LD50 divided by ED50 gives therapeutic index- the ratio of safety in other words. Indexes of around 100 are considered safe.
Pharmacodynamics refers to the process by which drugs work and take effect, there mechanism of action. There are 7 main drug actions:
• stimulating action through direct receptor agonism and downstream effects
• depressing action through direct receptor agonism and downstream effects (ex.: inverse agonist)
• blocking/antagonizing action (as with silent antagonists), the drug binds the receptor but does not activate it
• stabilizing action, the drug seems to act neither as a stimulant or as a depressant (ex.: some drugs possess receptor activity that allows to stabilize general receptor activation, like buprenorphine in opioid dependent individuals or aripiprazole in schizophrenia, all depending on the dose and the recipient)
• exchanging/replacing substances or accumulating them to form a reserve (ex.: glycogen storage)
• direct beneficial chemical reaction as in free radical scavenging
• direct harmful chemical reaction which might result in damage or destruction of the cells, through induced toxic or lethal damage (cytotoxicity or irritation)
The clinical trials process is a thorough process, that is often completed over a number of years across multiple sites. They are often very specific, typically beginning with animal testing, and ending with human testing. In the human testing phase, there is often a group of subjects, one group is given a placebo, and the other is administered a carefully measured therapeutic dose of the drug in question. After all of the testing is completed, the drug is proposed to the concerned regulatory authority and is either commercially introduced to the public via prescription, or deemed safe enough for over the counter sale. Specifically, phases consist of:
Phase 1- small (20-80) test of experimental drug to determine safety, dosing and identify side effects.
Phase 2- larger (100-300) safety and efficacy
Phase 3- large scale (500+) efficacy within target population, monitor side effects and compare standard treatments.
Phase 4- Licence studies to provide further information and detail on risk and efficacy.
Figure 2. Drug Development Process
Saturday, 14 January 2012
MRI and fMRI in a Nutshell
MRI (AKA nuclear magnetic resonance imaging (NMRI) or magnetic resonance tomography (MRT) is a medical imaging technique used in radiology to visualise detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body. It is a particularly useful clinical and research tool for imaging soft tissue such as the brain and has been harnessed in clinical research to support anatomical changes in syndromes such as autism, schizophrenia and severe depression to name but a few. One almost cliche study utilised MRI to establish anatomically changes in the anterior and posterior hippocampal structures in London taxi drivers (Gur et al. 200). It is routinely used in clinical practice in the detection of acquired brain injuries, such as tumour, stroke and TBI.
In order to understand how it works, it is necessary to summarise the atom. On its smallest scale the world is made up of atoms. Atoms consist of protons, neutrons and electrons that orbit or ‘spin’. Atoms with an uneven number of protons and neutrons have a 'net spin'. When atoms are outside of an MRI scanner the alignment of these net spins is randomly ordered. Under a magnetic field, they tend to align in parallel or anti-parallel. The MRI is a very powerful magnet, 30,000 times more power than the Earth’s natural polar magnetic field. Another magnetic field, the gradient field, is then applied to kick the nuclei to higher magnetization levels, with the effect depending on where they are located. When the gradient field is removed, the nuclei go slowly back to their original states (AKA relaxation), and the energy they emit is measured with a coil to recreate the positions of the nuclei. MRI thus provides a static structural view of brain matter. Magnetic field gradients cause nuclei at different locations to rotate at different speeds. By using gradients in different directions 2D images or 3D volumes can be obtained in any arbitrary orientation. Sagittal, coronal or horizontal slices can be obtained. Black areas on the scan represent no signal and white areas represent a signal (positive charge).
The brain is 70% water and water is a compound substance made up of hydrogen and oxygen elements. Hydrogen molecules are intrinsically magnetic and water concentration differentiates through different types of brain matter. MRI uses this to construct a grey scale image. For instance cerebrospinal fluid has very high water content and tumour and bone is very dense and low in water content. Images can be T1 or T2 weighted by changing the parameters of 'relaxation' time. White matter appears in a light grey in T1 and a dark grey in T2. Grey matter appears grey in both and cerebrospinal fluid (CSF) appears black in T1 and white in T2. T1 and T2 weighting is a helpful option in clinical scenarios where one type of matter is particularly important to identify (the extent of a tumour for example).
Exciting new techniques involving the introduction of high contrast agents are currently in development. They have some contraindications to health but they have now been approved for specific uses in clinical research and practice.
Functional magnetic resonance imaging or functional MRI (fMRI) is an MRI procedure that measures brain activity by detecting associated changes in blood flow. The primary form of fMRI uses the blood-oxygen-level-dependent (BOLD) contrast, discovered by Seiji Ogawa. The central thrust behind fMRI was to extend MRI to capture functional changes in the brain caused by neuronal activity. Differences in magnetic properties between arterial (oxygen-rich) and venous (oxygen-poor) blood provided this link. When neurons become active, local blood flow to those brain regions increases, and oxygen-rich (oxygenated) blood displaces oxygen-depleted (deoxygenated) blood. In a nutshell deoxygenated hemoglobin is more magnetic than oxygenated hemoglobin, which is virtually nonmagnetic. This difference leads to an improved MR signal since the nonmagnetic blood interferes with the magnetic MR signal less. This improvement can be mapped to show which neurons are active at a time.
fMRI is used to often used in avoiding key functional areas of the brain in prepartion for surgical or other invasive intervnetion. It is also often used to anatomically map the brain and detect the effects of tumors, stroke, head and brain injury, or degenerative diseases such as dementia. Research use is ahead of clinical use, mainly becuase clinical populations present logistical or ethical complications to scanning (scanning a child with ASD, with communication difficulties who require informed consented is an illustration of a collection of these difficulties). Despite this, in addition to the uses of MRI, fMRI has been used clinically to map functional areas, check left-right hemispherical asymmetry in language and memory regions, check the neural correlates of a seizure and test how well a drug works.
Like any technique, fMRI has advantages and disadvantages, and in order to be useful, the experiments that employ it must be carefully designed and conducted to maximize its strengths and minimize its weaknesses.
-Advantages-
-It can noninvasively record brain signals without risks of ionising radiation inherent in other scanning methods, such as CT or PET scans.
-It has satisfactory spatial resolution, particularly in collaboration with a normal MRi scan.
-It can record signal from all regions of the brain, unlike EEG/MEG, which are biased toward the cortical surface.
-It has led to major new understandings of human function, particular in light of real-time intervnetion studies.
-Disadvantages-
-The BOLD signal is only an indirect measure of neural activity and, as described before, could be influenced by elements other than the experimental manipulation (disease, sedation, anxiety, medications that dilate blood vessels, and attention (neuromodulation).
-BOLD signals reveal input rather than output and one isn't necessarily the other.
-The technique has been criticised for its poor temporal resolution. The BOLD response peaks approximately 5 seconds after neuronal firing begins in an area. While interleaved stimulus presentation can increase temporal resolution, it correspondingly reduces the data points collected.
-While the static magnetic field has no known long-term harmful effect on biological tissue, it can cause damage by pulling in nearby heavy metal objects converting them to projectiles.
-The most common risk to participants in an fMRI study is claustrophobia. But people with pacemakers are catastrophically at risk on entering a scanner.
-The scanner is very expensive.
-The costs mean that clinical practice has lagged behind privately funded research.
-fMRI research statisitcal methods have recently fallen under strutiny, thereby questionning past findings.
In order to understand how it works, it is necessary to summarise the atom. On its smallest scale the world is made up of atoms. Atoms consist of protons, neutrons and electrons that orbit or ‘spin’. Atoms with an uneven number of protons and neutrons have a 'net spin'. When atoms are outside of an MRI scanner the alignment of these net spins is randomly ordered. Under a magnetic field, they tend to align in parallel or anti-parallel. The MRI is a very powerful magnet, 30,000 times more power than the Earth’s natural polar magnetic field. Another magnetic field, the gradient field, is then applied to kick the nuclei to higher magnetization levels, with the effect depending on where they are located. When the gradient field is removed, the nuclei go slowly back to their original states (AKA relaxation), and the energy they emit is measured with a coil to recreate the positions of the nuclei. MRI thus provides a static structural view of brain matter. Magnetic field gradients cause nuclei at different locations to rotate at different speeds. By using gradients in different directions 2D images or 3D volumes can be obtained in any arbitrary orientation. Sagittal, coronal or horizontal slices can be obtained. Black areas on the scan represent no signal and white areas represent a signal (positive charge).
The brain is 70% water and water is a compound substance made up of hydrogen and oxygen elements. Hydrogen molecules are intrinsically magnetic and water concentration differentiates through different types of brain matter. MRI uses this to construct a grey scale image. For instance cerebrospinal fluid has very high water content and tumour and bone is very dense and low in water content. Images can be T1 or T2 weighted by changing the parameters of 'relaxation' time. White matter appears in a light grey in T1 and a dark grey in T2. Grey matter appears grey in both and cerebrospinal fluid (CSF) appears black in T1 and white in T2. T1 and T2 weighting is a helpful option in clinical scenarios where one type of matter is particularly important to identify (the extent of a tumour for example).
Exciting new techniques involving the introduction of high contrast agents are currently in development. They have some contraindications to health but they have now been approved for specific uses in clinical research and practice.
Functional magnetic resonance imaging or functional MRI (fMRI) is an MRI procedure that measures brain activity by detecting associated changes in blood flow. The primary form of fMRI uses the blood-oxygen-level-dependent (BOLD) contrast, discovered by Seiji Ogawa. The central thrust behind fMRI was to extend MRI to capture functional changes in the brain caused by neuronal activity. Differences in magnetic properties between arterial (oxygen-rich) and venous (oxygen-poor) blood provided this link. When neurons become active, local blood flow to those brain regions increases, and oxygen-rich (oxygenated) blood displaces oxygen-depleted (deoxygenated) blood. In a nutshell deoxygenated hemoglobin is more magnetic than oxygenated hemoglobin, which is virtually nonmagnetic. This difference leads to an improved MR signal since the nonmagnetic blood interferes with the magnetic MR signal less. This improvement can be mapped to show which neurons are active at a time.
fMRI is used to often used in avoiding key functional areas of the brain in prepartion for surgical or other invasive intervnetion. It is also often used to anatomically map the brain and detect the effects of tumors, stroke, head and brain injury, or degenerative diseases such as dementia. Research use is ahead of clinical use, mainly becuase clinical populations present logistical or ethical complications to scanning (scanning a child with ASD, with communication difficulties who require informed consented is an illustration of a collection of these difficulties). Despite this, in addition to the uses of MRI, fMRI has been used clinically to map functional areas, check left-right hemispherical asymmetry in language and memory regions, check the neural correlates of a seizure and test how well a drug works.
Like any technique, fMRI has advantages and disadvantages, and in order to be useful, the experiments that employ it must be carefully designed and conducted to maximize its strengths and minimize its weaknesses.
-Advantages-
-It can noninvasively record brain signals without risks of ionising radiation inherent in other scanning methods, such as CT or PET scans.
-It has satisfactory spatial resolution, particularly in collaboration with a normal MRi scan.
-It can record signal from all regions of the brain, unlike EEG/MEG, which are biased toward the cortical surface.
-It has led to major new understandings of human function, particular in light of real-time intervnetion studies.
-Disadvantages-
-The BOLD signal is only an indirect measure of neural activity and, as described before, could be influenced by elements other than the experimental manipulation (disease, sedation, anxiety, medications that dilate blood vessels, and attention (neuromodulation).
-BOLD signals reveal input rather than output and one isn't necessarily the other.
-The technique has been criticised for its poor temporal resolution. The BOLD response peaks approximately 5 seconds after neuronal firing begins in an area. While interleaved stimulus presentation can increase temporal resolution, it correspondingly reduces the data points collected.
-While the static magnetic field has no known long-term harmful effect on biological tissue, it can cause damage by pulling in nearby heavy metal objects converting them to projectiles.
-The most common risk to participants in an fMRI study is claustrophobia. But people with pacemakers are catastrophically at risk on entering a scanner.
-The scanner is very expensive.
-The costs mean that clinical practice has lagged behind privately funded research.
-fMRI research statisitcal methods have recently fallen under strutiny, thereby questionning past findings.
Thursday, 12 January 2012
“Cognition does not Exist in a Vacuum”
Before the 18th century people generally thought that the heart was responsible for emotions and thoughts. This sounds bizarrely impressive given what we know now, but remnants of this still exist with the metaphorical representation of the heart in its connection with the emotion of love. But people really once hypothesised that the heart did precisely what the brain does. The first record of a dissenting opinion on this came in the early 1700’s. Gall is renowned for his 18th century theory of “phrenology”. This theory explained how the shape of the skull, as a dictation of the shape of the brain, predicted various attributes. One could feel their way across the skull and detect the likelihood of barbarianism and other antiquated characteristics. Of course by modern standards his theories are almost entirely rubbished. However, almost by coincidence he was on the right path.... or was he?
Flouren’s 19th century animal lesion studies were the next landmark breakthrough in use of detailed behavioural analysis to study the underlying functions of the brain. Following this, names such as Kleist and Lashley made important contributions in identifying function based upon localisation of brain injury/lesion. A key 20th century case-in-point is Miller’s patient “M”, who experienced catastrophic lesion of the hippocampus during surgery. He suffered profound amnesia as a result, meaning he could not consolidate and store memories at all. For a slightly more up to date collection of evidence based lesion studies, Damasio provides a key text outlining what we now know about the localisation of brain function.
Lesion based research, is however, not without its criticisms. Firstly, it says little of functional systems and pathways. It explains little of individual difference and secondary impact of brain injury/lesion. Furthermore, as research gathered pace through history, researchers began to move away from a simplistic view of ‘tissue location=specific function” and began to recognise the inter-related relationships and systems that contribute to human brain function.
Alongside these key historical developments of localisation theory the levels at which we understand the brain have developed and evolved. Nowadays we try our best to understand the brain in terms of anatomy, chemistry, activity, function and behaviour. We have 52 distinct anatomically distinct areas dictated by conceptually useful approximate function and interrelatedness (see Brodman’s 52 areas). This has led to many benefits in helping those who have experienced neurological insult in their rehabilitation and planning, not to mention, helping guide neurosurgeons in avoiding damage to key language areas of the brain during surgery.
But let’s return to heart, or perhaps better still, Gall’s “phrenology”. There is a risk that modern imaging methods may fall into a similar trap to Gall. Collectively, and quite possibly to our detriment, we are very eager to discover more about mankind and his workings. The assumption of dysfunction equalling lesion is a faux pas made even in modern times, with the advent of modern structural and functional imaging research and for use in clinical enquiry. Recent research suggests that MRI research in particular should be reviewed and more conservative statistical procedures be deployed (see Vul et al. 2009). The brain is a wonderfully complex organ that demands a commensurate ways of understanding it. Later in my blogs I shall attempt to summarise modern structural and functional imaging techniques in order to illustrate how this history of human curiosity continues.
Flouren’s 19th century animal lesion studies were the next landmark breakthrough in use of detailed behavioural analysis to study the underlying functions of the brain. Following this, names such as Kleist and Lashley made important contributions in identifying function based upon localisation of brain injury/lesion. A key 20th century case-in-point is Miller’s patient “M”, who experienced catastrophic lesion of the hippocampus during surgery. He suffered profound amnesia as a result, meaning he could not consolidate and store memories at all. For a slightly more up to date collection of evidence based lesion studies, Damasio provides a key text outlining what we now know about the localisation of brain function.
Lesion based research, is however, not without its criticisms. Firstly, it says little of functional systems and pathways. It explains little of individual difference and secondary impact of brain injury/lesion. Furthermore, as research gathered pace through history, researchers began to move away from a simplistic view of ‘tissue location=specific function” and began to recognise the inter-related relationships and systems that contribute to human brain function.
Alongside these key historical developments of localisation theory the levels at which we understand the brain have developed and evolved. Nowadays we try our best to understand the brain in terms of anatomy, chemistry, activity, function and behaviour. We have 52 distinct anatomically distinct areas dictated by conceptually useful approximate function and interrelatedness (see Brodman’s 52 areas). This has led to many benefits in helping those who have experienced neurological insult in their rehabilitation and planning, not to mention, helping guide neurosurgeons in avoiding damage to key language areas of the brain during surgery.
But let’s return to heart, or perhaps better still, Gall’s “phrenology”. There is a risk that modern imaging methods may fall into a similar trap to Gall. Collectively, and quite possibly to our detriment, we are very eager to discover more about mankind and his workings. The assumption of dysfunction equalling lesion is a faux pas made even in modern times, with the advent of modern structural and functional imaging research and for use in clinical enquiry. Recent research suggests that MRI research in particular should be reviewed and more conservative statistical procedures be deployed (see Vul et al. 2009). The brain is a wonderfully complex organ that demands a commensurate ways of understanding it. Later in my blogs I shall attempt to summarise modern structural and functional imaging techniques in order to illustrate how this history of human curiosity continues.
Tuesday, 10 January 2012
Orientating Around the Brain
The following technical terms are used to orientate around and within the brain and its structures:
Top=dorsal/superior
Bottom=ventral/inferior
Front=rostral/anterior
Back=caudral/posterior
Medial=mid-line
Lateral=away from mid-line
Contralateral=opposite side as
Ipsilateral=same side as
Unilateral=one side only
Bilateral=both sides
Proximal=close
Distal=distant
Top=dorsal/superior
Bottom=ventral/inferior
Front=rostral/anterior
Back=caudral/posterior
Medial=mid-line
Lateral=away from mid-line
Contralateral=opposite side as
Ipsilateral=same side as
Unilateral=one side only
Bilateral=both sides
Proximal=close
Distal=distant
Tuesday, 27 December 2011
MUS and Neuropsychology
What Can Neuropsychology Contribute to the Identification and Treatment of Medically Unexplained Neurological Symptoms?
Medically Unexplained Symptoms (MUS) is an umbrella term for a broad collection of symptoms and syndromes that physical processes alone fails to explain. It has been criticised as type of 'non diagnosis' as it essentailly diagnoses what it is not rather than what it is. However, the term has gained popularity over other terms, such as cogniform disorder or somatisation because patients tend to view it as non-threatening, and because positive relationships to professionals (usually the GP) are a key correlate to positive outcome. Examples of MUS phenomena arguably include: inexplicable pain, inexplicable headache, fibromyalgia, chronic fatigue, and non epileptic attack disorder.
Up to one in five GP appointments is MUS related. It is important to statistically contextualise prevalency as sometimes medical experts are wrong and up to 5% of those diagnosed with MUS subsequently turn out to be medically explainable cases following long term follow-up. However, a mixture of factors including: a growth in civil prosecution, an increase in 'blame culture' and the advent of patient internet derived knowledge, has meant medics have approaches MUS with relentlessly fruitless further medical investigations. The costs and harms both physically, psychologically and financially of this trend is worrying and has attracted attention from psychologists and neuropsychologists alike.
The contribution clinical psychology and neuropsychology can make to MUS sufferers is at two levels: identification and treatment. Where complaints are made of a neurological nature symptom validity tests (SVTs) are routinely used in neuropsychological assessment to identify MUS. They are particular useful in questions over whether a patient has infact sustained a mild head injury or whether they are:
1 Completely malingering
2 or either consciousely or unconsciousely exaggerating symptoms
The BPS now advise routine use of SVTs even in clear cases of organic pathology, primarily to substantiate the reliability of test results and clinical interpretations. Each SVT has it's strengths and weaknesses. Each test aims to strike an appropriate balance between the likelihood of making type 1 versus type 2 error. Each test essentially aims to identify those who are making less than maximum effort. Similarly, 'forced choice' tests, tests that even when completed by random chance stand a 50% correct level, specifically aim to identify those who deliberately aim to mislead testers. Psychological assessments of personality and psychopathology can also be used as an adjunct in correctly identifying MUS. Subscales indicating anxiety, depression, somatisation, neuroticism and exaggeration of symptoms are often used as indicators of potential MUS. Unusual symptoms, symptoms out of context, long histories of attendance at A&E/GP are other indicators of increased MUS likelihood (see previous blog on DSM-IV indicators).
Most often psychological factors play a central explanatory role. It is believed approximately 70% of MUS patients share comorbidity with psychiatric symptoms, most often anxiety and depression, although the extrapolation of cause and effect complicate this simplistic statistic. At the level of treatment psychologists offer evidence based 'talking interventions' such as CBT and associated approaches. Such approaches focus upon: treating anxiety and depression symptoms, encouraging patients to acceptance their scenario and their symptoms, symptom management and dissemination of psychological formulation as an explanation of symptoms.
Psychologists have become increasingly interested in being involved at the primary care level. In Devon, Plymouth began a pilot project in 2008 focussing upon scripting GP messages on initial MUS diagnosis, specific risk assessment for MUS patients and approaches aimed at minimising unneccessary and potentially harmful medical investigations. Psychological approaches have identified the importance in 'getting in early'. Clinicians and researchers have identified a 6 month critical period for intervening (Bass/Stone/Halligan). Beyond this outcomes become increasingly pessimistic. MUS unsurprisingly fall into three crude groups, of which research is in process: 1. Those who are treatable; 2. Those who may become treatable; and 3. Those who will be highly resistant. Psychologists with considerable MUS experience will usually know which group a patient fits into following the first or second session.
Medically Unexplained Symptoms (MUS) is an umbrella term for a broad collection of symptoms and syndromes that physical processes alone fails to explain. It has been criticised as type of 'non diagnosis' as it essentailly diagnoses what it is not rather than what it is. However, the term has gained popularity over other terms, such as cogniform disorder or somatisation because patients tend to view it as non-threatening, and because positive relationships to professionals (usually the GP) are a key correlate to positive outcome. Examples of MUS phenomena arguably include: inexplicable pain, inexplicable headache, fibromyalgia, chronic fatigue, and non epileptic attack disorder.
Up to one in five GP appointments is MUS related. It is important to statistically contextualise prevalency as sometimes medical experts are wrong and up to 5% of those diagnosed with MUS subsequently turn out to be medically explainable cases following long term follow-up. However, a mixture of factors including: a growth in civil prosecution, an increase in 'blame culture' and the advent of patient internet derived knowledge, has meant medics have approaches MUS with relentlessly fruitless further medical investigations. The costs and harms both physically, psychologically and financially of this trend is worrying and has attracted attention from psychologists and neuropsychologists alike.
The contribution clinical psychology and neuropsychology can make to MUS sufferers is at two levels: identification and treatment. Where complaints are made of a neurological nature symptom validity tests (SVTs) are routinely used in neuropsychological assessment to identify MUS. They are particular useful in questions over whether a patient has infact sustained a mild head injury or whether they are:
1 Completely malingering
2 or either consciousely or unconsciousely exaggerating symptoms
The BPS now advise routine use of SVTs even in clear cases of organic pathology, primarily to substantiate the reliability of test results and clinical interpretations. Each SVT has it's strengths and weaknesses. Each test aims to strike an appropriate balance between the likelihood of making type 1 versus type 2 error. Each test essentially aims to identify those who are making less than maximum effort. Similarly, 'forced choice' tests, tests that even when completed by random chance stand a 50% correct level, specifically aim to identify those who deliberately aim to mislead testers. Psychological assessments of personality and psychopathology can also be used as an adjunct in correctly identifying MUS. Subscales indicating anxiety, depression, somatisation, neuroticism and exaggeration of symptoms are often used as indicators of potential MUS. Unusual symptoms, symptoms out of context, long histories of attendance at A&E/GP are other indicators of increased MUS likelihood (see previous blog on DSM-IV indicators).
Most often psychological factors play a central explanatory role. It is believed approximately 70% of MUS patients share comorbidity with psychiatric symptoms, most often anxiety and depression, although the extrapolation of cause and effect complicate this simplistic statistic. At the level of treatment psychologists offer evidence based 'talking interventions' such as CBT and associated approaches. Such approaches focus upon: treating anxiety and depression symptoms, encouraging patients to acceptance their scenario and their symptoms, symptom management and dissemination of psychological formulation as an explanation of symptoms.
Psychologists have become increasingly interested in being involved at the primary care level. In Devon, Plymouth began a pilot project in 2008 focussing upon scripting GP messages on initial MUS diagnosis, specific risk assessment for MUS patients and approaches aimed at minimising unneccessary and potentially harmful medical investigations. Psychological approaches have identified the importance in 'getting in early'. Clinicians and researchers have identified a 6 month critical period for intervening (Bass/Stone/Halligan). Beyond this outcomes become increasingly pessimistic. MUS unsurprisingly fall into three crude groups, of which research is in process: 1. Those who are treatable; 2. Those who may become treatable; and 3. Those who will be highly resistant. Psychologists with considerable MUS experience will usually know which group a patient fits into following the first or second session.
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