Delirium (Acute Confusional State): Causes, Identification, Assessment and Management

Introduction

Here is the definition of delirium from the shorter oxford textbook of psychiatry:

“delirium is a global impairment (clouding) of consciousness resulting in a reduced level of alertness, attention, perception of the environment, and thence cognitive performance.”

There are several terms used in this definition that can make it difficult to understand at first. It begins with a clouding of consciousness, which they say results in reduced alertness, attention, and perception, and these are cognitive or let's put it simply, mental abilities, so the overall mental abilities or cognitive performance is reduced. Now, let me quickly explain these and some other terms so you can fully comprehend this definition and the other signs and symptoms of delirium that we will be discussing.

Terminology

Perception

Perception occurs when the brain processes the raw sensory stimuli from the environment to generate meaningful information. For example, the light packets are the sensory data that, through the eyes and optic tract, reaches the visual cortex, which processes it to form an image. Similarly, sound waves are processed by the brain, so we hear voices that contain information. It is interesting and can be deceptive. Here, for example, we are seeing an apple, jumping, and rotating in a 3d space, even though the screen is flat. So, we are perceiving the light emitted from the screen which is the actual sensory data, as a 3d rotating apple. This apple is the final perception.

Attention 

Attention is our mental capacity to hold information actively in mind for processing, for example, mental manipulation, inference, making sense of information, deciding based on it etc. it has a limited capacity. On average, we can keep seven digits in mind at the same time.

Concentration

The ability to sustain attention is concentration. For example, if you count backwards from one thousand, how long can you do it without making a mistake.

Distractibility

Distractibility is a related term. It is simply like the inverse of our ability to filter out irrelevant stimuli and focus on the relevant ones.

Stupor

These are some cognitive functions, and these depend on the level of alertness. So, when a condition impairs alertness, these functions reduce and eventually pause. The patient appears in a sleep-like state, and we call this state stupor. These patients can still respond to at least some stimuli.

Coma

When they stop responding to stimuli, we say they are comatose. Please notice the perceptions and it may still reduce even responses to stimuli. Only when patients stop responding to stimuli, so we say they are in a coma.

Clouding of consciousness.

Any level of consciousness between complete alertness and stupor is what we call clouding of consciousness. 

So, now let's have a look at this definition again. 

“Delirium is a global impairment (couding) of consciousness resulting in a reduced level of alertness, attention, perception of the environment, and thence cognitive performance”.

I hope that now makes more sense. 

One key point about this definition is that it mentions no cause. Unlike conditions, for example, COVID-19, where we must find the evidence of its causative agent; the SARS-CoV-2, we define delirium by its clinical manifestations. So, let's discuss them.

Clinical Manifestations

Delirium has a wide range of manifestations, but there are some core features which are central to the diagnosis of delirium. And the course of these symptoms is also important.

These core features include a clouding or impairment of consciousness, visual misperceptions and hallucinations, reversal of sleep-wake cycle and variability of the symptoms over the day. Rapid onset is also important from the diagnostic point of view.

Clouding of consciousness 

Clouding of consciousness is the hallmark of delirium. They manifest it as drowsiness, decreased awareness of one’s surroundings, disorientation in time and place, and distractibility. At its most severe, the patient may be unresponsive (stuporous), but more commonly the impaired consciousness is quite subtle.

Rapid onset

Rapid onset is also one of its diagnostic characteristics. A further clue to the diagnosis is the onset has a temporal relationship with the cause. We'll describe it later. This rapid onset is most important to differentiate it from dementia. Most of the symptoms that occur in delirium also occur in dementia, but in which case, they arise over the years. In delirium, they begin within hours to a few days.

Variability

The symptoms of delirium change over the day, severity may intensify especially at night and then ease in the daytime, some symptoms may subside, new symptoms may arise. And this variability of the clinical picture is another diagnostic feature of delirium.

Reversal of Sleep-wake Cycle

Patients with delirium have a reversal of the sleep-wake cycle. They may sleep in the day and stay awake at night. And that could be one reason the symptoms appear to worsen at night. But a reversal for the sleep-wake cycle is also important.

Perceptual Abnormalities

We already described perception, and we said it reduces in delirium. Illusions and hallucinations are abnormalities of perception.

Illusion 

An illusion occurs when we misperceive a stimulus, in most cases a visual stimulus. For example, seeing a full-sized car sitting on a table when the car stands on the floor way behind the table. It is mostly a normal phenomenon. And note a stimulus is present but we misinterpret it. But sometimes, people perceive things without actual stimuli, like hearing voices or seeing something others can’t see.

We call them hallucinations:

Hallucinations

We can define hallucination simply as perception when there is no stimulus. It is frequently an abnormal phenomenon. Hallucinations occur principally in the visual and auditory modality; but uncommonly they can even be tactile, or olfactory, or gustatory.

• Tactile: the sense of touch
• Olfactory: the sense of smell
• Gustatory: sense of taste

Patients with delirium can experience illusions or visual misperceptions--like misinterpreting a stethoscope for a snake and hallucinations like seeing a giant scorpion hanging from the ceiling or some insects crawling on their skin. Patients with psychiatric disorders, like schizophrenia, experience auditory hallucinations. But patients with delirium experience visual hallucinations and visual misperceptions. These visual misperceptions are another diagnostic feature of delirium.

One link here is acetylcholine, which acts as a neurotransmitter in the brain and has a significant role in cognition. Its depletion is linked with visual hallucinations as well. And organic conditions with mental symptoms have impairments in this acetylcholine. Take, for example, delirium itself, Parkinson's disease, Dementia. Even anticholinergic medications can cause both visual hallucinations and cognitive impairment, and cholinergic medication is used to treat Parkinson's disease psychosis, which presents with visual hallucinations.

So, these are the core features of delirium. Patients with delirium may experience almost any psychiatric symptom; thought disturbances and mood symptoms are some other more common ones.

Other Symptoms of Delirium

Disturbances of thoughts

Thinking is slow and muddled, that is vague and confused. Patients may also exhibit delusions or ideas of reference.

Delusions

A delusion is an unshakeable belief (we cannot change it with logical explanations or evidence) that is held on inadequate grounds (they do not have a valid explanation or evidence for their belief, and that is not a conventional belief that the person might be expected to hold given their educational, cultural, and religious background. Previously we said illusions are mostly but not always normal. Hallucinations are mostly but not always abnormal. But a delusion is something that is always abnormal. So, someone who believes to be possessed by the supernatural is not delusional because it’s a cultural common belief. In the west, many young girls become convinced that they need to be thin and take extreme measures and their weight may reach life-threatening low levels and continue. And this is still not a delusion because they consider thinness socially desirable and that they educate most people about the risks of obesity is dangerous and the need for thinness.

Persecutory delusions are the most common ones, in which they develop a belief that someone wants to harm them.

Ideas of Reference

An idea of reference is a related term. It refers to an unnecessary tendency to link external events, things, or people to self. For example, someone enters the room, and the patient may think that he kills me. If this idea meets the criteria for delusion, we call a delusion of reference.

Epidemiology

What is epidemiology

Epidemiology deals with the distribution of diseases or health conditions in various ethnic, age groups, socio-economic groups, geographies. Some of these groups have higher rates, or we can say they have a higher predisposition for developing that condition.

These factors are not mutually exclusive, they can overlap. For example, delirium is more common in elderly, it is also more common in those who are hospitalized. So a hospitalized elderly is included in both these groups. Or, again we can say he has two predisposing risk factors for delirium. People with more of these risk factors are more likely to develop the condition.

Patients with certain medical conditions may also be predisposed to develop a condition. These are not epidemiological factors but I have included them here so you can learn the predisposing factors together.

Demographic Risk Factors

The most important demographic risk factor is old age. Alcohol users are also at an elevated risk as are people with functional impairment. Imagine an elderly woman in a wheelchair, who broke her leg and needs help from caretakers. If this elderly also had a long-term history of alcohol use, she would have all these demographic factors.

Functional Impairment 

To help you precisely understand, impairment is used in medical terms for a pathological defect or disease. The loss of function as a result of this defect, is the functional impairment. A broken leg is an impairment and the inability to walk, the need for a wheelchair, or help with self-care needs is functional impairment.

Medical Risk Factors

Now, let's assume, she develops delirium and comes to your for assessment, and you find that she also has developed dementia due to long-term alcohol use. And as you assess her further, you discover that she broke her leg because she fell due to a brain stroke. And as a result of the brain stroke, she also lost her eyesight. So that makes her more likely to experience another episode. Because if she had delirium once, she could have it again. Her cerebral reserve is reduced because dementia reduces brain volume, then she lost part of her cerebral cortex because of the stroke which also took away her eyesight. These are the medical predisposing factors for delirium.

So, so now that the patient is at even higher risk for delirium, let's assume she comes to you with the third episode of delirium while you are working in the emergency department. After the emergency management, you admit her to the medical unit. And when the patient improves, you send her to a residential home instead. So, now she is even at even higher risk for a third episode. The Elderly in the community are at risk of delirium, but the risk in residential homes is 4-8 times higher. A higher than one in patients who present to the emergency department have delirium. Patients who are admitted to the hospital are even more likely to have delirium. This makes sense because we admit only those patients who are more seriously ill. Especially those admitted to medical units. Because medical conditions are some more common causes, compared to for example those with psychiatric conditions, diseases of the eyes, nose etc. there is no mention but patients in the ICU are highly likely to have delirium as well.

We already mentioned delirium has a prevalence of around 1-2% In the community sample of elderly. People presenting to the emergency department have about as high as 20% rates of delirium (8—17%)

Up to 35% of people on admission to the hospital may have delirium. Hospitalised patients in medical units may have up to 64% rates, but all these rates are the highest values of the expected ranges that we have found in epidemiological studies. The actual values could be much lower than these.

Aetiology

Aetiology refers to all the factors and processes that eventually lead to the disease. Every condition is caused by multiple risk factors. Let's take COVID-19, for example. Is it the virus? Or is it pathogenicity? What about the lack of our immunity to it? And now that the entire world knows how to protect, why is the virus still spreading? Do you think there may be a role for our risky behaviours that we keep exposing ourselves or faulty ways of thinking like I will not get it?

Aetiology and related concepts on delirium

So, the virus is the causative factor, its pathogenicity is part of the pathophysiology, our lack of immunity is the predisposing factor. faulty ways of thinking and risky behaviours are risk factors which can predispose but when they eventually trigger the disease, so we know them as precipitating. And we collectively know these factors as aetiological factors.

With delirium, causative factors are especially diverse, as we will see.

For the individual cases, the aetiology involves multiple factors most of the time, for example, you admit an elderly man with uncontrolled diabetes suffers cardiac failure to the CCU where he is started on steroids and digoxin. But note that some cases may even be idiopathic — that is, we don’t know what caused the delirium. These cases require the most careful workup. Because treatment of the underlying cause is most important for the outcome.

In the elderly admitted to the hospital, drugs and infection are the most frequent cause of delirium.

Substances of abuse

Some of the most common drugs of abuse include alcohol, benzodiazepines, and opioids. Alcohol and benzodiazepine withdrawal cause a special type of delirium that we call delirium tremens.

Delirium Tremens

Apart from the general symptoms of delirium, delirium tremens is characterised by an autonomic instability like irregular heart rate. Epileptic fits may also occur. The prognosis of delirium tremens is even worse. Many people use benzodiazepines as their regular sleeping pills, and they may attempt to withdraw from them on their own because they don’t see it as a serious risk to their health. These patients could then present as idiopathic cases of delirium. So, it is important to ask about benzodiazepine use in such cases.

Medications

An extensive list of medications can cause delirium, but the most common ones are sedatives, medications with anticholinergic properties, steroids, and digoxin. While evaluating delirium, always look at whether the patient is receiving these medications. But since the list is extensive, always aim to cut down on the doses and number of medications to a bare minimum

Medical Conditions

Again, many conditions can cause delirium but septicaemia, high degree fever and organ failures like renal or liver failure, or even cardiac failure are among the common ones. Of thumb, delirium has a temporal relation with its cause. So, if someone develops a medical condition and then they develop delirium, we might assume that as a cause.

These are some interesting causes, especially important for the idiopathic delirium where no cause is evident. Sleep deprivation, for example, may not be revealed unless we enquire about it. Similarly, keep constipation and dehydration in mind. Sometimes, mental trauma and extreme physical pain may also induce delirium.

So, these were the common causes of delirium. But remember that the list is extensive.

Pathophysiology of delirium

The pathophysiology of delirium is less well understood but,

This slowing of activity correlates with the severity of the clinical picture. The more severe the clinical picture, the slower the activity on the EEG. Dopamine and acetylcholine are involved in the final common pathway. We already explained the role of acetylcholine. Dopamine is also a central nervous system stimulant neurotransmitter and has a role in cognition and hallucinations. This time auditory hallucinations, but also in delusions.

You can help remember this with the d of the dopamine for the d in the delusions and the d in the auditory hallucinations. You'll learn more about it in another lesson on schizophrenia, where it has a more significant role.

Studies implicate a range of other factors which include inflammatory, metabolic, and genetic factors. We will not discuss these. This is the end of the aetiology section. Now the assessment where we discuss the clinical and laboratory assessment.

Assessment

Clinical assessment

Clinical assessment includes the general history and bedside testing, including a physical and neurological examination.

History

In history, we enquire about the major symptoms of delirium that we discussed. For example, whether they experience visual symptoms. And we also elicit the course, to confirm its rapid onset and its temporal association with its cause, identify the fluctuation in symptoms and whether the symptoms worsen at night. Reversal of the sleep-wake cycle is also relevant here.

Bed-side testing

During history taking, we already develop an impression of whether the patient appears drowsy. So, we begin by testing orientation to time, place, and person. Simply assess whether the patient is aware of the location, the date and time, and whether they can recognise the people around.

That was bedside testing. Now, two investigations can help us in the diagnosis. Again, it’s a clinical diagnosis, but these investigations can help when we are in doubt.

We already explained the inverse relationship between the severity of clinical presentation and background activity on EEG. So, this can aid the diagnosis. But it is not too sensitive or specific.

The most sensitive and specific test is the Confusion Assessment Method. It is a clinical tool that can test patients on the bedside, and it takes only two minutes to apply. It is not much different from clinical assessment, but it has standardised the entire process. So, it can be especially useful for learning. When you practice a few times on it, you can then do the same. You can download it from that link.

This was about the diagnostic assessment of delirium. The assessment of underlying causes must be even more careful. Particularly in those cases in whom the cause is unknown. A thorough medical history, physical history, and investigations. This assessment varies case by case. Just as in most cases, we tailor our physical examination based on the history and the lab investigations based on both. Then we can go back and forth until we find the exact cause.

Patients with idiopathic delirium require the most attention. And in those cases, it is wise to start with causes that we are likely to overlook, for example, look whether the patient is on Catheter, which widespread practice twice in medical units. Using physical restraints is not common but keep them in mind. Enquire about constipation, whether they have been sleeping well, again an easily missed cause. Patients are frequently secretive about their drug use, or in case of benzodiazepines, they may not consider it serious, look for the other signs of drug withdrawal in such cases. Pain can also cause delirium, so to keep that in mind. Check for dehydration with a skin pinch. But the assessment should not stop here. We keep assessing until we know the cause. So, this concludes the assessment section, which we regard as a part of the management.

But in this next section, we discuss the rest of the management, focused on the preventive and therapeutic interventions.

Management

Treating the underlying cause is the most important treatment. Because the outcome depends on it.

But preventive therapies are even more important because no delirium is preferable to delirium, but also, preventive therapies are more effective than therapeutic. We have some non-pharmacological and pharmacological interventions to prevent delirium.

Non-pharmacological Treatment Options

HELP and eliminating the risk factors are among the nonpharmacological interventions.

Hospital Elderly Life Program

HELP is a structured program, which studies have shown effective in preventing delirium. It is a commercial product from the American College of Geriatrics that costs five thousand dollars for a 2-year subscription. Eliminating risk factors is the most workable option. 

Eliminating risk factors 

Target those who are highly predisposed, think about an elderly, who lost his eyesight, and broke his leg because of a fall is now hospitalised with multiple pathologies and receiving multiple medications, including anti-dementia treatment. So, find a list and think about what they can avoid.

Pharmacological Treatments

Effective pharmacological treatments include antipsychotics in low doses, gabapentin, and melatonin. Several antipsychotics have anticholinergic and sedative properties, haloperidol is a good option. Gabapentin is an antiepileptic, which also helps.

You can remember melatonin because this is the hormone that regulates the sleep-wake cycle. Remember the sleep-wake cycle reversal in delirium.

The world health organisation has classified delirium as mental and behavioural disorder. So, they do not recognise it as a medical condition. But it’s a medical emergency. Because the underlying causes are organic.

The mortality is high. It needs urgent medical attention. Because the prognosis depends on the treatment of the underlying cause. So, we require careful workup patients to identify them, especially when they are not clear.

Psychiatric management aims to relieve distress, control agitation, and prevent exhaustion that can occur because of this agitated behaviour.

We have some pharmacological and nonpharmacological treatment options. The nonpharmacological treatments are the mainstay, while we reserve the pharmacological treatments for those with severe agitation and hallucinations.

Now we know clouding of consciousness is the hallmark of delirium which results in poor cognition, disorientation to time and place, confusion. So, imagine you do not know where you are. Everyone seems a stranger, you are not aware of the time, and add to that the experience of frightening hallucinations, like seeing scorpions and snakes. So that’s more like a nightmare. And patients become anxious and agitated. Which is the best indication for psychiatric treatment? So, the most effective known way to treat it is to target the core manifestations. Confused patients may ask questions, you give them frequent explanations; they do not know where the who, so we orient, Ideally, we should nurse them in a single quiet room, and if possible, the same staff, the same clinician should take care of them. We should encourage relatives to visit more frequently and at night the lighting should be enough to allow orientation but not too much to impair sleep. Finally, for hallucinations, if for example, they see snakes; we reassure them that they can see them, but they are not real, they are part of your illness.

Antipsychotics are the first-line pharmacological treatment, but their use is limited by their side effects, especially sedation and anticholinergic effects. So, they are only used to control severe agitation and improve sleep. Haloperidol at a slight dose is most used for this purpose because it has a suitable effect and side-effect profile for delirium.

Prognosis

Many cases recover quickly. But the mortality is considerable. Prognosis relates to the underlying cause.

Regarding mortality, around one in 4 patients may die over the following three months. Just to be clear, mortality differs from case fatality. We always express mortality with a period, in a specific population. Here, it is also a crude death rate because the actual causes are always multiple. Case fatality is cause-specific mortality, so we can never relate it to delirium because delirium never causes death. The risk of death doubles over the next two years after an episode of delirium. Again, this is the standardised mortality ratio. The rate of death in patients with delirium compared to its rate of the population over two years.

Delirium has a complex relationship with dementia. Dementia predisposes to delirium. Similarly, delirium increases the risk of dementia. It also acts synergistically with the underlying neuropathology to increase the risk of cognitive decline.

Now, the elderly, people with dementia or physical illness, have a poor outcome. Which makes sense. Because, in old age, people have already become physically weak. Similarly, we just said delirium speeds up the rate of dementia so we can understand that. People with a pre-existing physical illness, for example, asthma, are more likely to die from the condition that caused delirium.

Causes of Delirium

Mnemonic: "COLD-PATHES"

• Constipation, cerebral haemorrhage
• Opiates, organ failure (liver, heart, kidney)
• Lithium
• Digoxin, diuretics, dehydration
• Pain, postoperative hypoxia
• Alcohol (intoxication, withdrawal), anticholinergics
• Thiamine deficiency
• Hypo/hyperglycaemia
• Encephalitis, epileptic fits
• Steroids, sedatives, septicaemia, space-occupying lesion, sensory deprivation

Functional Magnetic Resonance Imaging (fMRI)

Functional Magnetic Resonance Imaging (fMRI)

Introduction

Structural imaging reveals the static physical characteristics of the brain. It makes it useful in diagnosing disease. Functional imaging reveals dynamic changes in brain physiology that might correlate with cognitive functioning, for example. Neural activity consumes oxygen from the blood. This triggers an increase in blood flow to that region and a change for deoxyhemoglobin in that region. As the brain is always physiologically active, functional imaging needs to measure relative changes in physiological activity.

The most basic experimental design in functional imaging research is to subtract the activity in each part of the brain whilst doing one task away from the activity in each part of the brain whilst doing a slightly unfamiliar task. We call this cognitive subtraction.

Other methods, including parametric and factorial designs, can minimize many of the problems associated with cognitive subtraction. There is no foolproof way of mapping a point on one brain onto the putatively same point on another brain because of individual differences in structural and functional anatomy.

Current imaging methods cope with this problem by mapping individual data onto a common standard brain (that is, stereotactic normalization) and by diffusing regions of significance (a process we call smoothing).

A region of activity refers to a local increase in metabolism in the experimental task compared to the baseline, but it does not mean that the region is essential for performing the task. Lesion studies might provide evidence concerning the necessity of a region for a task.

Functional imaging can make crude discriminations about what someone is thinking and feeling and might outperform the traditional lie detectors. However, it is highly unlikely that they will ever be able to produce detailed accounts of another person’s thoughts or memories.

An fMRI measures regional cerebral blood flow. Cognitive functions are region-specific, if a task involves a certain cognitive function, the areas involved will become more active, need more oxygen and more blood. fMRI measures regional levels of blood oxygen by detecting magnetic changes in red blood cells when they become deoxygenated

Magnetic Resonance Imaging

Magnetic resonance imaging creates images of soft tissue in the body, which x-rays pass through undistorted (so computerized tomography would not capture well). The density/intensity of the images is water-based, with different amounts of water for different tissues. It enables a 3D image of the layout of these tissues. Structural MRI produces a static image of the brain structure. It has a high spatial resolution. It is used to overlap functional images on to.

Metal items and MRI

We remove metal items before the functional imaging because the strong electromagnetic fields will attract them. Patients who use pacemakers cannot have magnetic resonance imaging or its functional variant.

Underlying Mechanisms of fMRI

The fMRI uses a strong magnetic field to line up protons. It measures oxygenated blood by recording the spin of protons, which have a magnetic charge. After aligning protons in fMRI it sends a radio pulse through the lined-up protons, to record how they resonate.

Different proton resonance patterns.

Different protons (different tissues) resonate differently (magnetic susceptibility), allowing the composition of a tissue image. fMRI uses the differential response of oxygenated and deoxygenated blood for the imaging. Oxygenated blood resonates differently from deoxygenated blood, allowing the composition of an (indirect) image of the brain activity.

It is T1-contrast (measures a different magnetic property to functional scans).

The spatial resolution of fMRI

Although fMRI is not as spatially resolute as MRI, it can record 3x3x3 mm and more detail with a 7T (stronger tesla coil strength) scanner.

Both spatial and temporal T2 contrast rely on tesla strength. Temporal T2 contrast measures a different magnetic property to structural scans.

In structural MRI, the magnetic field aligns protons. It aligns protons in water molecules that have weak magnetic fields, initially randomly oriented, but some align with the external field.  A radio pulse knocks orientation by 90 degrees, which leads to a change in the magnetic field. After this change in the magnetic field, the protons become stead and we can repeat the procedure for fresh slices of the brain. A whole-brain image in 2 seconds (3 mm slices) 1: relaxation time. T1-images structural scans.

It relies on the brain to store a large amount of oxygen and glucose. It does not store oxygen though still consumes around 20% of the body’s oxygen supplies. The brain tissue does not store oxygen; oxygen must be supplied from the fresh blood supply. Active tissue consumes more oxygen compared to less active brain tissue. Oxygen-rich blood is lost in areas of higher brain activity.

Magnetic properties of blood

Oxyhemoglobin is diamagnetic while deoxyhemoglobin is paramagnetic. Hemoglobin molecules resonate differently in these different magnetic states.

Diamagnetic substance

A diamagnetic is magnetic when exposed to the external magnetic field for example oxyhemoglobin.

Paramagnetic substance

A paramagnetic substance is normally magnetic for example deoxyhemoglobin.

Blood Oxygenation Level Dependent (BOLD) Signal?

It compares the level of oxygenated with deoxygenated blood derived from the magnetic properties of blood. It is an indirect measure of brain activity.

Factors on while BOLD Signal depends:

1) Cerebral metabolic rate of oxygen (goes up when tissue is active *of genuine interest* more oxygen when spending energy, so de-oxygen goes down)

2) Cerebral blood flow

3) Cerebral blood volume

fMRI compares the differences between magnetic spins of protons in oxygenated blood and deoxygenated

Hemodynamic Response Function.

Initial Dip

Neurons consume oxygen leading to a small rise for deoxyhemoglobin causing reduction of BOLD signal.

Overcompensation

In response to the increased consumption of oxygen, blood flow to the region increases. Increased blood flow is greater than increased consumption >> BOLD signal increased

Undershoot

Blood flow and oxygen consumption dip before returning to original levels. This may reflect a relaxation of the venous system.

Active' areas

Active areas in fMRI refer to a physiological response that is greater relative to some other conditions. To label active areas, we need a baseline response, well-matched to the experimental task. Example: Petersen, Fox, Posner, Mintun, and Raichle (1988) Study brain activity involved in word recognition, phonology, and retrieval of word meaning, cognitive subtraction.

Research designs can exploit this difference by finding two tasks, an experimental task and a baseline task, which differ in terms of a few cognitive components.

Subtraction design

Subtraction is taking a task with the cognitive component in it, and then subtract another task with only that component is taken out

Neuronal structures underlying a single process P

Contrast: [Task with P] [control task without P].

Conjunction

Conjunction requires a set of orthogonal tasks that has a particular component in common. Look for regions of activation that are shared across several subtractions. A test for such activation common to several independent contrasts is called a conjunction. It resembles a factorial design in ANOVA.

Issues with subtraction design

1)    The assumption of pure insertion is the assumption that we can insert a single cognitive process into another set of cognitive processes without affecting the functioning of the rest.

2)    At baseline the brain is always active, and the level of activity is not consistent which makes it challenge where to make comparisons.

Donders coined the term pure insertion as a criticism of reaction time methods. One way to minimize the baseline/pure insertion problem is to isolate the same process by two or more separate comparisons and inspect the resulting simple effects for commonalities. 

Example of this cognitive subtraction in Petersen, Posner 1998

Brain activity involved in word recognition, phonology and retrieval of word meaning cognitive subtraction e.g. contrasts passive viewing of (words vs fixation cross) e.g. (read aloud word vs look at the word) e.g. generate (a word associated with viewed word vs read aloud a written word)

The issue with pure insertion is that adding an extra component does not affect the operation of earlier ones in the sequence.  BUT: interactions are likely to occur– Baseline task: should be as like the experimental task as possible.

Examples of conjunctions and factorial designs by Frith:

1)    Why cannot we tickle ourselves (Blakemore, Rees, and Frith,1998).

2)    Factors touch (felt/not) self-movements (moved/not)

Parametric fMRI design

To get around baseline continuous manipulation of the factor of interest. We treat the variable of interest as a continuous dimension rather than a categorical distinction. Associations between brain activity rather than differences between two or more conditions. passive listening to spoken words at six different rates. Different brain regions show different response profiles to different rates of word presentation. Adapted from Price et al. (1992), and Friston (1997). no baseline necessary.

Functional specialization

Functional specialization: region responds to a limited range of stimuli/conditions. This distinguishes it from the responsiveness of other neighboring regions (no localization).

Functional integration

How different regions communicate with each other. It models how activity in different regions is interdependent. Effective connectivity or functional connectivity between regions when performing a task. Use techniques like the principal component analysis. 

Example:

A word production vs repeating letters in patients with schizophrenia and controls.

Block design

In a block design, stimuli in one condition are grouped. Strong BOLD contrast: higher signal-to-noise ratio simple design and analysis - practice/fatigue effects cannot be used when participants should not know which condition is coming next.

Event-related design

When stimuli are presented completely randomly, we call it event-related (new as temporal difficulties, etc.) design.  This design works with infrequent and random stimuli. If conditions defined by the participant-sorting what happened in a trial (e.g. correct/incorrect trials; biostable percept (Necker cube); the presence of a hallucination - see right). Different stimuli or conditions are interspersed with each other (e fMRI). Intermingled conditions are subsequently separated for analysis. no practice/fatigue effects can be used when participants should not know which condition is coming next: randomization can be used when trials can only be classified after the experiment- weaker BOLD contrast: lower signal-to-noise ratio more complex design and analysis

Session

a scanning session, all the data collected from a participant. Usually comprises a structural scan and several runs of functional scans.

Run

A continuous period of scanning consists of a specified number of volumes

Volume

A Set of slices taken in succession: a 3D spatial image, with a temporal dimension. Expressed in TR (Repetition Time): how long does it take to acquire a volume.

Epoch

A period when a certain condition is presented. Conditions (epochs) can be grouped (blocked design) or randomly intermixed (event-related design).

Correcting for head movements:

Spatial resolution >> small spatial distortions–Individual differences in brain size and shape stereotactic normalization (adjust the measurement of overall dimensions to the 'standard brain'– Individual head aligned differently in scanner over time due to movements. Regions are harder to detect False-positive results. Physically restraining head (using foam or something) and participant instructions Correction

Smoothing

Spreads some raw activation level of a voxel to neighboring voxels. Smoothing enhances signal-to-noise ratio Compensates for individual differences in anatomy.

Assumption

Smoothing assumes that Cognition does not occur in single voxels. Increases the spatial extent of the active region. more likely to find overlap between participants

Steps of fMRI Analysis

Individual differences “averaging over many participants–Correction for head movement– Stereotactic normalization–Smoothing–Statistical comparison

Stereotactic normalization

Mapping regions on each brain onto a standard brain (brain template is squashed or stretched until it fits). Tailarach and Tournoux (1988).

Brain Atlas (based on one brain), Tailarach coordinates–X left/right–Y-front/back–Z top/bottom.

Alternative: Montreal Neurological Institute (average of 305 brains)—Voxels (volume elements), 3-D coordinates.

Tens of thousands of voxels “capitalization on chance Lower significance level (Bonferroni). Choosing a statistical threshold based on spatial smoothness (random field theory).

Analyze the pre-determined region. Reported, corrected, or uncorrected statistical parameters (ROI?)

We start a stat comparison by dividing up data according to design-then perform stat comparison.

Three points of interpretation:

1)    Inhibition versus excitation

2)    Activation versus deactivation

3)    Necessity versus sufficiency.

Inhibition versus excitation?

Functional imaging signals are assumed to be related to the metabolic activity of neurons, and synapses. However: activity can be excitatory or inhibitory. The BOLD signal is more sensitive to neuronal input into a region than the output from the region. Unclear whether functional imaging can distinguish between two neural functions.

Activation versus deactivation

Activation/deactivation Merely refers to the difference between the two conditions. Does not say anything about the direction of the difference.

Necessity versus sufficiency

Necessity: Are active regions critical to the task? Sufficiency: functional imaging shows us active regions, but these may not be crucial. Use methods in conjunction with other methods. 

Positron Emission Tomography (PET)

Positron Emission Tomography is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, regional chemical composition, and absorption. They use different tracers for different imaging, depending on the target process within the body. We inject a radiopharmaceutical—a radioisotope attached to a drug—into the body as a tracer. Gamma cameras emit and detect Gamma rays to form a three-dimensional image, similar to that of an X-ray image. Positron-emission tomography scanners can incorporate a computerized tomography scanner, and we call them positron-emission tomography-computerized tomography scanners. One disadvantage of a positron-emission tomography scanner is its high initial cost and ongoing operating costs.

Applications

Positron-emission tomography can give information about:

1. Metabolic changes
2. Regional cerebral blood flow
3. Ligand binding

Clinical Uses 

We can use positron-emission tomography in the assessment of several neurological conditions. It is especially helpful for differentiating dementia of Alzheimer's type from frontotemporal dementias. 

1. Cerebrovascular disease
2. Alzheimer’s disease
3. Epilepsy, prior to neurosurgery
4. Head injury

Pneumoencephalography

Pneumoencephalography (sometimes abbreviated PEG, and some knew it as an "air study") was a common medical procedure in which they would drain most of the cerebrospinal fluid from around the brain with a lumbar puncture and replaced it with air, oxygen, or helium to allow the structure of the brain to show up more clearly on an X-ray image. 

They derived it from ventriculography, an earlier and more primitive method where they would inject the air through holes drilled in the skull.

Risk factors for Parkinsonism

The following are some risk factors for Parkinson's disease. 

1. Pesticide exposure
2. Head injury
3. Drinking well water
4. Agricultural occupation
5. Use of beta-blockers.

Neuropsychiatric manifestations of Parkinson's disease

Mental state findings:

• Mood: depression, mania, apathy


• Cognitions: cognitive decline 


• Thoughts: delusions


• Perceptions: hallucinations, cheifly visual. 


• Appearance and behavior : stupor 

Conditions /Disorders:

• REM sleep behavior disorder 


• Sexual dysfunction 


• Mania


• Depression


• Delirium 


• Impulse control disorders

Tourette Syndrome

Clinical features

>> Diagnostic and Statistical Manual of Mental Disorders, 5th Edition.

• Multiple vocal and motor tics 
• Starting before the age of 18 and 
• Persisting for a duration of at least one year
• We have excluded other causes of tics.

LOSE

Learning difficulties 

Overactivity 

Social problems 

Emotional disturbances

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Maudsley Prescribing Guidelines (13th Edition) 

They recommend alpha-2 agonists such as Clonidine or Guanfacine as the first-line pharmacological treatment for Tics and Tourette Syndrome 

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American Family Physicians and Canadian Guidelines

Antipsychotics possess a variety of serious adverse effects (Pringsheim et al., 2012) and even though the evidence base for them is strong, we use them in cases not responding to alpha-2 agonists.

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References

1. Taylor, D. (2018). The Maudsley Prescribing Guidelines. The Maudsley Prescribing Guidelines. 
2. Kenney, C., Kuo, S.-H., & Jimenez-Shahed, J. (2008). Tourette’s syndrome. American Family Physician, 77(5), 651–658. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/18350763
3. Pringsheim, T., Doja, A., Gorman, D., McKinlay, D., Day, L., Billinghurst, L., … Sandor, P. (2012). Canadian Guidelines for the Evidence-Based Treatment of Tic Disorders: Pharmacotherapy. The Canadian Journal of Psychiatry, 57(3), 133–143. 

Cognitive Deficits in Multiple Sclerosis

Impairment of learning, abstraction, memory, and problem-solving occur in patients with multiple sclerosis. These impairments are present in 40% of patients with multiple sclerosis in the community. Sometimes, it is an early manifestation. 

1. Mostly the impairments are seen later in the course.
2. The impairments are mild and progress slowly. 
3. Well-practiced verbal skills are often preserved. 

Cognitive impairment correlates with total lesion load and degree of callosal atrophy on brain imaging. 

LAMP

• Learning
• Abstraction
• Memory
• Problem-solving

Clinical features of complex partial sezires, Mnemonic

"Pardon DJ Hell, you are Producing GAS that is AFFECting All the Fearful TEDS, CoSTing them MaDness" 

Perceptual:

• Distorted perceptions, Deja Vu


• Jamais Vu


• Hallucinations 

Psychomotor

• Grimacing and other body movements 


• Automatisms


• Stereotyped behaviors

Affective

• Fear and anxiety


• Euphoric or ecstatic states

Autonomic and visceral 

• Flushing


• Tachycrdia 


• Epigastric aura


• Dizziness


• Other bodily Sensations

Cognitive

• Speech disturbances


• Thought disturbances


• Memory disturbances


• Depersonalization, derealization 

Better imaging study for the assement of change in behavior

Patient has change in behavior. Would it be preferable to use CT with contrast or without contrast for assessment ?LikeShow more reactions

Comments

Sarmad Mushtaq Ct withcontrast 

Immo Mani With contrast

Valeed Ahmed Yess with contrast,,, inflammation and tumors etc can create change in behavior that can be better viewed by contrast enhanced CT, contrast agents can not enter the BB barrier except in arease of inflamation where the barrier is damages ir tumor where it is not formed,,,so the contrast enters there very well, making the area distinct due to more absroption of radiation

Mechanism of Dementia in Downs Syndrome

Which of the following is responsible for dementia seen in adults with Down’s syndrome?

A. Loss of genetic material in chromosome 21
B. Extra genetic material in chromosome 21
C. Genetic material lost from chromosome 14
D. Loss of genetic material corresponding to presenilin -1
E. Loss of genetic material corresponding to Apoe4

Ok extra genetic material is the correct answer. The gene that codes for b amyloid is located on chromosome 21. Since down syndrome is due to trisomy 21 so there is increased amount of genetic material that production of its product proteins. Product protein of the APP gene located on chromosome 21 is beta amyloid that is central to the aetiology of alzheimers

Sensory stimulation therapies for dementia

WAMB

• White noise


• Aroma therapy


• Music therapy, Massage


• Bright light therapy

Corticobasal Degeneration

Corticobasal ganglionic degeneration present with asymmetric basal ganglia (akinesia, rigidity, dystonia) and cerebral cortical (apraxia, cortical sensory loss, alien limb) manifestations. We see the alien limb with parietal lobe, medial frontal lobe, and corpus callosum pathology. Dementia is a variable but may be the presenting symptom. 

Oculomotor involvement like that in progressive supranuclear palsy may occur. But the major difference between PSP and corticobasal degeneration is that the latter is with limb coordination problems, and the former is with balance and walking problems. 

Prognosis

Survival ranges from 2.5 to 12 years, with a median of about 8 years. 

Neuropathology

Corticobasal degeneration pathology shows abundant ballooned, achromatic neurons, and focal cortical atrophy predominating in medial frontal and parietal lobes, plus degeneration of the substantia nigra. We also see astrocytic plaques in the cortex. corticobasal degeneration: neuronal tau pathology shows wispy, fine-threaded tau incus. Magnetic resonance imaging may show asymmetric atrophy in the frontal and parietal lobes contralateral to the dominantly affected limbs. 

Treatment

We have limited treatment options for corticobasal degeneration, with only a minority of patients responding to L-dopa preparations given for parkinsonism. Myoclonus may respond to benzodiazepines, particularly clonazepam. No specific treatment for dementia is available, but it may not be cholinergic, suggesting that cholinesterase inhibitors are of limited value. Depression is common in corticobasal degeneration, but few data exist on treatment response. 

Clinical Manual of Neuropsychiatry, 2017

Single-photon Emission Tomography SPET

Single-photon Emission Tomography SPET

Principle

uses single-photon (gamma-ray) emitting isotopes

given IV or inhaled

the resolution is lower than PET

Uses

SPET can give information about:

regional cerebral blood flow

ligand binding

Clinical uses include:

Alzheimer’s disease

When the symptomatology (e.g. hallucinations, epilepsy) occurs when the patient is not near a scanner; we can give a suitable ligand at the material time and the patient scanned afterward

Schizophrenia

reduced rCBF in frontal regions—‘hypofrontality’

Affective disorders

as that in schizophrenia, with reversal after antidepressant therapy

Alzheimer’s disease

decreased rCBF in posterior parietal and temporal regions

Xenon inhalation

Shows the failure of activation of frontal lobes in schizophrenics performing the Wisconsin Card Sorting Test