Transcript Psychiatric Disorders - McCausland Center | Brain Imaging

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Psychiatric disorders
Peter Liddle
Chris Rorden
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Disorders of Mind & Brain
 Mind and brain are two sides of one coin;
disorders of the mind are disorders of the
brain.
 Particular clusters of symptoms (syndromes)
tend to occur together in various different
mental illnesses
 The ways in which symptoms cluster together
tells us something about the structure of the
human mind and brain
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Anatomy of psychiatric disorders
Contemporary psychiatry implicates
neurotransmitters rather than anatomy.
– Schizophrenia :: dopamine
– Depression :: serotonin
To some degree, this may reflect the
popular treatments – neurotransmitters
specific to brain regions.
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Major symptom clusters
Reality distortion
Disorganization
Psychomotor poverty
Psychomotor excitation
Depression
Euphoria
Anxiety
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Reality distortion
Mismatch between representation of
reality in individual’s mind and
representation supported by objective
evidence
Hallucinations and delusions
– Tend to occur together
– Tend to respond similarly to dopamine
blocking medication
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 Hallucination: perception with quality of a
sensory perception but nor derived form
stimulation of a sense organ
– Individual usually falsely attributes perception’s
origin to external world
 Delusion: fixed belief derived by erroneous
inference or unjustified assumption that cannot
be accounted for by culture or religion
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Delusions
 Delusions usually false but the key issue is lack
of rational grounds and fixity.
 Ability to engage in logical deduction about other
issues is usually intact; certain ideas seem
exempted from the need for logic.
 Non-psychotic distortions of reality (eg in OCD
or in non-psychotic depression) reflect biased
thinking but are less resistant to debate
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Psychotic Reality Distortion
Can occur in schizophrenia, mania,
psychotic depression, brain injury or
degeneration
Themes: persecution; alien control,
religion, grandiosity, guilt
Influenced by culture, but some themes
are common across cultures
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Reality distortion in schizophrenia
Characteristic forms (but not present in every
case)
– Delusions of alien influence over thought,
volition, action, affect, bodily function –
characteristic
– Third person auditory hallucinations
Less specific but common forms:
– Persecutory delusions (52%), delusions of
reference (50%)
– Second person auditory hallucinations
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Affective psychosis
 Mood disorder with psychotic features is diagnosed
if psychotic illness is dominated by mood symptoms
unless there is reality distortion without substantial
mood symptoms for at least two weeks
 Delusions and hallucinations are usually mood
congruent (eg guilt, worthlessness, critical voices with
depressed mood; grandiose delusions and selfreinforcing halluciations in mania)
 Reality distortion shows similar response to
antipsychotic medication irrespective of diagnosis
Neuropsychological correlates of reality
distortion
 Reality Distortion can occur in absence of
general defect in reasoning.
 Defective internal monitoring of self-generated
mental activity (Frith & Done 1989; Mlakar et al,
1994)
 Jumping to conclusions – the bead test (Huq et
al, 1988)
 Patients with persecutory delusions tend to
attribute negative outcomes to external causes
(Bentall, 1994)
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Regional cerebral activity and reality
distortion
 Early SPECT studies reported over-activity in
medial temporal lobe (eg Musalek et al 1989)
 More recent PET studies demonstrate
overactivity in left parahippocamapl gyrus and
hippocampus (Liddle et al 1992; Silbwersweig
et al, 1995)
Liddle et al, 1992
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Neurochemistry and pharmacology of
reality distortion
Antipsychotic drugs that block dopamine
D2 receptors decrease reality distortion
Dopamine agonists (eg amphetamine,
cocaine) exacerbate delusions and
hallucinations
Amphetamine produces greater increase
in intra-synaptc dopamine in schizophrenia
than in healthy individuals (Laruelle et al
1996)
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Pharmacology of reality distortion
 Serotonin = 5-hydroxytryptamine, or 5-HT
 5HT2 receptor agonists such as LSD (which
reduce 5HT signalling via autoreceptors) are
hallucinogenic
 Glutamatergic blockers (eg ketamine) can also
produce reality distortion
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Hypothesis for generation of reality distortion
 Episodic memories rely on context for evaluation and validation;
semantic memories (eg Paris is capital of France) do not require
contextual validation
 Neural circuits in hippocampus generate a ‘validation’ signal when a
mental event (eg an episodic memory) fits its context promoting
consolidation of the memory
 Aberrant hippocampal firing might reinforce incidental thoughts
irrespective of context and allow consolidation without need of
contextual validation – delusion formation
 Internal speech might be processed without context thereby
becoming detached from internal source- hallucinations
 Dopamine hyperactivity might reinforce the effect of hippocampal
overactivity via the striato-thalamo-cortical feed back loops which
mediates the hippocampal signal (This might be blocked by
antipsychotic drugs)
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Disorganization syndrome
 Disjointed thought, emotion, behaviour
 Formal thought disorder, inappropriate affect,
bizarre behaviour
 Speech shows ‘looseness of associations’,
‘derailment’, replies can be tangential or
incoherent
 Occurs in schizophrenia (a core feature);
mania (less commonly); frontal lobe damage.
 Severity of disorganization is strong predictor
of poor occupational and social function
Neuropsychological correlates of
disorganization
Core executive processes, especially the
selection between competing mental
events. Poor Stroop performance (Liddle
& Morris, 1991);Errors of commission in
CPT (Frith et al 1992)
Abnormal spreading of semantic and
phonological associations (Spitzer et al
1994)
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Regional cerebral activity and
disorganization
Liddle et al, 1992
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Regional cerebral activity and
disorganization
 PET study (Liddle et al 1992):
– increased activity in medial frontal cortex/anterior
cingulate & thalamus;
– decreased activity in ventral prefrontal cortex, insula,
temporoparietal junction
 SPET studies (Ebmeier et al 1993; Yuasa et al, 1995)
– replicate finding of increased activity in medial
prefrontal cortex/ anterior cingulate (ACC)
 ACC strongly engaged in response selection, eg
in Stroop task
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Psychomotor poverty and excitation
Abnormalities of the rate at which the mind
generates thoughts, feelings and actions
 Psychomotor poverty:
 Psychomotor excitation
– Poverty of speech
– Pressure of speech
– Flat affect, anhedonia
– Excited or irritable mood
– Decreased voluntary
activity
– Motor hyperactivity
Psychomotor poverty & excitation:
context
 Psychomotor poverty
– Schizophrenia
(negative symptoms)
– Retarded depression
– Frontal lobe injury or
degeneration
– Basal ganglia
degeneration (eg
Parkinson’s disease
 Psychomotor excitation
– Mania
– Acute schizophrenia
– Basal ganglia
degeneration eg
Huntingtons’ disease
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Neuropsychological correlates of
psychomotor poverty
Associated with
– impaired memory,
– Abstraction
– Initiation and planning of activity
Decreased verbal fluency (Liddle & Morris, 1992;
Norman et al 1997)
Increased RT in choice RT tasks (Ngan & Liddle,
2000)
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Regional cerebral activity and
psychomotor poverty
Liddle et al, 1992
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Psychomotor poverty and brain structure
In schizophrenia; some studies report
psychomotor poverty is associated with
ventricular enlargement (Lewis, 1990)
Neurochemistry & pharmacology of
psychomotor poverty
Dopamine metabolism decreased (van
Praag & Korf, 1971)
Stimulants can reduce apathy (Marin et al
1995)
Dopamine blocking antipsychotics can
exacerbate psychomotor poverty (van
Putten et al, 1990)
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Neurochemistry & pharmacology of
psychomotor excitation
Drugs that promote dopaminergic
neurotransmission (eg amphetamine)
produce psychomotor excitation in
healthy people (Jaobs and Silverstone,
1986)
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Depression & Elation
 Depression
– Low mood disproportionate to
circumstances
– Sad facial expression, voice,
posture
– Anhedonia
– Cognitive distortions –negative
bias, including low selfesteem, guilt, hopelessness,
suicidal thought
– Somatic symptoms (loss of
sleep, appetite, libido etc)
– Sometimes associated with
psychomotor poverty
 Elation
– Euphoric mood
– Animated expression
– Elevated self-esteem and
optimism
– Decreased need for sleep
– often associated with
psychomotor agitation
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Mood disorders
Depression can occur in
– Major depressive disorder (15-20% of pop)
– Bipolar affective disorder (2% of pop)
– Brain injury or degeneration
– Drug induced mood disorder
– Schizophrenia (depression in >50% of
cases)
Neuropsychological correlates of
depression
Processing bias, preferential recall or
attention to negative material (Gotlib,
1991)
Decreased speed of processing
(Weingartner et al, 1981)
Impaired declarative memory (Zakzanis et
al, 1998)
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Brain structure and mood disorders
Decreased grey matter in (sub-genual)
anterior cingulate cortex in bipolar
disorder and in major depression
(Drevetts et al 1997)
Decreased hippocampal volume
associated with duration of illness
(Sheline et al, 1996). Possibly due to
damage by elevated cortisol during acute
episodes
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Regional cerebral activity and depression
 decreased activity in lateral prefrontal cortex
resolves as symptoms resolve (Baxter et al
1989).
 overactivity in anterior cingulate during acute
episodes (Mayberg et al, 1998)
 evidence underactivity in anterior cingulate and
medial prefrontal cortex in those prone to
relapse and also in cases that respond poorly
to treatment (Bench et al, 1992)
Regional cerebral activity associated
with elation
Global increase in regional brain activity
during manic episodes (elation +
psychomotor excitation) (Baxter et al
1985)
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Regional cerebral metabolism in bipolar
disorder (Baxter et al 1985)
• Depression
• Mania
• Depression
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Neurochemistry and pharmacology of
mood disorders
 Depression
– Depression is decreased by drugs that enhance
monoamine neurotransmission eg SSRIs such as
fluoxetine (Prozac) & SNRIs such as venlafaxine –
this suggests that serotonin and noradrenaline
neurotransmission is under-active in depression, but
evidence is inconclusive
– Cortisol regulation is disrupted– maybe this is the
core biochemical abnormality
 Elation
– Associated with increased dopamine
neurotransmission
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Bipolar affective disorder
 Genetic influence
– High concordance of bipolar affective disorder in monozygotic
twins between 0.67 and 0.85 (Glahn et al. 2004)-indicate
environmental factors must have a role to play.
– Occurs around the world at a consistent prevalence, suggests
alleles have been present for a long time.
 Why does this gene survive? Does it pose a benefit. As
an analogy, sickle cell trait can lead to illness but is
recessive and helps resistantance to malaria.
– In low doses the symptoms of hypomania could be
advantageous: increase in energy, faster thoughts, less sleep.
– Rates of mood disorders elevated among creative individuals
(Richards and Kinney, 1989; Jamison, 1989)
– Individuals with bipolar traits more likely to be leaders within
social groups (Gardner, 1982)
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Anxiety
 Feeling of unease, dread, fear together with
symptoms reflecting over-activity on the
sympathetic nervous system
–
–
–
–
–
–
Generalised anxiety disorder
Panic disorder - brief dramatic episodes
Specific phobias eg fear of spiders
Agoraphobia - fear of public places
Post-traumatic stress disorder
Obsessive-compulsive disorder
 Anxiety disorders frequently coexist, and are
often associated with depression
Regional cerebral activity associated
with anxiety
Provocation of anxiety produces
activation of frontal, limbic and paralimbic
cortex in patients and in healthy people
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Pharmacology of anxiety
Benzodiazepines (which promote GABA
activity) – effective anxiolytics but
addictive
Antidepressants are also effective antianxiety drugs
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Concepts of schizophrenia
 Characteristic symptoms
– Positive – presence of abnormal mental activity
Reality distortion
Disorganization
– Negative – diminution of normal mental activity
Psychomotor poverty
 Many other symptoms: psychomotor excitation;
depression
 Onset tends to occur early in adult life
 Deterioration in function (variable in degree)
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Reality distortion
 Delusions
–
–
–
–
–
*Thought insertion, withdrawal, broadcast
*Control – made will, made acts, made affect
*Somatic passivity
*Delusional perception
Persecution etc
 Hallucinations
– *Third person auditory (commenting, discussing); Audible
thought
– Second person auditory
– Olfactory, visual, tactile
* Schneider’s first rank symptoms
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Age of onset
male
female
10
20
30
40
50
years
From Jennen-Steinmetz et al 1997
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Characteristic time course
prodrome 1st acute relapse
epidsode
relapse residual
phase
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ICD 10 diagnostic criteria
 At least one strongly characteristic symptom
– Schneiderian first rank symptom (eg 3rd person hallucination;
delusion of control.)
– Persistent bizarre delusion
 OR two less characteristic symptoms
–
–
–
–
Other hallucinations
Formal thought disorder
Catatonia
Negative symptoms
 Duration: at least one month
 Exclusion of affective psychosis; exclusion of
overt brain disease, or drug toxicity
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Aetiology : predisposing factors
Genes
– twin concordance: MZ 45%, DZ 12-15%
– adoption: risk is determined by biological
parent
 Intra-uterine insult
– Maternal viral infection
– Maternal starvation
– Maternal stress
 Birth complications
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Aetiology: precipitating factors
Stress
Drug abuse– amphetamine, cocaine,
– marihuana etc
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Brain structure in schizophrenia
Ventricular enlargement (but effect size is
only 0.6 – therefore most cases in nromal
range)
Loss of grey matter in many brain
regions, most marked in medial temporal
lobe and thalamus
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Cognitive deficits in schizophrenia
•Executive function, attention,
memory (e.g. Green, 1998)
• Variation over time and between
patients is complex, symptoms tend
to be worse during acute episodes,
but also present during remission
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Pharmacology
Typical antipsychotics: eg
chlorpromazine; haloperidol: block
dopamine - alleviate reality distortion,
disorganization and excitation
Atypical antipsychotics: block dopamine
+ other transmitters (eg serotonin).
Slightly greater efficacy against positive
symptoms; moderate effect on negative
symptoms, small improvment in cognition
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Bipolar mood disorder
 Depressive episode
– Depressive syndrome
 Sad mood, anhedonia
 Negative thoughts,
hopelessness, suicidality
 Guilt (can be delusional)
 Somatic symptoms
often accompanied by:
– Psychomotor poverty
(retarded depression)
or
– Psychomotor excitation
(agitated depression)
 Manic episode
– Psychomotor excitation
 Elation or irritability
 Pressure of speech
 Overactivity, reduced
need for sleep
often accompanied by:
– Grandiose reality
distortion
 Grandiose delusions
 Mood congruent
hallucinations
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Aetiology of bipolar disorder
Genetics
• Concordance for affective disorders is 67% in
monozygotic twins and in 20% in dizygotic
twins (Bertelson et al., 1977), genetic factors
for unipolar depression related by partially
distinguishable
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Anatomy of bipolar disorder
Ventricular enlargement (e.g.
Pearlson & Veroff, 1981) usually
less marked than in schizophrenia
• Decreased grey matter in
anterior cingulate (Drevets et al.,
1997)
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Pharmacology of bipolar disorder
 Antipsychotics (which block dopamine):
effective in treating psychomotor excitation and
reality distortion during acute episodes of
mania
 Mood stabilizers (eg Lithium, and various
anticonvulsants)
 Antidepressants have a limited role as they
promote mania
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Psychopathy
• A personality disorder (enduring
throughout adult life) with two main
groups of features:
– Callous disregard for others (Lack of
empathy; lying; manipulative; glib; shallow
affect; lack of remorse or guilt)
– Impaired regulation of behaviour (impulsivity,
irresponsibility; need for stimulation)
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Aetiology of psychopathy
 Genes
– Concordance for antisocial personality disorder is
51% in monzygotic twins and 22% in dizygotic twins
 Brain injury:
– damage to frontal lobes in infancy can lead to
psychopathy
– Frontal damage in adulthood can produce
pseudopsychpathy – impaired behavioural
regulation without callousness (Phineas Gage)
 Adverse social circumstances ?
Cognition and information processing in
psychopathy
 Psychopaths do not show widespread
cognitive impairments (Hart et al., 1990), but
there is evidence of orbital frontal cortex
dysfunction (Lapierre et al., 1995)
 Reaction time to affect-laden words reduced in
healthy people but not psychopaths in lexical
decision task (Williamson et al, 1991); less
limbic activation while processing affect laden
words (Kiehl et al 2001)
 Abnormal ERPs for response inhibition (Kiehl
et al., 2000) and target detection (Kiehl et al
1999)
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Psychopaths exhibit a large fronto-central negativity during stimulus
detection tasks that is also present in patients with anterior temporal lobe
lesions (Kiehl et al., 1999)
Kiehl et al.
Yamaguchi & Knight (1993)
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Nonpsychopaths
Psychopaths
Johnson (1989)
800ms
Controls
Temporal lobe
damaged patients
Parietal lobe
damaged patients
5001000ms
Controls
Temporal
lobectomy