Schizophrenia

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Schizophrenia

• Stacy Zeigler

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NIMH

• Schizophrenia is a chronic, severe, and disabling
  brain disorder
• Affects 1.1 of the U.S. population age 18 and
  older in a given year.
• People with schizophrenia sometimes hear voices
  others dont hear, believe that others are
  broadcasting their thoughts to the world, or
  become convinced that others are plotting to harm
  them.

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• Symptoms develop in men- late teens or early
  twenties
• women in the twenties and thirties, but in rare
  cases, can appear in childhood.
• Hallucinations, delusions, disordered thinking,
  movement disorders, flat affect, social
  withdrawal, and cognitive deficits

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Brain Research Reviews (2009)

• Superior temporal gyrus volume change in
  schizophrenia a review on region of interest
  volumetric studies

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Superior temporal gyrus (STG)

• Production, interpretation and self monitoring of
  language implicated in AH
• Superior temporal gyrus
• 1 of 3 gyri in temporal lobe
• Brain volume/structure change may be linked to a
  brain region

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Region of Interest (ROI) analysis

• STG structural differences
• Advantages
• Anatomical validity, definition of landmarks in
  native space and quantitative measures of voxels
• Limitations
• Labor intensive and time consuming

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Studies considered

• Published up to July 2008 as an article
• Compared schizophrenia patients with healthy
  group
• Data on volume of STG and its subregions
• Used ROI volumetric method
• Individuals with schizophrenia and related
  diagnoses
• Early onset schizophrenia included
• Follow-up included

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Details

• 2771 subjects
• 1444 patients
• 1327 controls
• 46 studies (5follow up)
• 11.8 to 72 years old
• Male patients 3 times more than females
• Illness duration 0.44 to 23.3 years

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• 24 of studies- no significant difference in STG
  volume and/or subregions between schizophrenic
  patients and controls
• 43 unileratal effects in STG or subregional
  volume change
• Reduced on left side of STG more reported
• 37 bilateral reduction effect in STG or
  subregional volumes
• 6 studies- mixed effects (unilateral/bilateral)

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• Most showed reduced effect in STG or several
  subregional volumes
• 43 of studies- unilateral reduction
• More pronounced on left side
• Left STG- substrate of auditory and language
  processing and may be related to common symptoms
• The review support STG or its subregions as
  candidate region related to hallucinations

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Raij et al. (2009)-procedure

• 11 subjects with AVH and able to rate subjective
  reality
• Practiced task then entered fMRI scanner
• Cylinder shaped response keys in both hands
• Each beginning and each end
• If no AVH in 18 sec? rate the reality or loudness
  of latest AVH by moving cursor via response key

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Analysis of coupling

• Tested coupling of IFG with other brain regions
  during AVH vs. non-AVH periods
• One sample t test used to test the resulting
  contrast images for hallucination-related changes
  in the connectivity of IFG with other brain parts
• Correlated contrast images with SRH across
  subjects

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• Strength of AVH-related activation in the IFG
  correlated with the SRH
• Correlation of SRH with coupling between left IFG
  and left auditory cortex strongest in Heschls
  gyrus
• Bilateral IFG signals correlated strongly with
  SRH

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Brain (2008) 131 3169-77

• Auditory Verbal Hallucinations Predominantly
  Activate the Right Inferior Frontal Area

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Method

• 24 Subjects
• Frequent AVH and frequent moments without AVH
• Right handed
• Antipsychotic meds during study
• 17 males
• 7 females
• 18 schizophrenia
• 3 schizo-affective disorder
• 3 psychosis not otherwise specified

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Method- continued

• Comprehensive Assessment of Symptoms and History
  (CASH)
• Diagnosis
• Edinburgh Handedness Inventory
• The Positive and Negative Syndromes Scale (PANSS)
• Symptom assessment
• Psychotic Symptom Rating Scales- Auditory
  Hallucinations Rating Scale (PSYRATS-AHRS)

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Procedure

• fMRI scans made continuously (8 min)
• Patients squeeze balloon during AVH
• Release when AVH subsided
• Language activation measured (8 min)
• Paced letter fluency task
• Letter displayed on screen in front of them and
  patients silently generate word
• Letters presented in 8 activation blocks
• Each block 30 sec
• Each activation block- 10 different letters
• 1 letter every 3 sec

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Procedure- continued

• 2 more letter fluency trials
• Patients generate words aloud
• Used to measure behavioural performance while
  they were in the scanner
• Activation maps via Philips Achieva 3 Tesla
  Clinical MRI scanner

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Procedure- continued

• 3D PRESTO SENSE sequence
• Fast scan sequence
• Full brain coverage in .609 sec
• Combines 3D PRESTO pulse sequence with parallel
  imaging (SENSE) in 2 directions using a
  commercial 8 channel SENSE
• SENSE parallel imaging technique using multiple
  receiver head coils
• 800 3D PRESTO SENSE images aquired

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Data Analysis

• Preprocessing
• Reorientation and within-subject image
  realignment due to head motion
• Comparing hallucinating and non-hallucinating
  periods
• Squeezed balloon upon onset of hallucination
• Stopped squeezing balloon when hallucinations
  stopped

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Data Analysis- continued

• Letter fluency paradigm
• Activation model created
• Contrast activity when letter presented and rest
  periods
• Following first level analyses, second level
  random- effects analyses conducted for both
  hallucination and letter fluency paradigm
• Random effects group-wise conjunction analysis
  conducted
• Identifies a common processing component by
  finding area activated in independent
  subtractions

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Data Analysis- continued

• Lateralization indices calculated using
  individual t-tests
• Lateralization indices difference in
  thresholded signal intensity changes in L vs. R
  hemispheres divided by sum of thresholded
  signal intensity changes
• Mask created using AAL (anatomical automatic
  labeling) atlas
• Differences in indices compared via paired sample
  t-test

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Data Analysis- continued

• Pearsons correlations used to assess
  associations between
• Subjective loudness of AVH and activation of
  Heschls gyrus
• Number of voices and activation of superior
  temporal gyrus
• Lateralization index of AVH and degree to which
  emotional content of AVH was scored as negative

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Results

• Subjects chronically psychotic
• PANSS score average 73
• Average AVH several times/hour lasting a few
  minutes
• Hear voices inside and outside head (most)
• Loudness- normal speaking
• Most patients (18)- voices derogatory
• 6 patients- voices more neutral

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PSYRATS-AHRS interview
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During the scan- balloon task

• 18 hallucinations in 8 min
• Duration- 20 sec
• Total duration of hallucinations- 362 sec

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Letter Fluency Task

• 96 correct performance
• 8 of the 24 patients- AVH during language and
  during resting blocks

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fMRI

• Group analysis- multiple brain regions activated
• Most extended activation in right inferior
  frontal area
• Right insula and Brocas homologue
• Highly significant activation
• Left motor cortex and right cerebellum
• Significant activation during AVH
• Left insula, bilateral supramarginal gyri, right
  superior temporal gyrus
• Not significantly activated during AVH
• Brocas area and left superior temporal gyrus

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Language Task

• Extensive activation of Brocas area and
  contralateral homologue (lesser degree)
• both extending into insula, bilateral temporal
  area (superior and middle gyri), left more than
  right, anterior cingulate gyri
• Masks (created with AAL atlas) overlaid on group
  results

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Group conjunction analysis

• Several areas activated
• Right inferior frontal gyrus (including Brocaa
  homologue)
• Right dorsolateral prefrontal cortex (DLPFC)
• Left insula and right anterior insula

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Lateralization

• Mean lateralization index
• -0.11 for hallucination paradigm
• 0.14 for word generation task
• Lower lateralization during AVH compared to word
  generation
• Individual lateralization indices of
  hallucinatory activation not correlated to
  lateralization indices of word generation

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Lateralization- continued

• No association with
• AVH loudness and Heschls gyrus activation
• Number of voices and superior temporal gyrus
• No difference in activation during AVH between
  individual with voices inside or outside head
• More negative emotional content of voices
  associated with stronger lateralization of
  hallucinatory activation to right hemisphere

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AVH

• AVH most extensive activation in right inferior
  frontal area (right insula and right homologue of
  Brocas area)
• Significant activation during AVH in superior
  temporal and supramarginal gyri (mostly right
  hemisphere), and left insula
• Brocas area or left superior temporal gyrus- no
  significant activation during AVH

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Word production task

• Activitation of left inferior frontal area
  (Brocas area and left dorsolateral prefrontal
  cortex)
• Left insula, left superior and middle temporal
  gyri, anterior cingulate gyrus
• Right side homologues activated, but to smaller
  degree
• Activation during inner speech more extended
  compared to hallucinatory activity
• Primarily results from difference in the applied
  paradigm

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Corrections

• Number and duration of AVH differed
• Variable and less extended activation
• Conjuction analysis applied

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AVH vs. language production

• AVH activate right homologues of language areas
• Especially the insula and Brocas area homologue
• Normal language production activates frontal and
  temporal language areas in left hemisphere
• Large inter-individual variability in
  lateralization of activity during AVH
• Activation correlated with AVH negative emotional
  valence

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Where do AVH come from?

• Previous reports- Brocas area activation
• AVH arise from speech production area
• Right inferior frontal area associated with AVH
• Left hemisphere dominates right in language
  production (right handed subjects)
• Psychotic patients- AVH single words or
  truncated sentences and negative emotions
• AVH?right hemisphere language areas
• May explain low linguistic complexity and
  derogatory content characteristic of AVH

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Limitations

• Non-specific acoustic activation due to scanner
  sounds
• Dampened activity in primary auditory cortex
  during AVH
• Cerebral activation pattern due to AVH and motor
  activity
• But for the right inferior frontal area to be
  activated due to motor activity would be unusual

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• http//www.youtube.com/watch?v7zMz3l7IXKA

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Other pics- sakai (review)
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Robbins and Arnsten- review
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Javitt (2009) review
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Hugdahl et al (review)
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Modinos et al.