Stacy Zeigler

NIMHSchizophrenia 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 don’t hear, believe that others are broadcasting their thoughts to the world, or become convinced that others are plotting to harm them.

Symptoms develop in men- late teens or early twentieswomen 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

Brain Research Reviews (2009)Superior temporal gyrus volume change in

schizophrenia: a review on region of interest volumetric studies

Superior temporal gyrus (STG)Production, interpretation and self

monitoring of language; implicated in AHSuperior temporal gyrus

1 of 3 gyri in temporal lobeBrain volume/structure change may be linked

to a brain region

Region of Interest (ROI) analysisSTG structural differencesAdvantages:

Anatomical validity, definition of landmarks in native space and quantitative measures of voxels

Limitations:Labor intensive and time consuming

Studies consideredPublished up to July 2008 as an articleCompared schizophrenia patients with

healthy groupData on volume of STG and its subregionsUsed ROI volumetric methodIndividuals with schizophrenia and related

diagnosesEarly onset schizophrenia includedFollow-up included

Details2771 subjects

1444 patients1327 controls

46 studies (5=follow up)11.8 to 72 years oldMale patients 3 times more than femalesIllness duration= 0.44 to 23.3 years

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 changeReduced on left side of STG more reported

37% bilateral reduction effect in STG or subregional volumes

6 studies- mixed effects (unilateral/bilateral)

Most showed reduced effect in STG or several subregional volumes

43% of studies- unilateral reductionMore 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

Raij et al. (2009)-procedure11 subjects with AVH and able to rate

subjective realityPracticed task then entered fMRI scannerCylinder shaped response keys in both hands

Each beginning and each endIf no AVH in 18 sec rate the reality or

loudness of latest AVH by moving cursor via response key

Analysis of couplingTested coupling of IFG with other brain

regions during AVH vs. non-AVH periodsOne 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

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 Heschl’s gyrus

Bilateral IFG signals correlated strongly with SRH

Brain (2008) 131: 3169-77Auditory Verbal Hallucinations

Predominantly Activate the Right Inferior Frontal Area

Method 24 Subjects

Frequent AVH and frequent moments without AVH

Right handedAntipsychotic meds during study17 males7 females18= schizophrenia3= schizo-affective disorder3= psychosis not otherwise specified

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)

Procedure fMRI scans made continuously (8 min)

Patients squeeze balloon during AVHRelease when AVH subsided

Language activation measured (8 min)Paced letter fluency taskLetter displayed on screen in front of them and

patients silently generate wordLetters presented in 8 activation blocks

○ Each block= 30 secEach activation block- 10 different letters

○ 1 letter every 3 sec

Procedure- continued2 more letter fluency trials

Patients generate words aloudUsed to measure behavioural performance

while they were in the scannerActivation maps via Philips Achieva 3 Tesla

Clinical MRI scanner

Procedure- continued3D PRESTO SENSE sequence

Fast scan sequenceFull brain coverage in .609 secCombines 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

Data AnalysisPreprocessing

Reorientation and within-subject image realignment due to head motion

Comparing hallucinating and non-hallucinating periodsSqueezed balloon upon onset of hallucinationStopped squeezing balloon when hallucinations

stopped

Data Analysis- continuedLetter 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 conductedIdentifies a ‘common processing component’ by

finding area activated in independent subtractions

Data Analysis- continuedLateralization indices calculated using

individual t-testsLateralization 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

Data Analysis- continuedPearson’s correlations used to assess

associations between:Subjective loudness of AVH and activation of

Heschl’s gyrusNumber of voices and activation of superior

temporal gyrusLateralization index of AVH and degree to

which emotional content of AVH was scored as negative

ResultsSubjects chronically psychotic

PANSS score average= 73Average AVH several times/hour; lasting a few

minutesHear voices inside and outside head (most)Loudness- normal speakingMost patients (18)- voices derogatory6 patients- voices more neutral

PSYRATS-AHRS interview

During the scan- balloon task18 hallucinations in 8 minDuration- 20 secTotal duration of hallucinations- 362 sec

Letter Fluency Task96% correct performance8 of the 24 patients- AVH during language

and during resting blocks

fMRIGroup analysis- multiple brain regions activatedMost extended activation in right inferior frontal

areaRight insula and Broca’s homologue

Highly significant activationLeft motor cortex and right cerebellum

Significant activation during AVHLeft insula, bilateral supramarginal gyri, right

superior temporal gyrusNot significantly activated during AVH

Broca’s area and left superior temporal gyrus

Language TaskExtensive activation of Broca’s 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

Group conjunction analysisSeveral areas activated

Right inferior frontal gyrus (including Broca’a homologue)

Right dorsolateral prefrontal cortex (DLPFC)Left insula and right anterior insula

LateralizationMean lateralization index

-0.11 for hallucination paradigm0.14 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

Lateralization- continuedNo association with:

AVH loudness and Heschl’s gyrus activationNumber 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

AVHAVH most extensive activation in right

inferior frontal area (right insula and right homologue of Broca’s area)

Significant activation during AVH in superior temporal and supramarginal gyri (mostly right hemisphere), and left insula

Broca’s area or left superior temporal gyrus- no significant activation during AVH

Word production taskActivitation of left inferior frontal area (Broca’s

area and left dorsolateral prefrontal cortex)Left insula, left superior and middle temporal

gyri, anterior cingulate gyrusRight side homologues activated, but to smaller

degreeActivation during inner speech more extended

compared to hallucinatory activityPrimarily results from difference in the applied

paradigm

CorrectionsNumber and duration of AVH differed

Variable and less extended activationConjuction analysis applied

AVH vs. language productionAVH activate right homologues of language

areasEspecially the insula and Broca’s area

homologueNormal 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

Where do AVH come from?Previous reports- Broca’s area activation

AVH arise from speech production areaRight inferior frontal area associated with AVHLeft hemisphere dominates right in language

production (right handed subjects)Psychotic patients- AVH= single words or

truncated sentences and negative emotionsAVHright hemisphere language areasMay explain low linguistic complexity and

derogatory content characteristic of AVH

LimitationsNon-specific acoustic activation due to

scanner soundsDampened activity in primary auditory cortex

during AVHCerebral activation pattern due to AVH and

motor activityBut for the right inferior frontal area to be

activated due to motor activity would be unusual

http://www.youtube.com/watch?v=7zMz3l7IXKA

Other pics- sakai (review)

Robbins and Arnsten- review

Javitt (2009) review

Hugdahl et al (review)

Modinos et al.