Schizophrenia Stacy Zeigler

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 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 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

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 AH Superior temporal gyrus 1 of 3 gyri in temporal lobe Brain volume/structure change may be linked to a brain region

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

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

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

43% unileratal effects in STG or subregional volume change 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)

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

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

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

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: 3169-77 Auditory Verbal Hallucinations Predominantly Activate the Right Inferior Frontal Area

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

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 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

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

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

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

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

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

Data Analysis- continued Pearson’s correlations used to assess associations between: Subjective loudness of AVH and activation of Heschl’s 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

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

PSYRATS-AHRS interview

During the scan- balloon task 18 hallucinations in 8 min Duration- 20 sec Total duration of hallucinations- 362 sec

Letter Fluency Task 96% correct performance 8 of the 24 patients- AVH during language and during resting blocks

fMRI Group analysis- multiple brain regions activated Most extended activation in right inferior frontal area Right insula and Broca’s 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 Broca’s area and left superior temporal gyrus

Language Task Extensive 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 analysis Several areas activated Right inferior frontal gyrus (including Broca’a homologue) Right dorsolateral prefrontal cortex (DLPFC) Left insula and right anterior insula

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

Lateralization- continued No association with: AVH loudness and Heschl’s 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

AVH AVH 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 task Activitation of left inferior frontal area (Broca’s 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

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

AVH vs. language production AVH activate right homologues of language areas Especially the insula and Broca’s 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

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

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

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.