At Risk in the Danger Zone

RESEARCH NEWS

At Risk in the Danger Zone
What can we do to give Australian teenagers a better chance against psychosis?

Funded by NSW Health, SRI is now finalising production of Australia’s first schizophrenia medical information poster – aimed at alerting parents to early onset symptoms

Currently, the gap between early onset and diagnosis often extends for 2 years because
parents do not recognise that their son or daughter is unwell. Usually, by the time psychiatric help is requested, the patient’s symptoms and disability have become well-established and therefore less able to respond well to treatment. But even when young people are presented
for early assessment, there are no definitive tests to confirm the diagnosis. Major global research efforts are now being aimed at improving early detection.

Testing the Tests

SRI CEO Prof. Vaughan Carr and colleagues have completed a study* of ‘At Risk Mental State’ (ARMS) assessment criteria, a clinical measurement tool to help decide whether a young person is at risk of developing a psychotic disorder. ARMS criteria take account of such factors
as low-level symptoms, affected first-degree relatives, and recent changes in mood state or mental functioning.

Using ARMS criteria, the research team analysed the collected data and follow-up material
on 74 patients who had been assessed as high risk between 1997 and 2002 at the Psychological Assistance Service (PAS) of Hunter Mental Health, and found that the criteria had produced a 50% ‘false-positive’ result. That is, 37 of the 74 patients had not developed a psychotic
disorder as predicted by the ARMS criteria.

The team then investigated which additional factors such as birth complications, social integration, odd beliefs, drug use and negative symptoms could be added to the
test criteria to improve predictive accuracy.

After analyses of many alternatives, the team concluded that the predictive accuracy
of the ARMS criteria would be most improved by including the additional assessment points, in order of importance, of:

1. Odd beliefs and magical thinking;
2. Marked impairment in role functioning;
3. Blunted or inappropriate affect;
4. Transient hallucinations;
5. Marked social isolation.

If these five items had been added to the original assessment of 74 patients, 31 of the 37 patients who later became psychotic could have been correctly identified, and 32 of the 37 patients who did not later become psychotic could have been correctly identified. That is, the accuracy of the tests would have been improved from 50% to around 85%.

*Mason O, Startup M, Halpin S, Schall U, Conrad A, Carr V. State and trait predictors of transition to first episode psychosis among individuals with at risk mental states. Schizophrenia Research 2004; 71: 227-237.

Memory Performance Measures the Family Link

RESEARCH NEWS

Memory Performance Measures the Family Link

Try remembering what happened at your last birthday party. Notice how your brain summons
up a series of images and impressions, each one linked to many others, forming a network of connected memory nodes (called ‘schema’) around which your attention zooms like a very fast train. That’s long-term memory.

Now try remembering this sentence: “Julie Barlow’s phone number is 7216 8367.” Short-term
memory is what you use to retain such information temporarily, before writing it down, for instance.

Memory dysfunction is a consistent characteristic of schizophrenia, and earlier studies have indicated that the illness causes particular deficits in short-term memory – whether applied to remembering auditory, visual or other information. As short-term memory performance depends upon the integrity of the brain’s prefrontal cortex, investigating the deficit may provide a clue to how the illness affects this important cognitive area of the brain.

At the University of Western Australia, SRI-supported PhD scholar Aaron Kent and colleagues have measured the memory performance of normal control subjects, and compared it with the performances of people with schizophrenia, and of their siblings.

Different tests were used to assess auditory memory (by spoken information), visual memory
(by showing pictures), and working memory (by number and letter sequences).

The working memory deficiencies recorded in people with schizophrenia (S) are reflected to a lesser extent in their first-degree relatives (R) compared to the normal working memory performance of controls (C).

As expected, the performance levels of the schizophrenia group was found to be impaired, relative to siblings and controls, in all three testing methods. The siblings, however, achieved similar scores to the controls in the auditory and visual memory tests, but uniformly lower scores
in the working memory test which used sequences of letters and numbers. Significantly, this test involved using mental mechanisms associated with the ‘executive function’ abilities of the prefrontal cortex, known to be affected by schizophrenia.

So consistent were the lower scores of siblings in this particular task that the study* suggests such tasks may be included in some future array of tests for schizophrenia risk in individuals.

The study was supported by the Rebecca Cooper Foundation.

* Kent AR, Fox AM, Michie PT, Jablensky AV. Differential impairment of working memory performance
in first-degree relatives of individuals with schizophrenia. Acta Neuropyschiatrica 2004: 16:149-153.

Investigating the Causes of the Imbalanced Mind

RESEARCH NEWS

Investigation the Causes of the Imbalanced Mind

Gamma-amminobutyric acid (GABA) is a chemical messenger that is widely distributed in the brain. Its natural function is to act as an inhibitory neurotransmitter, reducing the activity
of the neurons to which it binds, thereby ‘muting’ transmitted messages. Excitatory transmitters such as glutamate perform the opposite role of amplifying messages. So when we say, “the balance of the mind is disturbed”, or “spinning out”, we could be reflecting the interplay
of these inhibitory and excitatory neurotransmitters.

Postmortem tissue sections from the prefrontal cortex of normal control (left) and schizophrenia-affected (right)
brains. The darker staining shown on the left indicates the presence of 45% more GAT-1 GABA transporter – part of the chemical system which prevents the brain becoming overexcited.

Some researchers believe that one of the purposes of GABA is to control the fear or anxiety that can occur when neurons are overexcited. Anti-anxiety drugs such as diazepam (Valium), for example, work by enhancing the effects of GABA.

Since 1980, many studies have suggested that decreased GABA in the brain also contributes to some schizophrenia symptoms, such as delusional ideas and manic behaviour related to
overexcited brain activity. More recent research has focused attention on the group of proteins which transport GABA across neuronal and glial cell membranes. Current thinking is that deficiencies in these GABA ‘transporters’ may be the cause of abnormal GABA-ergic brain
activity.

At the University of Sydney, SRI PhD scholar Sonja Schleimer and colleagues have examined postmortem tissue from the prefrontal cortex of schizophrenia-affected brains and from
normal controls to distinguish any differences in GABA transporters.

After a year’s research, the SRI team has reported that schizophrenia tissue contains levels of GAT-1 GABA transporter 45% less than control tissue, while the GAT-3 GABA transporter
increased by 23%. The apparantly complementary change in the levels of these transporters in schizophrenia is a promising path for future research.

The study* was supported by the Rebecca Cooper Foundation.

*Schleimer SB, Hinton T, Dixon G, Johnston GAR. GABA Transporters GAT-1 and GAT-3 in the Human Dorsolateral Prefrontal Cortex in Schizophrenia. Neuropsychobiology 2004: 50; 226-230.

Street Drugs and Schizophrenia

RESEARCH NEWS

Street Drugs and Schizophrenia
Several SRI studies are investigating why schizophrenia is so often associated with heavy usage of illicit drugs

A number of recent surveys have indicated that 40-60% of people with schizophrenia have a history of heavy use of drugs such as cannabis, cocaine, amphetamines and heroin, as well as alcohol and tobacco. These drugs exacerbate the disabilities associated with the illness, and compound the already severe difficulties of treating it successfully.

Two SRI-supported studies are now investigating the links between schizophrenia and
drug abuse, using a variety of research methods.

Major Federal Funding for Cannabis Study

The National Health and Medical Research Council (NHMRC) has awarded $365,000 to SRI
researchers including Vaughan Carr, Philip Ward, Ulrich Schall, Amanda Baker, Pat Johnston and Martin Cohen for an investigation into first-episode schizophrenia and cannabis use.

Twenty-five per cent of Australian adolescents use cannabis regularly. Long-term heavy usage can impair frontal brain functioning, affecting the capacities for attention, working memory, and concentration – all dysfunctions associated with schizophrenia’s ‘negative’ symptoms.

Conducted in Newcastle and Sydney, the study will be the first to use the sophisticated
Brain Atlasing neuroimaging techniques to investigate how continuous heavy cannabis use affects the structure and function of the brain in adolescents without schizophrenia compared with brain changes associated with first-episode schizophrenia patients who do or do
not use cannabis frequently.

Preliminary results from a pilot study have shown similar patterns of reduced brain activation in heavy cannabis users and patients with first-episode schizophrenia, suggesting the possibility of common processes underlying these two conditions.

Early results from the NHMRC funded project show similar areas of reduced functionality in schizophrenia-affected
brains (left) and long-term cannabis users’ brains (right).

SRI’s Brain Atlasing Initiative and collaborative link with Prof. PaulThompson’s group
at the Laboratory of Neuroimaging, UCLA, was a vital ingredient in the successful application for NHMRC funding for this project.

Memory, Cannabis and Schizophrenia

Cognitive impairments are among the most debilitating symptoms of schizophrenia, and of
these verbal learning and recall show the greatest degree of impairment. Verbal learning and memory are also impaired by long term cannabis use in people who do not have schizophrenia. Does this similarity of symptoms indicate a similarity of brain dysfunction?

To investigate this, SRI-affiliated scientist Dr Nadia Solowij and PhD student Colleen Respondek from the University of Wollongong have commenced a study for which two groups of research subjects will be recruited, one with schizophrenia and one without. The schizophrenia group is composed of long-term heavy cannabis users, light cannabis users, and non-cannabis
users. The second group is identical in its categories of cannabis use, but without schizophrenia.

FMRI brain scans will be taken of all subjects as they perform identical memory and recall
tasks. These images will then be compared to discern significant differences in brain activity between groups, thereby clarifying any differences in the neurological effects on memory function of schizophrenia, cannabis use, and schizophrenia with cannabis use.

The cannabis study is funded by the Clive and Vera Ramaciotti Foundation for Medical
Research, with additional support from the Illawarra Institute for Mental Health and University of Wollongong. The schizophrenia component of the study is supported by SRI.

Exploring the Neural Geography of Emotional Responses

RESEARCH NEWS

Two new studies shed light on the communication breakdowns of schizophrenia.

One of the core characteristics of schizophrenia is the breakdown it causes in interpersonal communication, and many studies have indicated that this is due to a corresponding breakdown
in the brain’s ability to recognise and respond appropriately to the emotions of others.

Pursuing this line of research, SRI affiliated scientist Prof. Lea Williams is extending her investigations into how schizophrenia affects emotion processing in the brain.

As reported in the January 2001, Prof. Williams and her team have confirmed that the illness causes a dysfunction of normal signalling between the brain’s limbic system and frontal
lobes. As the limbic system, including the amygdala, is responsible for emotionally interpreting received impressions, this dysfunction may produce difficulties in the interpretation of emotionally loaded information.

Prof. Williams and her collaborators have now completed two further studies; the first investigated how antipsychotic medication affects the perception of emotion; the second explored
the role of limbic/frontal lobe dysfunction and arousal in producing the symptoms of paranoia in schizophrenia.

The effects of medication on emotion processing

For the first study, Prof. Williams and collaborators utilised visual scanpaths to assess the effects of antipsychotic medications. Of 28 schizophrenia subjects, 15 were prescribed the atypical (newer) medication Risperidone, and 13 prescribed the older medication Haloperidol. A control group of healthy unmedicated subjects was also assessed.

Video-oculography technology was used to track eye movements of all subjects while viewing images of happy, sad and neutral facial expressions. All subjects were also tested on
their ability to correctly identify the emotional content of the facial images shown.

The effects of medication. Typical scanpaths of a neutral face: A- Unmedicated control subject without schizophrenia.
B – Schizophrenia subject treated with risperidone. C – Schizophrenia subject treated with haloperidol.

Compared to the control group, both schizophrenia groups showed a general restriction of visual scanning, reflected in a pattern of shorter eye movements and fewer fixations of longer duration. However, the haloperidol and risperidone-treated groups differed in their ability to attend to specific features of the face (eyes, mouth). Haloperidol-treated subjects showed reduced fixation to the specific features of all expressions, in addition to restricted scanning. By contrast, risperidone-treated subjects were better at attending to these specific features and correspondingly better at recognising the expressions.

These findings indicate that atypical treatments such as Risperidone may aid the emotional function of people with schizophrenia. Given that we rely on facial emotions for our everyday
interactions, the findings suggest that these treatments may modulate the ability to interpret and respond to the emotional content of interpersonal relations.

The Sources of paranoia

Prof. Williams’ second study followed on from her earlier 2000 research, which used fMRI scans to reveal the brain activity of healthy and schizophrenia-affected subjects while they viewed alternate pictures of threat-related and neutral facial expressions. In the earlier study, while healthy subjects recorded strong activity in the limbic/amygdala areas when viewing threat-related images, schizophrenia subjects showed no activity here, but strong responses in the prefrontal ‘thinking’ areas.

The new study was designed to discover whether this dysfunction of emotion processing in the brain was particularly evident in patients exhibiting paranoid symptoms, and also whether
it was modulated by similar abnormalities in other ‘body’ arousal responses to emotional stimulation. Arousal responses were recorded via skin conductance electrodes modified for the fMRI environment.

fMRI scans A-B show activity at different levels of the brain in normal controls when viewing a series of fear images (example right). Scans C-D pinpoint where brain activity is comparitively reduced in paranoid and non-paranoid schizophrenia subjects. Paranoid subjects showed reduced activity in the amygdala and visual areas, whereas non-paranoid schizophrenia subjects showed reduced activity only in the hypocampal gyrus area (GH).

27 schizophrenia subjects (13 paranoid, 14 non-paranoid) participated, along with 22 healthy controls. As before, fMRI brain scans were recorded as subjects viewed alternating facial
images expressing fear or neutral emotion. Simultaneously, the skin conductance electrodes placed on the fingers provided a measure of autonomic arousal.

The schizophrenia subjects produced more skin conductance arousal responses and less limbic/amygdala activity than the healthy subjects, and both these abnormalities were particularly
pronounced in the subjects with paranoid schizophrenia.

These results suggest that while schizophrenia appears to increase the sensitivity and amplitude of instinctive or autonomic responses to emotional stimuli, it decreases the brain’s ability to process such stimuli appropriately. In the case of threat or fear-related stimuli, the extreme sensitivity and the dysfunction of normal limbic/amygdala links to the prefrontal cognitive areas
result in the cognitive misinterpretations typical of paranoia.

1. Emotion perception in schizophrenia: an eye movement study comparing the effectiveness of risperidone vs. haloperidol. Published in Psychiatry Research, 2003.
2. Dysregulation of arousal and amygdala-prefrontal systems in paranoid schizophrenia. Published in American Journal of Psychiatry, March 2004.

The Bank With Deposits Worth More Than Money

RESEARCH NEWS

The Bank With Deposits Worth More Than Money
Michael Costa opens Hunter DNA Bank for Schizophrenia Research

At the DNA Bank’s opening on 28 November. L-R: Craig Hamilton, NISAD’s Dr Paul Tooney, Prof. John Rostas, Prof.
Rodney Scott, Minister for The Hunter Michael Costa, Prof. Mike Calford.

Possibly the most valuable bank in Australia was officially opened on 28 November at the John Hunter Hospital, Newcastle. An SRI initiative, the Hunter DNA Bank for Schizophrenia and Allied Disorders is dedicated to collecting DNA samples from schizophrenia volunteers and their relatives for use in investigating the genetic causes of the illness.

While the risk for schizophrenia in the general population is 1 per cent, the risk for a child with a schizophrenia-affected parent is 10 per cent, even if the child is brought up by adoptive parents. It is believed that more than one inherited gene is responsible for the predisposition, which must be present for schizophrenia to occur. While it is believed that the predisposition is coupled with environmental stresses such as birth complications, drug abuse and urban living, the proportion of risk carried by the genetic vulnerability has been placed as high as 80 per cent.

Using the new ‘gene-chip’ technology, researchers will use the DNA Bank resource to test thousands of genes simultaneously, searching for the genetic ‘signature’ of schizophrenia that will aid diagnosis, help develop better treatments, and maybe lead to a cure. In opening the Brain Bank, Minister for the Hunter Michael Costa was joined by radio personality Craig Hamilton, who provided a blood sample.

The DNA Bank is co-supported by SRI, the Hunter Medical Research Institute, the University of Newcastle and the Hunter Area Pathology Service.