Brain Imaging, Cognitive Enhancement and Early Schizophrenia

Schizophrenia is a chronic and highly disabling disorder, making it imperative to apply
interventions that alter its deleterious effects as early as possible. Impairments in
neurocognition and social cognition, which appear to be linked to impaired structural and
functional integrity in key brain regions, are the strongest predictors of functional
disability in early course schizophrenia,making them key targets for early intervention.
Although pharmacologic treatment of cognitive impairments is currently limited,our studies
and others, including meta-analyses have shown that cognitive rehabilitation can be effective
for addressing cognitive impairment in chronic patients. Most notably, Cognitive Enhancement
Therapy (CET), a unique integrated approach to the rehabilitation of social and non-social
cognitive impairments developed and tested by Hogarty and colleagues in our group, has shown
substantial and lasting effects in chronic schizophrenia patients. Recently, the
investigators have shown that the beneficial effects of CET can be successfully extended to
those in the early phase of the disorder, resulting in large functional improvements.

The investigators have posited that CET can be particularly effective as an early
intervention strategy by capitalizing on a fronto-temporal plasticity reserve, and the
investigators are now observing compelling, albeit preliminary evidence that CET can indeed
slow the progression of gray matter loss in these very regions of the brain, which is
associated with significantly improved cognition (see Preliminary Studies). Preserved
structural integrity and improved brain function in fronto-temporal regions may be the
critical mechanisms for supporting cognitive improvement in early course schizophrenia, yet
remarkably little is known about the neurobiologic effects of cognitive rehabilitation, the
durability of these effects post-treatment, and whether an initial fronto-temporal reserve
portends a greater treatment response. Our exciting preliminary findings of the
neuroprotective effects of CET represent the first study to demonstrate that the structural
integrity of the brain in the early course of schizophrenia can be altered using cognitive
rehabilitation. It is critical that these morphologic findings are examined with more
advanced imaging techniques in larger samples to gain a precise understanding of the
underlying neurobiologic mechanisms and predictors of cognitive and functional enhancement in
early course schizophrenia. These goals are reflective of the strategic plan of NIMH to
identify underlying neural mechanisms of mental disorders that can facilitate treatment, and
personalize care to optimize treatment response. To accomplish this, the investigators
propose to use comprehensive structural and functional imaging methods to study 102 new early
course schizophrenia patients treated for 18 months in a randomized trial of CET or Enriched
Supportive Therapy (EST) and: Aim #1: Confirm the neuroprotective effects of CET on
fronto-temporal brain structure. Structural magnetic resonance imaging (MRI) assessments will
be collected along with cognitive and functional outcome data at baseline, 9, and 18 months.
It is hypothesized that patients treated with CET will demonstrate decreased loss of
fronto-temporal gray matter relative to EST, and that this neuroprotection will be a
mechanism of cognitive and functional improvement. Effects on other key brain regions will
also be explored; Aim #2: Examine the effects of CET on fronto-temporal brain function.
Functional MRI data using established executive and social cognition paradigms will be
collected at baseline, 9, and 18 months along with cognitive and functional outcome data. It
is hypothesized that CET patients will demonstrate enhanced fronto-temporal brain activity
during these tasks relative to EST (see Section 3C.6.2 for specific predictions), and that
this enhanced brain activity will be a mechanism of cognitive and functional improvement.
Changes in fronto-temporal functional connectivity and their relations with improved brain
structure and cognition will also be explored; and Aim #3: Examine the durability of CET
effects on fronto-temporal brain structure and function, cognition, and functional outcome at
1 year post-treatment. Identical neuroimaging, cognitive, and behavioral data will be
collected as those assessed during active treatment. It is hypothesized that the differential
neurobiologic benefits of CET relative to EST observed in Aims 1 and 2, and the cognitive and
functional benefits of CET observed during active treatment will be sustained 1 year
post-treatment.

Exploratory Aim: Explore the effects of a fronto-temporal structural and functional reserve
on CET treatment response. Moderator analyses will examine whether pre-treatment
fronto-temporal structural and functional brain reserves (operationalized in Section 3C.8.2)
predict larger cognitive and functional gains in CET. Exploratory analyses will also examine
the degree to which later (18 mo) treatment improvement is dependent upon early (9 mo)
neuroprotection and increased brain function, which may reflect plasticity.

Inclusion Criteria:

Patients will be included if they have:

1. a diagnosis of schizophrenia or schizoaffective disorder verified by the SCID (in our
data patients with both conditions respond similarly to CET);

2. duration since first psychotic symptom of < 5 years;

3. stable positive symptoms (Clinical Global Impression score of < 4 for at least 2
months [i.e., 2 consecutive visits]);

4. are currently maintained on and compliant with prescribed antipsychotic medication;

5. age 18-35 years;

6. significant social and cognitive disability based on the Cognitive Style and Social
Cognition Eligibility Interview25 utilized in previous CET studies;

7. current IQ > 80; and

8. the ability to read (sixth grade level or higher) and speak fluent English. This is a
study of early course schizophrenia, not first-episode schizophrenia. A duration of
illness since first psychotic symptom of < 5 years is adequate to define the early
phase of the illness, particularly given that the average duration of untreated
psychosis is a year or more.76 Eligibility criteria regarding IQ are justified from
previous experience with CET indicating that individuals with severe mental incapacity
are better served with less cognitively advanced programs.

Exclusion Criteria:

In order to avoid confounders likely to affect cognition and limit response to cognitive
rehabilitation, we will exclude those with:

1. significant neurological or medical disorders that may produce cognitive impairment
(e.g., seizure disorder, traumatic brain injury);

2. persistent suicidal or homicidal behavior;

3. a recent (within the past 3 months) history of substance abuse or dependence; and

4. any MRI contraindications such as ferromagnetic objects in the body.