Judith Gault, Ph.D.
Dr. Gault collaborates with UC Denver neurosurgeons
Aviva Abosch, MD PhD and Steven Ojemann, MD and neurophysiologist John
Thompson, PhD in order to identify biomarkers of psychiatric disease.
Schizophrenia and obsessive compulsive disorder (OCD)
are both common and severe mental illnesses with unknown causes that, due to
their early age of onset and chronic course with many largely unmet needs, are
particularly devastating.(Mathers 2008) For the 40% of patients with OCD
with poor response to both a form of cognitive behavioral therapy, exposure and
response therapy, and pharmacological interventions, a neurosurgical
intervention, deep brain stimulation (DBS), represents a major biomedical
advancement.(Skoog and Skoog 1999)
Fifty percent of otherwise treatment refractory subjects are
responsive to DBS targeting nucleus accumbens (NAc).(Pepper, Hariz et al.
2015) Successful targeting of the NAc is dependent on identifying a
stimulation induced biomarker of hedonic valence, or smile induction.(Haq,
Foote et al. 2011) However, this hedonic biomarker is necessary, but not
sufficient, to predict effective DBS therapy and is not always found.
Additional biomarkers are needed to inform NAc targeting in DBS surgery.
Neurosurgical interventions employed to treat OCD all rely
on disruption of the cortical-striato-thalamo-cortical circuitry. (Skoog
and Skoog 1999, Brown, Mikell et al. 2016) Remarkably this is the same
circuitry has been heavily implicated in schizophrenia pathogenesis.
Antipsychotic action is dependent on blocking dopamine D2-like receptors in
NAc. (Seeman, Chau-Wong et al. 1975, Masri, Salahpour et al.
2008) Convergent evidence supports targeting of NAc with DBS to treat
symptoms of schizophrenia and the first subject with schizophrenia to receive
DBS treatment has improvement in both the positive symptoms of psychosis and negative
symptoms of a lack of motivation. (Liu, Hao et al. 2014, Ma and Leung
2014) (Corripio, Sarro et al. 2016)
However, as with OCD, it is important to develop additional
biomarkers to allow precise DBS targeting of NAc and demonstrate target
engagement to inform the clinical trial. Subjects with schizophrenia have
aberrancies in sensory processing and describe becoming overwhelmed with
sensory information.(Jeffs 2000, Saks 2007) Measured with EEG, gating of
an auditory evoked response, the positive wave occurring 50 msec after a tone
(P50), is one assessment of sensory processing has been used as a biomarker of
schizophrenia disease.(Olincy, Braff et al. 2010, Javitt and Freedman
2015) Diminished P50 response to the second of paired auditory clicks is a
measure of auditory gating. Subjects with schizophrenia or OCD or Parkinson’s
disease (PD) have impaired gating of their P50 response and demonstrate similar
responses to both the first and second click.(Olincy, Braff et al. 2010, Javitt
and Freedman 2015) P50 response occurs in the dorsolateral prefrontal
cortex, mediodorsal thalamus and the hippocampus— within the same
cortico-striato-thalamo-cortical circuity implicated in both schizophrenia and
OCD.(Tregellas, Davalos et al. 2007) We are employing P50 as: 1) an
intraoperative biomarker to detect sub territories within deep brain
structures that are involved in sensory processing; and 2) as a biomarker
of target engagement by assessing changes in P50 in response to stimulation.
In addition, we are characterizing the resting state
neurophysiology of the NAc in subjects with OCD. Our preliminary data is
promising and we have identified an aberrancy in NAc neurophysiology. The next
steps are to determine the frequency of the aberrancy in OCD subjects, and
determine if there is a synchronous equivalent measure that can be made with
EEG measurements to allow us to monitor the aberrancy in a noninvasive way and
determine if when corrected, symptoms of OCD subside. We anticipate that these two
approaches towards identifying neurophysiological biomarkers will be helpful in
treating depressive and psychotic symptoms in patients.