S70 Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384

recent work has demonstrated that antipsychotics specifically reduce the

volume and thickness of the anterior cingulate cortex (ACC) but not that of

the primary visual (V1) cortex. Decreased ACC volume is associated with

no significant loss of either neurons or astrocytes, but rather, an increase

in the density of these cells suggesting the drug-induced changes are likely

to reflect alterations in synaptic or dendritic architecture. This work has

translational relevance to human neuroimaging studies of psychiatric ill-

ness treated with antipsychotics, including SCZ. In particular, this approach

facilitates “reverse-translation”, potentially informing the neurobiological

mechanisms underlying antipsychotic drug-induced volumetric abnormali-

ties reported from neuroimaging studies in SCZ patients. Furthermore, this

work may ultimately, may inform the clinical use of these drugs.

References:[1] Vernon et al., Biol Psychiatry. 2011; 69(10): 936-44.

[2] Vernon et al., Biol Psychiatry. 2012; 71(10): 855-63.

CLINCIAL INSIGHTS DERIVED FROM RODENT MODELS OF

ANTIPSYCHOTIC-INDUCED METABOLIC PERTRUBATIONS

Margaret K. Hahn1,2, Gary Remington3,4, Araba Chintoh4,6, Celine Teo4,

Paul Fletcher4, Jose Norbrega4, Melanie Guenette4,5, Tony Cohn1,4,

Adria Giacca6

1University of Toronto, Department of Psychiatry; 2Center for Addiction and

Mental Health, Complex Mental Illness; 3Department of Psychiatry, Univerity

of Toronto; 4Centre for Addiction and Mental Health, Toronto, ON, Canada;5Institute of Medical Sciences, University of Toronto, Canada; 6Department of

Physiology, University of Toronto, Canada

Antipsychotic medications, currently the cornerstone of treatment for

schizophrenia, have been associated with significant metabolic side effects,

including dyslipidemia, weight gain and glucose dyregulation. In turn,

these factors are understood to contribute to increased cardiovascular (CV)

morbidity and premature mortality observed in serious mental illness. Un-

derstanding underlying mechanisms of these adverse effects, and also how

they may overlap with therapeutic efficacy, is imperative to developing

targeted interventions to attenuate cardiometabolic risk factors, and effec-

tive anti-psychotic treatments devoid of these side-effects. In this respect,

the field has turned to in vivo work in animals to model what is observed

clinically and elucidate possible underlying mechanisms of antipsychotic-

induced metabolic disturbances. As will be discussed, rodents serve as

useful models for some, but not all aspects of metabolic side-effects. Glu-

cose dysregulation, which can occur through both adiposity-dependent,

and adiposity–independent pathways, may arguably offer the strongest

translational value from rodents to humans. This talk will review what we

have learned from preclinical models of antipsychotic-induced metabolic

dysregulation, focusing on glucose dysregulation, plausible underlying

mechanisms, including our group’s recent work elucidating the role of

receptor binding profiles of antipsychotic medications, and contributions

of the central nervous system (CNS) to these perturbations. Discussion will

also turn to preclinical investigations of plausible interlinks between CNS

control of glucose metabolism and therapeutic pathways of antipsychotic

medications.

DOPAMINE D2 RECEPTORS REGULATE THE ANATOMICAL BALANCE OF

BASAL GANGLIA CIRCUITRY

Christoph Kellendonk, Maxime Cazorla, Fernanda Delmondes de Carvalho,

Muhammad O. Choha, Mariya Shegda, Nao Chuhma, Steve Rayport,

Susanne Ahmari, Holly Moore

Columbia University, New York State Psychiatric Institute, New York, NY

In the classical model of basal ganglia, striatal output projections are or-

ganized into two distinct pathways; the direct pathway – which directly

projects to the substantia nigra (SNr) – and the indirect pathway – which

projects to the external globus pallidus (GPe) and then relays through inter-

mediate neurons to the SNr. Both pathways are thought to be anatomically

segregated and to exert opposing effects on locomotor activity, motiva-

tional behavior and cognition. Single-cell tracing studies have challenged

the strict dichotomy between these pathways revealing that the vast ma-

jority of “direct” neurons possess collaterals to the GPe. Here, we show that

these collaterals, which bridge between the direct and indirect pathway are

highly plastic in the adult animal and are bi-directionally regulated by stri-

atal dopamine D2 receptors (D2R). Overexpression of D2Rs in the striatum

of the mouse selectively increases the extent of GPe collaterals of the direct

pathway via its effects on neuronal excitability of the indirect pathway. In

contrast, genetic downregulation of D2Rs selectively decreases the density

of striatonigral GPe collaterals. Increased direct pathway collaterals are

associated with stronger inhibition of pallidal neurons in vivo and with

disrupted behavioral activation after optogenetic stimulation of the direct

pathway. Remarkably, we found that chronic blockade with haloperidol, an

antipsychotic medication used to treat schizophrenia, decreases the extent

of bridging collaterals and rescues the locomotor imbalance. These findings

suggest a role for bridging collaterals in regulating the concerted balance

of striatal output connectivity and may have important implications for the

understanding of schizophrenia, a disease that involves excessive activation

of striatal D2Rs and that is traditionally treated with D2R blockers.

Workshop

NEUROSTIMULATION FOR PSYCHOTIC SYMPTOMS

Chairpersons: Remko van Lutterveld and Bob Oranje

Discussant: Renaud Jardri

Tuesday, 8 April 2014 6:30 PM – 8:30 PM

Overall Abstract: In recent years, there is increasing interest in neurostim-

ulation as a treatment option for psychotic symptoms. These include 1-Hz

repetitive magnetic stimulation (rTMS), with which brain activity is mod-

ulated using magnetic pulses at a 1-Hz frequency, theta-burst magnetic

stimulation (TBS), which is a similar technique using intermittent short

trains of magnetic pulses, transcranial direct current stimulation (tDCS),

which uses electrical current to alter brain activity and magnetic seizure

therapy (MST), which induces seizures through magnetic fields. In the cur-

rent symposium we present data from four research groups investigating

the efficacy and neural mechanisms of these promising neurostimulation

techniques. Dr. Jerome Brunelin will present data on the first double

blind sham-controlled randomized clinical trial of tDCS in the treatment

of psychotic symptoms as well as unpublished results concerning the

neural correlates of this technique. Dr. Philipp Homan will present new

findings regarding neuroimaging markers predicting response to rTMS and

tDCS neurostimulation therapy. Dr. Remko van Lutterveld will present new

findings concerning a large TBS double blind sham-controlled randomized

clinical trial on severity of auditory verbal hallucinations and Dr. Daniel

Blumberger will present new data regarding the first clinical trial using MST

to treat psychotic symptoms. Dr. Renaud Jardri will lead the discussion,

with a special focus on future direction to advance this research.

EFFECTS OF TRANSCRANIAL DIRECT CURRENT STIMULATION ON

TREATMENT-RESISTANT PYSCHOTIC SYMPTOMS AND BRAIN

FUNCTIONAL-CONNECTIVITY IN PATIENTS WITH SCHIZOPHRENIA

Jerome Brunelin1, Marine Mondino2, Renaud Jardri3, Emmanuel Poulet2

1CH le Vinatier; 2University of Lyon, UCB Lyon 1, CH Le Vinatier, Lyon, France;3CHRU Lille, Université de Lille, France

Objective: Even if mechanisms of action remain unclear, non invasive brain

stimulation techniques are thought to be usefull to alleviate treatment-

resistant auditory hallucinations and negative symptoms in patients with

schizophrenia. Our objective was to test whether transcranial Direct current

Stimulation (tDCS) applied over the left temporoparietal junction (assumed

“inhibitory” – cathode) and the left prefrontal cortex (assumed “excitatory”

– anode) can impact clinical symptoms and functional connectivity of tar-

geted regions in patients with schizophrenia presenting treatment-resistant

auditory verbal hallucinations. We hypothesized that tDCS alleviates symp-

toms by modulating functional connectivity of a distributed brain network

involving langage-related and self-recognition areas.

Method: In a double blind sham-controlled randomized clinical trial, thirty

patients with schizophrenia and treatment-resistant auditory verbal hallu-

cinations were randomly allocated to receive either 20 minutes of active

2mA tDCS or sham stimulation twice a day during 5 consecutive working