Margaret Niznikiewicz, Ph.D. - US grants

DESCRIPTION: (provided by applicant) The broad aim of this five year study is to advance our understanding of language dysfunction in schizophrenia spectrum disorder using event-related potential, event-related gamma, experimental neuropsychological and clinical measures in three DSM-IV diagnosed clinical groups: chronic schizophrenia (CS), first episode schizophrenia (FES) and schizotypal personality disorder (SPD), and their matched normal controls. The use of the three clinical groups will afford studying both differences and similarities in language impairment across the schizophrenia spectrum. Similarities and differences in language processing in males and females in these three clinical groups will be studied as a secondary goal. In order to arrive at a comprehensive model of language dysfunction in the schizophrenia spectrum, we will use a heuristic model of language in which semantic organization includes three distinct but interacting components referred to as properties, processes, and content of semantic networks. Properties refer to connectivity weights among words, and to the size and the coherence of networks. Processes refer to activation, inhibition, and context use (both local and global). Network contents including words, numbers, and symbols will not be measured. We propose a gradual breakdown in language function with most impairment in CS>FES>SPD. We will test these hypotheses in a five-year study of three schizophrenia spectrum groups: 1) 30 patients with CS; 2) 30 patients with FES; and 3) 30 individuals with SPD, and 30 normal controls matched to each clinical group (n=90). Each control group will be matched for age, gender and parental SES to its respective clinical group and all subjects will be right handed, with English as their primary language. We will use ERP, event-related gamma, experimental neuropsychological, and clinicaldata (Thought Disorder Index TDI), to study language disorder in the three clinical groups. We thus predict over-activation in semantic networks as indexed by the N400, word-pair study at short stimulus onset asynchrony (SOA) in SPD, FES, and CS. The evidence of abnorma inhibitory/context utilization processes will be found in the N400, sentence and paragraph studies, with most severe impairment in CS>FES>SPD. The evidence of abnormal properties in semantic networks will be found in the neuropsychological study of word recall, in the N400, word-pair, short SOA study, and in the event-related gamma data, it FES and CS, but not in SPD. Correlational analyses among the four data sets will seek to characterize the relationships among the four domains of analysis.We predict that females will show less impairment than males on all these measures.

[unreadable] DESCRIPTION (provided by applicant): Language dysfunction in schizophrenia is believed to be an important component of schizophrenic psychopathology and a contributing factor to formal thought disorder. The features commonly observed in schizophrenic language include poverty of speech, derailment, loose associations, loss of goal, perseveration, tangentiality, and distractibility. In this application, we will focus on semantic aspects of language dysfunction in schizophrenia, more specifically the processes and structure of semantic memory in schizophrenia. There are two major hypotheses in the field regarding abnormal processes in semantic memory in schizophrenia. One holds that schizophrenia patients suffer from overactivation within semantic networks whereby activation spreads faster and/or more broadly, thus reaching semantic associates that would not be activated in the normal individuals. The other view holds that it is the late, controlled processes rather than early processes of automatic activation, which are abnormal in schizophrenia. Both theories can account for peculiar characteristics of schizophrenic language. In fact, almost all of the evidence in support of one or the other view comes from priming studies using either behavioral, or event related potential (ERP) measures. However, there are no published studies that explore brain activation in a priming paradigm in schizophrenia that map functional abnormalities onto the brain areas in a direct way. A major goal of this application is to contrast word priming using short and long stimulus onset asynchronies (SOAs) in order to evaluate differences in brain activation as a function of SOA in both normal and schizophrenic individuals. An additional goal of this application is to test whether categorical and associative priming paradigms are associated with unique patterns of activation and thus can inform our understanding of memory structure in both normal and schizophrenic individuals. In the case of schizophrenia, the question is whether persons suffering from this disorder have a structure of semantic memory similar to non-afflicted individuals, or whether that structure is different, given the fact that schizophrenia is partially genetically mediated and with a major developmental component. It is thus possible that abnormal links might develop within semantic memory and these may, in turn, contribute, at least in part, to some aspects of abnormal language observed in schizophrenia. Accordingly, a further goal of this application will be to explore brain activation patterns associated with processing of word- pairs that are related by either category membership or associative strength in both normal and schizophrenic individuals. Again, there are no published fMRI studies of semantic memory structure in schizophrenia, and only one fMRI study in normal individuals. Schizophrenia sufferers often use disordered language which makes successful social interactions difficult. However, understanding of underlying causes of language disorder in schizophrenia is far from complete, with most evidence coming from behavioral or event related potential studies. Thus, in this application we propose to use fMRI to describe possible abnormalities in semantic memory structure in schizophrenia and identify which brain structures are involved in mediating these abnormalities. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Auditory verbal hallucinations (AH) have long been a hallmark of schizophrenia (SZ) symptomatology and one of its major diagnostic features (Andreasen and Flaum, 1991; DSM-IV). It has been demonstrated that the brain regions implicated in AH are involved in different aspects of language processing. This brain network includes the temporal cortex and especially the superior temporal gyrus (STG), anterior cingulate (ACC), inferior frontal gyrus (IFG), and temporo-parietal junction (TPJ). Until recently, AH were primarily controlled with antipsychotic medication which was often ineffective. In this application, we propose to use a cutting-edge biofeedback method of real-time functional imaging neuro-feedback (rt-fMRI) to reduce the frequency of AH and to better understand brain processes involved in AH. We adopt the Hugdahl 2009 model of AH according to which AH result from abnormalities in self-monitoring of speech, in selective attention and in auditory perceptual processes. We focus on the role of auditory cortex, specifically the STG, as a target area of neuro-feedback training for the treatment of AH in SZ. Based on existing literature, we posit that that improved function in the STG will normalize the entire network involved in the experience of AH. We predict that the activation in the STG (and regions forming AH network: IFG, ACC, and TPJ) will increase as a result of receiving feedback from that region which will lead to a better performance on the task of recognizing self/other voice as measured by fMRI activation levels pre-and post-rt-fMRI training and by reduction in positive symptoms and especially AH. The rt-fMRI neuro-feedback relies on recent advances in computer technology that allows subjects to see the level of activation in the selected brain region and to regulate ths activation following the training provided. Subjects are taught to up-regulate or down-regulate fMRI signal within a specific brain region selected based on the activation task. Importantly, reported activation changes are possible only if the subject receives a feedback from his/her target area and not when she/he receives it from a different subject or a different area than the target one (sham). It has been recently demonstrated that this approach may be helpful in many clinical conditions, among them schizophrenia (Haller 2010; Sitaran 2011;Linden 2012;Veit 2009; Hartwell 2012; Li 2012, Ruiz 2011). In this study we propose to study 30 chronic SZ patients and 30 normal control (NC) individuals (half of them will receive real and half will receive a sham fMRI feedback). We will use both fMRI (including two measures of connectivity) and clinical measures of the effectiveness of the rt-fMRI feedback. Based on the existing literature and our preliminary data, we predict that we will successfully improve auditory processing within the STG and within the targeted network and that it will lead to improvement in the clinical symptoms and especially in the frequency of AH.

This is a resubmission application, originally in response to RFA-MH-16-406 and consists of R61 and R33 phases. Auditory verbal hallucinations (AH) have long been a hallmark of schizophrenia (SZ) and are one of its major diagnostic features Andreasen and Flaum 1991; DSM-IV). They are difficult to manage with existing treatment options. Here, we propose that neurofeedback aimed to regulate the superior temporal gyrus (STG) activation will not only lead to activation changes in the STG, but also to changes in the default mode network (DMN) (R61), as well as to reductions in AH (R33), and that the brain and clinical changes will be correlated (R33). The theoretical framework for the current proposal is an AH model that assumes that AH result from abnormalities in a network of regions including STG, and medial prefrontal cortex (MPFC) and posterior cingulate cortex (PCC), the two latter regions are core medial hubs of DMN that are related to self-referential processing. This model is supported by theoretical papers Northoff and Qin 2010, Alderson-Day,2016, and experimental evidence Gur 1995, Liddle 1992, Dierks 1999 as well as our preliminary data (PD). In both R61 and R33 we will study SZ patients with medication resistant AH in the rt-fMRI intervention arm and in the sham-rt-fMRI arm. In both arms, the task and the rt-fMRI session structure will be identical. The SZ-intervention group will receive feedback from the STG while SZ-sham group will receive feedback from the motor cortex. In addition, 2 functional fMRI tasks will examine the effect of rt-fMRI neurofeedback and of sham-rt-fMRI on brain response. In the R61, we will randomly assign 48 SZ patients to either SZ-intervention (n=24) or SZ-sham-rtfMRI (n=24). The STG targeted neurofeedback is predicted to bring changes in brain regions involved in AH (STG and DMN) in SZ-intervention group only. The R61 GO criterion will be BOLD signal reduction in the STG, and resting state connectivity reduction between MPFC-PCC, post rt-fMRI-feedback in SZ-intervention group. In the R33, SZ-intervention group (random n=52) will receive 5 sessions of rt-fMRI feedback targeting STG, while SZ-sham group (random n=52) will receive 5 sham-rt-fMRI sessions. Based on our PD, we predict that rt-fMRI feedback aimed at STG will reduce AH which will be, in turn, associated with reductions in the STG activation and in the DMN connectivity (i.e., brain changes achieved in R61 and replicated in R33) in SZ- intervention group only. Five sessions of rt-fMRI feedback will address the question of dose response at brain and clinical levels. The impact of rt-fMRI neurofeedback and of sham-rt-fMRI on AH (primary outcome), and on delusions, negative symptoms and working memory (WM) (exploratory outcome) will be assessed with clinical and neuropsychological measures. In an exploratory aim, based on the existing literature Garrity 2007; Whitfield-Gabrieli 2009; Rotarska-Jagiela 2010, we predict the improvement in delusions, negative symptoms and in WM score, only post-rt-fMRI neurofeedback targeting the STG and not post-sham-rt-fMRI.