Hypofrontality in schizophrenia: Distributed dysfunctional circuits in neuroleptic-naive patients

Mental Health Clinical Research Centre and PET Imaging Center, University of Iowa College of Medicine and Hospitals and Clinics, Iowa City, IA 52242, USA
The Lancet (Impact Factor: 45.22). 07/1997; 349(9067):1730-1734. DOI: 10.1016/S0140-6736(96)08258-X

ABSTRACT BackgroundThere have been reports that patients with schizophrenia have decreased metabolic activity in prefrontal cortex. However, findings have been confounded by medication effects, chronic illness, and difficulties of measurement. We aimed to address these problems by examination of cerebral blood flow with positron emission tomography (PET).MethodsWe studied 17 neuroleptic-naïve patients at the early stages of illness by means of image analysis and statistical methods that can detect abnormalities at the gyral level.FindingsAn initial omnibus test with a randomisation analysis indicated that patients differed from normal controls at the 0·06 level. In the follow-up analysis, three separate prefrontal regions had decreased perfusion (lateral, orbital, medial), as well as regions in inferior temporal and parietal cortex that are known to be anatomically connected. Regions with increased perfusion were also identified (eg, thalamus, cerebellum, retrosplenial cingulate), which suggests an imbalance in distributed cortical and subcortical circuits.InterpretationThese distributed dysfunctional circuits may form the neural basis of schizophrenia through cognitive impairment of the brain, which prevents it from processing input efficiently and producing output effectively, thereby leading to symptoms such as hallucinations, delusions, and loss of volition.

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    • "In terms of cognitive dysfunction, the most consistent findings are within the domains of executive function, working memory, inhibitory control, and reasoning (Weinberger et al., 1986; Goldman-Rakic, 1994; Weickert et al., 2000a; Silver et al., 2003; Ravizza et al., 2010). Almost three decades of functional and structural neuroimaging studies in schizophrenia provide converging evidence of localized abnormal activity and connectivity of the prefrontal cortex (Weinberger et al., 1986; Andreasen et al., 1997; Manoach et al., 1999, 2000; Barch et al., 2001; Meyer-Lindenberg et al., 2001; Perlstein et al., 2001, 2003; Callicott et al., 2003; Tan et al., 2006; Potkin et al., 2009). The concomitant refinement of cognitive executive processes, the physical maturation of neural circuitry underlying executive function, and the onset of schizophrenia in adolescence or early adulthood suggests that a failure in these maturational processes may play a critical role in the pathophysiology of schizophrenia. "
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    ABSTRACT: The schizophrenia brain is differentiated from the normal brain by subtle changes, with significant overlap in measures between normal and disease states. For the past 25 years, schizophrenia has increasingly been considered a neurodevelopmental disorder. This frame of reference challenges biological researchers to consider how pathological changes identified in adult brain tissue can be accounted for by aberrant developmental processes occurring during fetal, childhood, or adolescent periods. To place schizophrenia neuropathology in a neurodevelopmental context requires solid, scrutinized evidence of changes occurring during normal development of the human brain, particularly in the cortex; however, too often data on normative developmental change are selectively referenced. This paper focuses on the development of the prefrontal cortex and charts major molecular, cellular, and behavioral events on a similar time line. We first consider the time at which human cognitive abilities such as selective attention, working memory, and inhibitory control mature, emphasizing that attainment of full adult potential is a process requiring decades. We review the timing of neurogenesis, neuronal migration, white matter changes (myelination), and synapse development. We consider how molecular changes in neurotransmitter signaling pathways are altered throughout life and how they may be concomitant with cellular and cognitive changes. We end with a consideration of how the response to drugs of abuse changes with age. We conclude that the concepts around the timing of cortical neuronal migration, interneuron maturation, and synaptic regression in humans may need revision and include greater emphasis on the protracted and dynamic changes occurring in adolescence. Updating our current understanding of post-natal neurodevelopment should aid researchers in interpreting gray matter changes and derailed neurodevelopmental processes that could underlie emergence of psychosis.
    Frontiers in Cellular Neuroscience 05/2013; 7:60. DOI:10.3389/fncel.2013.00060 · 4.18 Impact Factor
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    • "It has been assumed that the thalamocortical projections can be gated by neuronal regions in the MD thalamus or the IFG in schizophrenia (Andreasen et al., 1997; Negyessy and Goldman-Rakic, 2005). Thus, we adopted an approach that would allow us to model nonlinear biological responses expected for the HCST by the means of nonlinear DCMs. "
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    ABSTRACT: Nonlinear Dynamic Causal Modelling (DCM) for fMRI provides computational modelling of gating mechanisms at the neuronal population level. It allows for estimations of connection strengths with nonlinear modulation within task-dependent networks. This paper presents an application of nonlinear DCM in subjects at high familial risk of schizophrenia performing the Hayling Sentence Completion Task (HSCT). We analysed scans of 19 healthy controls and 46 subjects at high familial risk of schizophrenia, which included 26 high risk subjects without psychotic symptoms and 20 subjects with psychotic symptoms. The activity-dependent network consists of the intra parietal cortex (IPS), inferior frontal gyrus (IFG), middle temporal gyrus (MTG), anterior cingulate cortex (ACC) and the mediodorsal (MD) thalamus. The connections between the MD thalamus and the IFG were gated by the MD thalamus. We used DCM to investigate altered connection strength of these connections. Bayesian Model Selection (BMS) at the group and family level was used to compare the optimal bilinear and nonlinear models. Bayesian Model Averaging (BMA) was used to assess the connection strengths with the gating from the MD thalamus and the IFG. The nonlinear models provided the better explanation of the data. Furthermore, the BMA analysis showed significantly lower connection strength of the thalamocortical connection with nonlinear modulation from the MD thalamus in high risk subjects with psychotic symptoms and those who subsequently developed schizophrenia. These findings demonstrate that nonlinear DCM provides a method to investigate altered connectivity at the level of neural circuits. The reduced connection strength with thalamic gating may be a neurobiomarker implicated in the development of psychotic symptoms. This study suggests that nonlinear DCM could lead to new insights into functional and effective dysconnection at the network level in subjects at high familial risk.
    NeuroImage 02/2013; 73. DOI:10.1016/j.neuroimage.2013.01.063 · 6.36 Impact Factor
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    • "Tasks affording emotion discrimination and self-reflection have yielded hyperactivity of the region of the precuneus and PCRS in schizophrenia patients when compared with controls (Reske et al., 2009; Holt et al., 2011). Abnormally high metabolic rates and blood flow of these regions in schizophrenia patients have been reported as well (Andreasen et al., 1997; Haaznedar et al., 1997). "
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    ABSTRACT: Psychotic symptoms in schizophrenia are related to disturbed self-recognition and to disturbed experience of agency. Possibly, these impairments contribute to first-person large-scale egocentric learning deficits. Sixteen inpatients with schizophrenia and 16 matched healthy comparison subjects underwent functional magnetic resonance imaging (fMRI) while finding their way in a virtual maze. The virtual maze presented a first-person view, lacked any topographical landmarks and afforded egocentric navigation strategies. The participants with schizophrenia showed impaired performance in the virtual maze when compared with controls, and showed a similar but weaker pattern of activity changes during egocentric learning when compared with controls. Especially the activity of task-relevant brain regions (precuneus and posterior cingulate and retrosplenial cortex) differed from that of controls across all trials of the task. Activity increase within the right-sided precuneus was related to worse virtual maze performance and to stronger positive symptoms in participants with schizophrenia. We suggest that psychotic symptoms in schizophrenia are related to aberrant neural activity within the precuneus. Possibly, first-person large-scale egocentric navigation and learning designs may be a feasible tool for the assessment and treatment of cognitive deficits related to self-recognition in patients with schizophrenia.
    10/2012; 1(1):153–163. DOI:10.1016/j.nicl.2012.10.004
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