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


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.

10 Reads
  • Source
    • "A third study showed that the right posterior parietal cortex (BA 7/40) was overactive during target anticipation during a working memory task in schizophrenic patients (Quintana et al., 2003a). In addition to these findings in posterior or superior/dorsal parietal cortex, a number of studies have found that the metabolism, task-induced responses or functional connectivity of medial parietal cortex (i.e., the posterior cingulate gyrus and/or precuneus) is abnormally elevated in schizophrenic patients (Andreasen et al., 1997; Ebisch et al., 2014; Haznedar et al., 1997; Holt et al., 2011a; Holt et al., 2011b; Reske et al., 2009). Overall, these reports suggest that the function of both the medial and dorsal parietal cortex may be altered in schizophrenia. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Schizophrenia is associated with subtle abnormalities in day-to-day social behaviors, including a tendency in some patients to “keep their distance” from others in physical space. The neural basis of this abnormality, and related changes in social functioning, is unknown. Here we examined, in schizophrenic patients and healthy control subjects, the functioning of a parietal–frontal network involved in monitoring the space immediately surrounding the body (“personal space”). Using fMRI, we found that one region of this network, the dorsal intraparietal sulcus (DIPS), was hyper-responsive in schizophrenic patients to face stimuli appearing to move towards the subjects, intruding into personal space. This hyper-responsivity was predicted both by the size of personal space (which was abnormally elevated in the schizophrenia group) and the severity of negative symptoms. In contrast, in a second study, the activity of two lower-level visual areas that send information to DIPS (the fusiform face area and middle temporal area) was normal in schizophrenia. Together, these findings suggest that changes in parietal–frontal networks that support the sensory-guided initiation of behavior, including actions occurring in the space surrounding the body, contribute to social dysfunction and negative symptoms in schizophrenia.
  • Source
    • "We therefore have been exploring hypothetical genes that are developmentally regulated and PCP- or methamphetamine-responsive as candidate schizophrenia-related molecules in the rat or mouse brain. These screening analyses have been performed in the neocortex and thalamus because: (i) neurochemical, neuropathological, neurophysiological, and brain imaging studies in vivo or in the postmortem brains of schizophrenic patients have consistently highlighted the malfunctions of neural circuits within and/or between the prefrontal and temporal cortex, and other neocortical regions, and thalamic nuclei [4]–[10]; and (ii) the neocortex, thalamus, and their connections have been shown to be major targets for the therapeutic actions of antipsychotic drugs or psychotomimetic effects of NMDA receptor antagonists or dopamine agonists in humans [11]–[14] and experimental animals [15]–[18]. We have identified such candidate genes including CCN1 [19], SAP97 [20], and Lmod2 [1], and a novel gene mrt1 encoding sorting nexin proteins with PX-, PDZ-, and SH-domains [21] from the rat neocortex or thalamus by employing a differential cloning technique or DNA microarray. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Schizophrenia and similar psychoses induced by NMDA-type glutamate receptor antagonists, such as phencyclidine (PCP) and ketamine, usually develop after adolescence. Moreover, adult-type behavioral disturbance following NMDA receptor antagonist application in rodents is observed after a critical period at around 3 postnatal weeks. These observations suggest that the schizophrenic symptoms caused by and psychotomimetic effects of NMDA antagonists require the maturation of certain brain neuron circuits and molecular networks, which differentially respond to NMDA receptor antagonists across adolescence and the critical period. From this viewpoint, we have identified a novel developmentally regulated phencyclidine-responsive transcript from the rat thalamus, designated as prt6, as a candidate molecule involved in the above schizophrenia-related systems using a DNA microarray technique. The transcript is a non-coding RNA that includes sequences of at least two microRNAs, miR132 and miR212, and is expressed strongly in the brain and testis, with trace or non-detectable levels in the spleen, heart, liver, kidney, lung and skeletal muscle, as revealed by Northern blot analysis. The systemic administration of PCP (7.5 mg/kg, subcutaneously (s.c.)) significantly elevated the expression of prt6 mRNA in the thalamus at postnatal days (PD) 32 and 50, but not at PD 8, 13, 20, or 24 as compared to saline-treated controls. At PD 50, another NMDA receptor antagonist, dizocilpine (0.5 mg/kg, s.c.), and a schizophrenomimetic dopamine agonist, methamphetamine (4.8 mg/kg, s.c.), mimicked a significant increase in the levels of thalamic prt6 mRNAs, while a D2 dopmamine receptor antagonist, haloperidol, partly inhibited the increasing influence of PCP on thalamic prt6 expression without its own effects. These data indicate that prt6 may be involved in the pathophysiology of the onset of drug-induced schizophrenia-like symptoms and schizophrenia through the possible dysregulation of target genes of the long non-coding RNA or microRNAs in the transcript.
    PLoS ONE 06/2014; 9(6):e97955. DOI:10.1371/journal.pone.0097955 · 3.23 Impact Factor
  • Source
    • "Altered brain activation has often been reported in frontal regions during cognitive demanding tasks [1,2]. The term hypofrontality has been used by several authors to define this effect, which also has been seen in first-episode patients with schizophrenia [2] and neuroleptic-naive patients [1]. Recent studies present however a more complex picture, including for instance compensatory increased activation in other brain regions [1], altered brain activation in schizophrenia is seen as a reflection of the cognitive impairments in this patient group [2]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background In patients with schizophrenia, altered brain activation and motor activity levels are central features, reflecting cognitive impairments and negative symptoms, respectively. Newer studies using nonlinear methods have addressed the severe disturbances in neurocognitive functioning that is regarded as one of the core features of schizophrenia. Our aim was to compare brain activation and motor activity in a patient during pharmacological treatment that was switched from a first- to a second-generation antipsychotic drug. We hypothesised that this change of medication would increase level of responding in both measures. Case presentation We present the case of a 53-year-old male with onset of severe mental illness in adolescence, ICD-10 diagnosed as schizophrenia of paranoid type, chronic form. We compared brain activation and motor activity in this patient during pharmacological treatment with a first-generation (perphenazin), and later switched to a second-generation (risperidone) antipsychotic drug. We used functional magnetic resonance imaging (fMRI) to measure brain activation and wrist worn actigraphy to measure motor activity. Conclusion Our study showed that brain activation decreased in areas critical for cognitive functioning in this patient, when changing from a first to a second generation antipsychotic drug. However the mean motor activity level was unchanged, although risperidone reduced variability, particularly short-term variability from minute to minute. Compared to the results from previous studies, the present findings indicate that changing to a second-generation antipsychotic alters variability measures towards that seen in a control group, but with reduced brain activation, which was an unexpected finding.
    BMC Research Notes 08/2013; 6(1):332. DOI:10.1186/1756-0500-6-332
Show more