Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic-naïve patients

Andreasen, Nancy C.; O'Leary, Daniel S.; Flaum, Michael; Nopoulos, Peg; Watkins, G. Leonard; Ponto, Laura L. Boles; Hichwa, Richard D.

doi:10.1016/s0140-6736(96)08258-x

Cited by 545 publications

(294 citation statements)

References 27 publications

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“…Taken together with the results of other studies that have directly assessed the relationship of fronto-temporal dysfunction to illness severity (Andreasen et al, 1997;Lawrie et al, 2002;Fu et al, 2005), these findings indicate that the degree of left STG overactivation and abnormally positive STG-prefrontal interactions may be state-dependent, correlating with the severity of active illness, and tending to normalize during remission. However, patients in the current study were clinically stable and had mild to moderate symptoms indicating that abnormal fronto-temporal connectivity may be a trait-like variable.…”

Section: Discussionsupporting

confidence: 71%

“…While both groups in the current study activated VLPFC equally (Ragland et al, 2005), as in Jennings et al (1998) and Barch et al (2001), other studies have found increased task-related activity of VLPFC in schizophrenia (Kim et al, 2003;Bonner-Jackson et al, 2005;Tan et al, 2005). Overactivation of left inferior frontal cortex has also been observed in a resting PET study (Andreasen et al, 1997), and intriguingly, treatment with either haldoperidol or clozapine reduced VLPFC activity (Lahti et al, 2003).…”

Section: Discussionsupporting

confidence: 52%

“…In contrast, schizophrenia patients showed less STG deactivation (relative overactivation) and a positive prefrontal-STG correlation. Further evidence of reciprocal changes in left frontal and left temporal regions was provided by Yurgelen-Todd et al (1996) in an fMRI study of word fluency; by Andreasen et al (1997) in a resting-state PET study; and by Ragland and colleagues in a series of studies of word encoding and recognition (Ragland et al, 2001;.…”

Section: Introductionmentioning

confidence: 91%

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Alterations of fronto-temporal connectivity during word encoding in schizophrenia

Wolf

Gur

Valdez

et al. 2007

Psychiatry Research: Neuroimaging

106

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Cognitive deficits, including impaired verbal memory, are prominent in schizophrenia and lead to increased disability. Functional neuroimaging of patients with schizophrenia performing memory tasks has revealed abnormal activation patterns in prefrontal cortex and temporo-limbic regions. Aberrant fronto-temporal interactions thus represent a potential pathophysiological mechanism underlying verbal memory deficits, yet this hypothesis of disturbed connectivity is not tested directly with standard activation studies. We performed within-subject correlations of frontal and temporal timeseries to measure functional connectivity during verbal encoding. Our results confirm earlier findings of aberrant fronto-temporal connectivity in schizophrenia, and extend them by identifying distinct alterations within dorsal and ventral prefrontal cortex. Relative to healthy controls, patients with schizophrenia had reduced connectivity between the dorsolateral prefrontal cortex (DLPFC) and temporal lobe areas including parahippocampus and superior temporal gyrus. In contrast, patients showed increased connectivity between a region of ventrolateral prefrontal cortex (VLPFC) and these same temporal lobe regions. Higher temporal-DLPFC connectivity during encoding was associated with better subsequent recognition accuracy in controls, but not patients. Temporal-VLPFC connectivity was uncorrelated with recognition accuracy in either group. The results suggest that reduced temporal-DLPFC connectivity in schizophrenia could underlie encoding deficits, and increased temporal-VLPFC connectivity may represent an ineffective compensatory effort.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 91%

See 1 more Smart Citation

Alterations of fronto-temporal connectivity during word encoding in schizophrenia

Wolf

Gur

Valdez

et al. 2007

Psychiatry Research: Neuroimaging

106

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“…To our knowledge, this is the first application of the ASL method to investigate differences in resting perfusion in a schizotypy group. Given that the study groups only differed on the presence of schizotypal traits, and that hippocampal hyperperfusion has been reported in patients with psychosis (Friston et al, 1992; Liddle et al, 1992; Malaspina et al, 2004; Pinkham et al, 2011; Schobel et al, 2013, 2009; Talati et al, 2014, 2015; although see Andreasen et al, 1997; Catafau et al, 1994; Early et al, 1987; Parellada et al, 1994), and in people at CHR of sychosis (Allen et al, 2017, 2016; Schobel et al, 2013), our study findings suggest that increased hippocampal activity (reflected in an elevation of regional perfusion) is also involved in the expression of subclinical psychotic‐like experiences.…”

Section: Discussionmentioning

confidence: 99%

“…Beyond the hippocampus, other brain regions of significantly elevated resting perfusion in schizophrenia patients compared with healthy controls have involved the basal ganglia and middle temporal lobes (Pinkham et al, 2011), cerebellum, brainstem, and thalamus (Scheef et al, 2010). Noteworthy, while not directly focusing on the hippocampus as a specific region, initial PET and SPECT studies did not find increased perfusion in medial temporal regions (Andreasen et al, 1997; Catafau et al, 1994; Early, Reiman, Raichle, & Spitznagel, 1987; Parellada et al, 1994). A possible source for the inconsistencies noted among individual studies is that resting perfusion research in patients with schizophrenia is complicated by antipsychotic exposure (Lahti et al, 2006; Lahti, Weiler, Holcomb, Tamminga, & Cropsey, 2009; Medoff, Holcomb, Lahti, & Tamminga, 2001).…”

Section: Introductionmentioning

confidence: 99%

Increased resting perfusion of the hippocampus in high positive schizotypy: A pseudocontinuous arterial spin labeling study

Modinos

Egerton

McMullen

et al. 2018

Human Brain Mapping

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Arterial spin labeling (ASL) provides absolute quantification of resting tissue cerebral blood flow (CBF) as an entirely noninvasive approach with good reproducibility. As a result of neurovascular coupling, ASL provides a useful marker of resting neuronal activity. Recent ASL studies in individuals at clinical high risk of psychosis (CHR) have reported increased resting hippocampal perfusion compared with healthy controls. Schizotypy refers to the presence of subclinical psychotic‐like experiences in healthy individuals and represents a robust framework to study neurobiological mechanisms involved in the extended psychosis phenotype while avoiding potentially confounding effects of antipsychotic medications or disease comorbidity. Here we applied pseudo‐continuous ASL to examine differences in resting CBF in 21 subjects with high positive schizotypy (HS) relative to 22 subjects with low positive schizotypy (LS), as determined by the Oxford and Liverpool Inventory of Feelings and Experiences. Based on preclinical evidence that hippocampal hyperactivity leads to increased activity in mesostriatal dopamine projections, CBF in hippocampus, midbrain, and striatum was assessed. Participants with HS showed higher CBF of the right hippocampus compared to those with LS (p = .031, family‐wise error corrected). No differences were detected in the striatum or midbrain. The association between increased hippocampal CBF and HS supports the notion that hippocampal hyperactivity might be a central characteristic of the extended psychosis phenotype, while hyperactivity in subcortical dopamine pathways may only emerge at a higher intensity of psychotic experiences.

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A Unitary Model of Schizophrenia

Andreasen

1999

Arch Gen Psychiatry

549

115

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inding a unifying concept behind the diversity of signs and symptoms in schizophrenia is a central challenge to contemporary research. A neo-Bleulerian unitary model is described, which defines the illness as a neurodevelopmentally derived "misconnection syndrome," involving connections between cortical regions and the cerebellum mediated through the thalamus (the cortico-cerebellar-thalamic-cortical circuit [CCTCC]). An abnormality in this circuitry, normally used to coordinate both motor and mental activity, leads to misconnections in many aspects of mental activity, or "cognitive dysmetria." As Bleuler originally proposed, "thought disorder" is the primary defining feature of schizophrenia, rather than the more obvious signs and symptoms such as delusions and hallucinations. Cognitive dysmetria, or a disorder in the CCTCC, may provide a heuristic theoretical framework for strategies to explore etiology, pathophysiology, intervention, or prevention.

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Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic-naïve patients

Cited by 545 publications

References 27 publications

Alterations of fronto-temporal connectivity during word encoding in schizophrenia

Alterations of fronto-temporal connectivity during word encoding in schizophrenia

Increased resting perfusion of the hippocampus in high positive schizotypy: A pseudocontinuous arterial spin labeling study

A Unitary Model of Schizophrenia

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