Hypofrontality in schizophrenia: a meta‐analysis of functional imaging studies

Hill, K.; Mann, Louisa; Laws, Keith R.; Stephenson, C.; Nimmo‐Smith, Ian; McKenna, Peter J.

doi:10.1111/j.1600-0447.2004.00376.x

Cited by 293 publications

(180 citation statements)

References 128 publications

(204 reference statements)

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“…We have recently demonstrated involvement of dopamine D 1 receptors (McLean et al 2009a) while others have shown serotonin 5-HT 1A receptor involvement (Nagai et al 2009) in mechanisms for improvement of PCP-induced deficits in this task. This work combined with recent results from a preliminary study using female Long Evans rats suggests that the sub-chronic PCP treated rats have reduced prefrontal cortical dopamine activation in this task providing considerable support for this as a model of cognition in schizophrenia, as hypofrontality is a key feature of schizophrenia pathology (Hill et al 2004). In our study, sub-chronic vehicle treated rats showed significantly increased prefrontal cortical dopamine levels during the retention phase of the task only, as measured by in vivo microdialysis.…”

Section: Novel Object Recognitionmentioning

confidence: 60%

Animal models of cognitive dysfunction and negative symptoms of schizophrenia: Focus on NMDA receptor antagonism

Neill

Barnes

Cook

et al. 2010

Pharmacology & Therapeutics

475

322

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Cognitive deficits in schizophrenia remain an unmet clinical need. Improved understanding of the neuro-and psychopathology of these deficits depends on the availability of carefully validated animal models which will assist the development of novel therapies. There is much evidence that at least some of the pathology and symptomatology (particularly cognitive and negative symptoms) of schizophrenia results from a dysfunction of the glutamatergic system which may be modelled in animals through the use of NMDA receptor antagonists. The current review examines the validity of this model in rodents. We review the ability of acute and sub-chronic treatment with three non-competitive NMDA antagonists; phencyclidine (PCP), ketamine and MK801 (dizocilpine) to produce cognitive disturbances of relevance to schizophrenia in rodents and their subsequent reversal by first-and second-generation antipsychotic drugs. Effects of NMDA receptor antagonists on the performance of rodents in behavioural tests assessing the various domains of cognition and negative symptoms are examined: novel object recognition for visual memory, reversal learning and attentional set shifting for problem solving and reasoning, 5-choice serial reaction time for attention and speed of processing; in addition to effects on social behaviour and neuropathology. The evidence strongly supports the use of NMDA receptor antagonists to model cognitive deficit and negative symptoms of schizophrenia as well as certain pathological disturbances seen in the illness. This will facilitate the evaluation of much-needed novel therapies for improved therapy of cognitive deficits and negative symptoms in schizophrenia.

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Section: Novel Object Recognitionmentioning

confidence: 60%

Animal models of cognitive dysfunction and negative symptoms of schizophrenia: Focus on NMDA receptor antagonism

Neill

Barnes

Cook

et al. 2010

Pharmacology & Therapeutics

475

322

View full text Add to dashboard Cite

show abstract

“…In addition many studies, in both humans (Langsjo et al, 2004;Vollenweider et al, 1997aVollenweider et al, , 1997b and animals (Chih-Liang et al, 2011;Dawson et al, 2013), have been dedicated to elucidate the impact of acute, subanesthetic ketamine treatment on regional brain functioning, with PFC hypermetabolism (hyperfrontality) most consistently reported. The paradox of this ketamine-induced hyperfrontality given the hypofrontality characteristic of long-term schizophrenia (Hill et al, 2004) has not been resolved. Surprisingly, despite the widespread use of ketamine treatment as a translational model there is a relative paucity of data on how acute ketamine treatment impacts on the functional interactions between brain regions and the neural subsystems known to be dysfunctional in schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

Subanesthetic Ketamine Treatment Promotes Abnormal Interactions between Neural Subsystems and Alters the Properties of Functional Brain Networks

Dawson

McDonald

Higham

et al. 2014

Neuropsychopharmacol

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Acute treatment with subanesthetic ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, is widely utilized as a translational model for schizophrenia. However, how acute NMDA receptor blockade impacts on brain functioning at a systems level, to elicit translationally relevant symptomatology and behavioral deficits, has not yet been determined. Here, for the first time, we apply established and recently validated topological measures from network science to brain imaging data gained from ketamine-treated mice to elucidate how acute NMDA receptor blockade impacts on the properties of functional brain networks. We show that the effects of acute ketamine treatment on the global properties of these networks are divergent from those widely reported in schizophrenia. Where acute NMDA receptor blockade promotes hyperconnectivity in functional brain networks, pronounced dysconnectivity is found in schizophrenia. We also show that acute ketamine treatment increases the connectivity and importance of prefrontal and thalamic brain regions in brain networks, a finding also divergent to alterations seen in schizophrenia. In addition, we characterize how ketamine impacts on bipartite functional interactions between neural subsystems. A key feature includes the enhancement of prefrontal cortex (PFC)-neuromodulatory subsystem connectivity in ketamine-treated animals, a finding consistent with the known effects of ketamine on PFC neurotransmitter levels. Overall, our data suggest that, at a systems level, acute ketamine-induced alterations in brain network connectivity do not parallel those seen in chronic schizophrenia. Hence, the mechanisms through which acute ketamine treatment induces translationally relevant symptomatology may differ from those in chronic schizophrenia. Future effort should therefore be dedicated to resolve the conflicting observations between this putative translational model and schizophrenia.

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“…The specificity of the purported relationships between task performance and the frontal lobes requires further examination in schizophrenia using imaging techniques. However, a meta-analytic review of imaging studies has confirmed the presence of ' hypofrontality ' in schizophrenia patients, both for resting and cognitive challenge studies (see Hill et al 2004).…”

Section: Introductionmentioning

confidence: 99%

The neuropsychology of the schizo-obsessive subtype of schizophrenia: a new analysis

et al. 2009

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Background. Interest in the neuro-cognitive profile of patients with schizophrenia and co-morbid obsessive compulsive disorder (schizo-OCD) is rising in response to reports of high co-morbidity rates. Whereas schizophrenia has been associated with global impairment in a wide range of neuro-cognitive domains, OCD is associated with specific deficits featuring impaired performance on tasks of motor and cognitive inhibition involving frontostriatal neurocircuitry.Method. We compared cognitive function using the CANTAB battery in patients with schizo-OCD (n=12) and a schizophrenia group without OCD symptoms (n=16). The groups were matched for IQ, gender, age, medication, and duration of illness.Results. The schizo-OCD patients made significantly more errors on a task of attentional set-shifting (ID-ED set-shift task). By contrast, no significant differences emerged on the Stockings of Cambridge task, the Cambridge Gamble Task or the Affective Go/NoGo tasks. No correlation emerged between ID-ED performance and severity of schizophrenia, OCD or depressive symptoms, consistent with neurocognitive impairment holding trait rather than statemarker status. Schizo-obsessives also exhibited a trend toward more motor tics emphasizing a neurological contribution to the disorder. Conclusion.Our findings reveal a more severe attentional set-shifting deficit and neurological abnormality that may be fundamental to the neuro-cognitive profile of schizo-OCD. The clinical implications of these impairments merit further exploration in larger studies.

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Hypofrontality in schizophrenia: a meta‐analysis of functional imaging studies

Abstract: Meta-analysis supports resting hypofrontality in schizophrenia. Task-activated hypofrontality is also supported, but there is little from voxel-based studies to suggest that this is associated with an altered pattern of regional functional architecture.

Cited by 293 publications

References 128 publications

Animal models of cognitive dysfunction and negative symptoms of schizophrenia: Focus on NMDA receptor antagonism

Animal models of cognitive dysfunction and negative symptoms of schizophrenia: Focus on NMDA receptor antagonism

Subanesthetic Ketamine Treatment Promotes Abnormal Interactions between Neural Subsystems and Alters the Properties of Functional Brain Networks

The neuropsychology of the schizo-obsessive subtype of schizophrenia: a new analysis

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