Neural correlates of tactile prepulse inhibition: a functional MRI study in normal and schizophrenic subjects

Kumari, Veena; Gray, Jeffrey A.; Geyer, Mark A.; ffytche, Dominic H.; Soni, William; Mitterschiffthaler, Martina; Vythelingum, Goparlen N.; Simmons, Andrew; Williams, Steve; Sharma, Tonmoy

doi:10.1016/s0925-4927(02)00123-3

Cited by 162 publications

(147 citation statements)

References 52 publications

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“…Moreover, Owen and Downes (1990) found that patients with frontal lobe damage required more moves to solve the problem, and also exhibited prolonged subsequent thinking time in the SOC task. Our finding that high and low PPI subjects differ in their performance of tasks involving the prefrontal cortex supports the putative role of the prefrontal cortex in the modulation of PPI, a claim which is consistent with previous animal and human studies (Hazlett et al, 1998;Hazlett and Buchsbaum, 2001;Zavitsanou et al, 1999;Bubser and Koch, 1994;Kumari et al, 2003).…”

Section: Relationship Between Neuropsychological Performance and Prepsupporting

confidence: 92%

Haloperidol Differentially Modulates Prepulse Inhibition and P50 Suppression in Healthy Humans Stratified for Low and High Gating Levels

Csomor

Stadler

Feldon

et al. 2007

Neuropsychopharmacol

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102

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Schizophrenia patients exhibit deficits in sensory gating as indexed by reduced prepulse inhibition (PPI) and P50 suppression, which have been linked to psychotic symptom formation and cognitive deficits. Although recent evidence suggests that atypical antipsychotics might be superior over typical antipsychotics in reversing PPI and P50 suppression deficits not only in schizophrenia patients, but also in healthy volunteers exhibiting low levels of PPI, the impact of typical antipsychotics on these gating measures is less clear. To explore the impact of the dopamine D 2 -like receptor system on gating and cognition, the acute effects of haloperidol on PPI, P50 suppression, and cognition were assessed in 26 healthy male volunteers split into subgroups having low vs high PPI or P50 suppression levels using a placebocontrolled within-subject design. Haloperidol failed to increase PPI in subjects exhibiting low levels of PPI, but attenuated PPI in those subjects with high sensorimotor gating levels. Furthermore, haloperidol increased P50 suppression in subjects exhibiting low P50 gating and disrupted P50 suppression in individuals expressing high P50 gating levels. Independently of drug condition, high PPI levels were associated with superior strategy formation and execution times in a subset of cognitive tests. Moreover, haloperidol impaired spatial working memory performance and planning ability. These findings suggest that dopamine D 2 -like receptors are critically involved in the modulation of P50 suppression in healthy volunteers, and to a lesser extent also in PPI among subjects expressing high sensorimotor gating levels. Furthermore, the results suggest a relation between sensorimotor gating and working memory performance.

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Section: Relationship Between Neuropsychological Performance and Prepsupporting

confidence: 92%

Haloperidol Differentially Modulates Prepulse Inhibition and P50 Suppression in Healthy Humans Stratified for Low and High Gating Levels

Csomor

Stadler

Feldon

et al. 2007

Neuropsychopharmacol

Self Cite

102

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“…The sensory overload resulting from reduced sensorimotor gating is thought to give rise to cognitive fragmentation, attentional deficits, and some of the complex clinical symptoms associated with this disorder (Geyer et al, 1990). PPI in rodents is modulated by activity in a welldefined cortico-striato-pallido-pontine circuitry (Swerdlow et al, 1992(Swerdlow et al, , 2001), which has been confirmed by functional imaging studies in humans (Kumari et al, 2003(Kumari et al, , 2007Postma et al, 2006;Campbell et al, 2007). PPI levels predict gray matter availability in frontal cortical areas in patients with schizophrenia (Kumari et al, 2008), which extends to the hippocampal, striatal, thalamic, and temporal regions in healthy subjects (Kumari et al, 2005).…”

Section: Introductionmentioning

confidence: 88%

Improvement of Prepulse Inhibition and Executive Function by the COMT Inhibitor Tolcapone Depends on COMT Val158Met Polymorphism

Giakoumaki

Roussos

Bitsios

2008

Neuropsychopharmacol

129

105

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Recent evidence suggests that prepulse inhibition (PPI) levels relate to executive function possibly by a prefrontal cortex (PFC) dopamine (DA) link. We explored the effects of enhanced PFC DA signaling by the nonstimulant catechol-O-methyltransferase (COMT) inhibitor tolcapone, on PPI and working memory of subjects homozygous for the Val (low PFC DA) and the Met (high PFC DA) alleles of the COMT Val158Met polymorphism. Twelve Val/Val and eleven Met/Met healthy male subjects entered the study. Tolcapone 200 mg was administered in two weekly sessions, according to a balanced, crossover, double-blind, placebo-controlled design. PPI was assessed with 5 dB and 15 dB above background prepulses, at 30-, 60-, and 120 ms prepulse-pulse intervals. Subjects also underwent the n-back and the letter-number sequencing (LNS) tasks. PPI was lower in the Val/Val compared to the Met/Met group in the placebo condition. Tolcapone increased PPI significantly in the Val/Val group and tended to have the opposite effect in the Met/Met group. Baseline startle was not affected by tolcapone in the Val/Val group but it was slightly increased in the Met/Met group. Tolcapone improved performance in the n-back and LNS tasks only in the Val/Val group. Enhancement of PFC DA signaling with tolcapone improves both PPI and working memory in a COMT Val158Met genotype-specific manner. These results suggest that early information processing and working memory may both depend on PFC DA signaling, and that they may both relate to PFC DA levels according to an inverted U-shaped curve function. Neuropsychopharmacology (2008) 33, 3058-3068; doi:10.1038/npp.2008 published online 4 June 2008 Keywords: prepulse inhibition; sensorimotor gating; prefrontal cortex; dopamine; cognition; working memory INTRODUCTIONThe enzyme catechol-O-methyltransferase (COMT) is the main catabolic pathway by which dopamine (DA) is removed from the cortical synaptic cleft in humans (Karoum et al, 1994). Indeed, COMT is found in high concentrations in the cortex relative to subcortical regions (Matsumoto et al, 2003) consistent with the absence of functional DA transporters in cortical areas such as the prefrontal cortex (PFC) and hippocampus (Mazei et al, 2002). The Val158Met polymorphism in the COMT gene leads to an amino-acid substitution (valine (Val) to methionine (Met)) and results in the Met/Met variant showing 40% less enzymatic activity than the Val/Val (Chen et al, 2004). There is now abundant evidence (reviewed in Harrison and Weinberger, 2005;Tunbridge et al, 2006) that Met158 allele loading is dose dependently associated with superior performance on a variety of cognitive tests assessing executive function, as well as prefrontal physiology as assessed by neuroimaging. The evidence suggests that PFC DA facilitates 'focusing and stabilizing' activity in PFC networks during executive cognition, ie enhances prefrontal physiologic 'efficiency' by reduction of prefrontal noise (Cools et al, 2002;Mattay et al, 2002Mattay et al, , 2003.Prepulse inhibition (PPI) is thought...

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“…The apparent overlap in the neural substrates regulating PPI, with those implicated in the pathophysiology of schizophrenia, is part of the support for the construct validity of animal models for impaired PPI in schizophrenia and has been used in an iterative cross-species strategy. In this strategy, PPI changes after neural circuit manipulations in laboratory animals have been used to develop and then test hypotheses about specific circuit disturbances in patients (e.g., Kumari et al 2003), and in some cases, circuit-based therapeutics are being modeled based on PPI deficits in rats (e.g., Posch et al 2012;Angelov et al 2014;Ma and Leung 2014). Often, when substrates have been demonstrated to regulate PPI in rodents, the fact that PPI is deficient in schizophrenia patients has been used as the basis for justifying a fine grain analysis of those substrates in rats, in terms of their anatomical, neurochemical, and molecular properties.…”

Section: The Evolution Of Prepulse Inhibition As a Validated Animal Mmentioning

confidence: 99%

Animal Models of Deficient Sensorimotor Gating in Schizophrenia: Are They Still Relevant?

Swerdlow

Light

2015

Translational Neuropsychopharmacology

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Animal models of impaired sensorimotor gating, as assessed by prepulse inhibition (PPI) of startle, have demonstrated clear validity at face, predictive, and construct levels for schizophrenia (SZ) therapeutics, neurophysiological endophenotypes, and potential causative insults for this group of disorders. However, with the growing recognition of the heterogeneity of the schizophrenias, and the less sanguine view of the clinical value of antipsychotic (AP) medications, our field must look beyond "validity," to assess the actual utility of these models. At a substantial cost in terms of research support and intellectual capital, what has come from these models, that we can say has actually helped schizophrenia patients? Such introspection is timely, as we are reassessing not only our view of the genetic and pathophysiological diversity of these disorders, but also the predominant strategies for SZ therapeutics; indeed, our field is gaining awareness that we must move away from a "find what's broke and fix it" approach, toward identifying spared neural and cognitive function in SZ patients, and matching these residual neural assets with learning-based therapies. Perhaps, construct-valid models that identify evidence of "spared function" in neural substrates might reveal opportunities for future therapeutics and allow us to study these substrates at a mechanistic level to maximize opportunities for neuroplasticity. Such an effort will require a retooling of our models, and more importantly, a re-evaluation of their utility. For animal models to remain relevant in the search for schizophrenia therapeutics, they will need to focus less on what is valid and focus more on what is useful.

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Neural correlates of tactile prepulse inhibition: a functional MRI study in normal and schizophrenic subjects

Cited by 162 publications

References 52 publications

Haloperidol Differentially Modulates Prepulse Inhibition and P50 Suppression in Healthy Humans Stratified for Low and High Gating Levels

Haloperidol Differentially Modulates Prepulse Inhibition and P50 Suppression in Healthy Humans Stratified for Low and High Gating Levels

Improvement of Prepulse Inhibition and Executive Function by the COMT Inhibitor Tolcapone Depends on COMT Val158Met Polymorphism

Animal Models of Deficient Sensorimotor Gating in Schizophrenia: Are They Still Relevant?

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