Deficits In Schizophrenia Patients Research Articles

Time discrimination deficits in schizophrenia patients with first-rank (passivity) symptoms

Schizophrenia patients with first-rank (passivity) symptoms (FRS) report a loss of clear boundaries between the self and others and that their thoughts and actions are controlled by external forces. One of the more widely accepted explanatory models of FRS suggests a dysfunction in the ‘forward model’ system, whose role consists in predicting the sensory consequences of actions [Frith, C., 2006. The neural basis of hallucinations and delusions. Comptes Rendus Biologies 328, 169–175.]. There has been recent interest in the importance of timing precision underlying both the functioning of the forward model, and in processes contributing to the mechanisms of self-recognition [Haggard, P., Martin, F., Taylor-Clarke, M., Jeannerod, M., Franck, N., 2003. Awareness of action in schizophrenia. Neuroreport 14, 1081–1085.]. In the current study, we examined whether schizophrenia patients with FRS have a time perception impairment, using an auditory discrimination task requiring judgments of temporal intervals. Thirty-five schizophrenia patients (15 with, and 20 without, FRS), and 16 non-clinical controls completed the task. The results showed that patients with FRS experienced time differently by underestimating the duration of time intervals. Given the role of timing in shaping sensory awareness and in the formation of causal mental associations, a breakdown in timing mechanisms may affect the processes relating to the perceived control of actions and mental events, leading to disturbances of self-recognition in FRS.

Specific cognitive deficits in a group at genetic high risk of schizophrenia

Neuropsychological deficits in schizophrenia patients and their relatives have been thought to represent possible genetic vulnerability markers or endophenotypes of the disorder. The present study describes results from the Edinburgh High Risk Study of computerized testing using the Cambridge Neuropsychological Test Automated Battery (CANTAB) on a group at genetic high risk (HR) of schizophrenia and a control group. A total of 97 HR and 25 control participants were assessed on three tests from the CANTAB - spatial span, spatial working memory, and Stockings of Cambridge. Analyses of covariance were used to compare the HR and control groups on the main outcome measures whilst controlling for intelligence quotient (IQ). Subsequent analysis examined the effects of the presence of symptoms on group differences. HR participants had significantly reduced spatial memory capacity [F(1, 118)=4.06, p=0.046] and significantly reduced planning processing speed [F(1, 116)=4.16, p=0.044] compared with controls even after controlling for general intelligence (IQ). Although HR individuals made more errors and showed poorer problem-solving and strategy performance compared with controls, these differences were not significant after controlling for IQ. Subsequent analysis indicated that the presence or absence of psychotic symptoms in the HR group did not influence these specific cognitive deficits. Spatial memory capacity and planning processing speed may represent cognitive endophenotypes characterising the genetic predisposition to schizophrenia in this HR group.

Association of Cerebral Deficits With Clinical Symptoms in Antipsychotic-Naive First-Episode Schizophrenia: An Optimized Voxel-Based Morphometry and Resting State Functional Connectivity Study

The purpose of the present study was to characterize the association between clinical symptoms and anatomical and functional cerebral deficits in a relatively large sample of antipsychotic-naive first-episode schizophrenia patients using optimized voxel-based morphometry and resting state functional connectivity analysis. Participants were 68 antipsychotic-naive first-episode schizophrenia patients and 68 matched healthy comparison subjects. Both patients and healthy comparison subjects were scanned using a volumetric three-dimensional spoiled gradient recall sequence and a gradient-echo echo-planar imaging sequence. Psychopathology of first-episode schizophrenia patients was evaluated using the Positive and Negative Syndrome Scale (PANSS). Optimized voxel-based morphometry was used to characterize gray matter deficits in schizophrenia patients. The clinical significance of regional volume reduction was investigated by examining its association with symptoms in patients with first-episode schizophrenia and with alterations in resting state functional connectivity when brain regions with gray matter volume reduction were used as seed areas. Significantly decreased gray matter volume was observed in schizophrenia patients in the right superior temporal gyrus (Brodmann's area 41), right middle temporal gyrus (Brodmann's area 21), and right anterior cingulate gyrus (Brodmann's area 32). Decreased gray matter volume in these brain regions was related to greater disturbance as shown on PANSS scores for positive symptoms, general psychopathology symptoms, thought disturbance, activation, paranoia, and impulsive aggression as well as total PANSS scores. A positive correlation was observed between PANSS scores for thought disturbance and temporo-putamen connectivity, and negative correlations were found between temporo-precuneus connectivity and total PANSS scores as well as scores for negative symptoms and anergia. The findings revealed volume loss in the right superior temporal gyrus, right middle temporal gyrus, and right anterior cingulate gyrus among antipsychotic-naive first-episode schizophrenia patients. In addition, the functional networks involving the right superior temporal gyrus and middle temporal gyrus were associated with clinical symptom severity. No abnormalities were observed in resting state connectivity with regions of identified gray matter deficits.

Increased extent of object-selective cortex in schizophrenia

Schizophrenia patients exhibit deficits in various stages of visual information processing. Despite recent informative efforts to examine visual processing in schizophrenia with functional magnetic resonance imaging (fMRI), much remains unknown about the basic function, structure, and organization of key early visual processing areas in schizophrenia. This study examined magnitude and topography of regional brain activity in three early visual processing areas: early retinotopically organized areas (V1-V4), motion-sensitive areas (human area MT, hMT+), and object-recognition areas (lateral occipital complex, LO). Using visual stimuli that are known to preferentially activate each respective region, we compared responses in these areas in 22 schizophrenia patients and 19 normal controls. Activity in all three regions was of similar amplitude in schizophrenia patients and normal controls. Activity in retinotopically organized areas and hMT+ showed good spatial overlap between groups. However, activation of LO was more widely distributed in patients compared with normal controls. The findings of abnormal spatial organization of LO in schizophrenia patients may converge with behavioral evidence of deficits in schizophrenia patients for object-recognition tasks that are believed to be mediated by LO activity.

Improvements in Autobiographical Memory in Schizophrenia Patients after a Cognitive Intervention

Background: Schizophrenia is associated with a reduction in accessing specific autobiographical information. This is consistent with the abnormal development of personal identity that characterizes this mental disorder. Using a schizophrenic population, the present study evaluates the effect of a cognitive intervention on autobiographical memory and the capacity to project oneself in the future. Sampling and Method: The intervention consisted of group sessions, during which participants were trained to recollect specific events reported in their diary. Furthermore, exercises to stimulate their thoughts about their personal identity were proposed. An autobiographical memory test was administrated before the intervention, after the intervention and at the 3-month follow-up. In addition, neuropsychological and affective assessments were conducted before and after treatments. Patients’ performances were compared to those from the control group. Results: The ability to recall specific events was improved by the cognitive intervention, and the benefits were preserved 3 months later. However, no neuropsychological or affective benefit was found. Conclusion: Despite positive results on specific memory, any significant benefits have yet to be extended to other clinical variables such as symptom reduction and neuropsychological/social functioning. Nevertheless, the results revealed that cognitive remediation therapy could be a useful additional intervention for autobiographical memory deficits in schizophrenia patients.

Optimized mismatch negativity reflects deficits in schizophrenia patients in a combined EEG and MEG study

Optimized mismatch negativity reflects deficits in schizophrenia patients in a combined EEG and MEG study

Optimized mismatch negativity paradigm reflects deficits in schizophrenia patients: A combined EEG and MEG study

Mismatch negativity (MMN) and its neuromagnetic analog (MMNm) are event-related brain responses elicited by changes in a sequence of auditory events and indexes early cognitive processing. It consistently detects neural processing deficits in schizophrenia. So far MMN is assessed with different methods (electroencephalography, EEG; magnetoencephalography, MEG) and with different paradigms: the “traditional” oddball design with rare deviants (20%) or the “optimum” design with 50% deviants varying in one of five parameters each. These MMN measures may not reflect one unitary mechanism which is equally affected in schizophrenia. We compared both designs in 12 patients with schizophrenia and controls using MEG and EEG. Automated, observer-independent data analysis rendered the procedures suitable for clinical applications. The optimum design was fastest to detect MMN and MEG had the best signal-to-noise ratio. In addition MMN was mostly reduced in schizophrenia if measured with MEG in the optimum paradigm. Optimized paradigms improve sensitivity and speed for the detection of schizophrenia endophenotypes. Dysfunctions in this disorder may lie primarily in the fast and automatic encoding of stimulus features at the auditory cortex.

Effects of olanzapine, risperidone and haloperidol on prepulse inhibition in schizophrenia patients: A double-blind, randomized controlled trial

Prepulse inhibition (PPI), whereby the startle eyeblink response is inhibited by a relatively weak non-startling stimulus preceding the powerful startle eliciting stimulus, is a measure of sensorimotor gating and has been shown to be deficient in schizophrenia patients. There is considerable interest in whether conventional and/or atypical antipsychotic medications can “normalize” PPI deficits in schizophrenia patients. 51 schizophrenia patients participated in a randomized, double-blind controlled trial on the effects of three commonly-prescribed antipsychotic medications (risperidone, olanzapine, or haloperidol) on PPI, startle habituation, and startle reactivity. Patients were tested at baseline, Week 4 and Week 8. Mixed model regression analyses revealed that olanzapine significantly improved PPI from Week 4 to Week 8, and that at Week 8 patients receiving olanzapine produced significantly greater PPI than those receiving risperidone, but not haloperidol. There were no effects of medication on startle habituation or startle reactivity. These results support the conclusion that olanzapine effectively increased PPI in schizophrenia patients, but that risperidone and haloperidol had no such effects. The results are discussed in terms of animal models, neural substrates, and treatment implications.

Prepulse Inhibition and P50 Suppression Are Both Deficient but not Correlated in Schizophrenia Patients

Inhibitory measures such as prepulse inhibition of the acoustic startle reflex (PPI) and event related potential P50 suppression have been widely reported to show deficits in schizophrenia patients. The relationship between PPI and P50 suppression in schizophrenia patients has remained unclear. One hundred fifty-six schizophrenia patients and 104 normal comparison subjects (NCS) were tested on PPI and P50 suppression. Eighty-one patients and 70 NCS had valid and scorable data on both PPI and P50 suppression paradigms. As in the larger groups, these cohorts had deficits on both PPI (p < .05) and P50 suppression (p < .05). Analyses revealed a weak, but significant correlation between PPI and P50 suppression in the NCS group (r = .33, p < .05) but not in the patient group (r = .03, ns). Although PPI and P50 suppression were both reduced in the patients, they were not correlated. This divergence suggests that these gating functions are complementary or redundant levels of "protection" against processes that may lead to cognitive fragmentation.

Smoking Cessation and Schizophrenia

Back to table of contents Previous article Next article Images in NeuroscienceFull AccessSmoking Cessation and SchizophreniaSherry Leonard PH.D.Catherine E. Adams PH.D.,Sherry Leonard PH.D.Search for more papers by this authorCatherine E. Adams PH.D.Search for more papers by this author,Published Online:1 Nov 2006AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail The issue of smoking among those with mental illness is becoming an important one. Smoking rates are declining in the general population (21%), but the prevalence of tobacco use among those with mental illness remains high (50%), particularly among patients with schizophrenia (80%). It has been suggested that for schizophrenia patients, smoking represents a form of self-medication—an attempt to treat underlying biological deficits. Recent evidence suggests that this may indeed be the case. Schizophrenia patients have reduced numbers of nicotinic receptors, the first line of response to nicotine in cigarettes. Smoking normalizes sensory processing deficits in schizophrenia patients and their first-degree relatives. Low expression of the α7 nicotinic receptor has been linked to sensory processing and cognitive deficits in a rodent model of schizophrenia. Nicotinic receptors are pentameric ion channels that flux calcium. They are present both pre- and postsynaptically in brain. Presynaptic activation by nicotine, or the endogenous agonist acetylcholine, results in the release of a large number of different neurotransmitters affecting multiple synapses. It is the neuroadaptation in these transmitter systems that likely results in long-lasting addiction to tobacco. Postsynaptically, the α7 nicotinic receptor lies in or near the NMDA postsynaptic density, where calcium influx leads to changes in gene expression. Indeed, the expression of more than 250 genes has been observed to change in the hippocampus of human smokers. Gene expression was differentially regulated in smoking schizophrenia subjects in specific patterns. Aberrant expression was observed for approximately 70 genes in nonsmoking schizophrenia subjects, and expression was normalized for these genes in smoking schizophrenia subjects, with little change in smoking comparison subjects. These results are consistent with a self-medication hypothesis and also suggest underlying neuropathology in the abnormal response to smoking. A reduced nicotinic receptor level represents one layer of molecular pathology that may be associated with the propensity to smoke in schizophrenia patients. Compensation of this deficit might benefit both drug treatment and smoking cessation in this disorder. A recent phase I trial of DMXB-A, an α7 agonist, resulted in improvements in both sensory deficits and cognition, suggesting that medication targeted to the nicotinic cholinergic system is beneficial for schizophrenic neuropathology. Smoking cessation is also a problem for this patient group. An article by Baker et al. in the current issue reports on a use of nicotine replacement therapy, motivational interviewing, and cognitive behavior therapy for psychotic disorder. The findings indicate that the combination therapy was more effective than nicotine replacement therapy alone. It is possible that DMXB-A, or similar drugs, would provide a better adjuvant treatment for smoking cessation than the nicotine patch. Figure 1. The glutamatergic synapse model on the left shows pre- and postsynaptic α7 nicotinic receptors. The photomicrograph on the right shows presumed interneurons in DBA/2 mouse hippocampus. The interneurons are labeled with [ 125 I]α-bungarotoxin, a selective antagonist at the α7 subtype of nicotinic receptor. Binding is found on both the cell bodies (red arrows) and dendrites (yellow arrows) of the hippocampal cells. Aurora, Colo.Address reprint requests to Dr. Tamminga, UT Southwestern Medical Center, Department of Psychiatry, 5323 Harry Hines Blvd., #NE5.110, Dallas, TX 75390-9070; [email protected] (e-mail). FiguresReferencesCited byDetailsCited ByBritish Journal of Psychiatry, Vol. 215, No. 6Smoking cessation programs for persons with schizophrenia: An urgent unmet needRevista de Psiquiatría y Salud Mental (English Edition), Vol. 9, No. 4CNS Drugs, Vol. 30, No. 10Revista de Psiquiatría y Salud Mental, Vol. 9, No. 4Increased Risk of Acute Myocardial Infarction After Acute Episode of Schizophrenia: 6 Year Follow-Up Study1 March 2010 | Australian & New Zealand Journal of Psychiatry, Vol. 44, No. 3Neuropsychology Review, Vol. 17, No. 3 Volume 163Issue 11 November, 2006Pages 1877-1877THE AMERICAN JOURNAL OF PSYCHIATRY November 2006 Volume 163 Number 11 Metrics PDF download History Published online 1 November 2006 Published in print 1 November 2006

Aging and visual motion discrimination in normal adults and schizophrenia patients

Motion perception is impaired in many neuropathological conditions, including schizophrenia. Motion perception also declines in the course of normal aging. In this study, we ask whether aging is an additive factor in the motion-discrimination deficits of schizophrenia patients. We examined motion perception in schizophrenia patients ( n = 44) and non-psychiatric controls ( n = 40) whose ages ranged from 18 to 55. The tasks included velocity discrimination and contrast detection. Thresholds for each of the two tasks were determined for each subject using psychophysical methods. Schizophrenia patients showed significantly increased thresholds (degraded performance) for velocity discrimination compared with the controls. Degraded performance in patients was not related to age. In controls, however, velocity discrimination thresholds were significantly increased beginning by age 45. Performance on a contrast-detection task, which does not require precise discrimination of motion signals, was not significantly affected by age in either group. Aging, even in its early stages, degrades motion discrimination in normal adults. Aging, however, does not adversely affect motion-discrimination deficits in schizophrenia patients through age 55. A similar motion-discrimination deficit in schizophrenia patients and aging normal adults suggests that the mechanisms underlying motion processing in schizophrenia and normal aging may be associated.

Naive Theory Impairment in Schizophrenia

The ability to represent mental states of self and others to account for behavior is called theory of mind (ToM). This study examined whether ToM deficit in schizophrenia patients is a specific deficit in the cognitive component of interpersonal skills or a more global deficit, involving impaired information processing skills. Schizophrenia inpatients (N = 41) were compared with a control group of healthy subjects (N = 22) and to nonschizophrenia psychiatric patients (24 with affective disorders, seven with other psychosis) over a range of ToM tasks and another naive theory (theory of biology; ToB). Psychiatric inpatients as a whole showed significant deficit compared with the control group of healthy subjects in ToM tasks. The schizophrenia patients showed significantly larger deficits compared with patients suffering from affective disorder, while the performance of patients with nonschizophrenia psychosis was intermediate. In contrast, no difference was observed in the performance of the different groups on the ToB tasks. The fact that a deficit was found in ToM but not in ToB suggests a specific deficit in a cognitive component of interpersonal skills in schizophrenia rather than a general deficit in information processing skills. Naive theories deficits in schizophrenia seem to be domain-dependent.

The family of sensorimotor gating disorders: Comorbidities or diagnostic overlaps?

Prepulse inhibition (PPI) of startle is an operational measure of the pre-attentive filtering process known as sensorimotor gating. Originally identified in patients with schizophrenia, PPI deficits have been observed in multiple but not all psychiatric disorders. Thus, as with most signs and symptoms of psychiatric disorders, deficits in PPI cut across diagnostic categories. It remains unclear whether the diversity of disorders exhibiting deficient PPI bespeaks diagnostic overlaps or comorbidities. Given the recent focus on treatments for cognitive deficits of schizophrenia independently of treating psychosis, the relationship of PPI deficits to cognitive deficits becomes of interest. Although PPI cannot be considered to be a cognitive process per se, abnormalities in pre-attentive information processing may be predictive of or lead to complex cognitive deficits. Animal models of PPI deficits produced by dopamine agonists reliably predict existing antipsychotics. Nevertheless, since neither PPI nor cognitive deficits in schizophrenia are ameliorated by standard antipsychotics, current research is exploring the predictive value of non-dopaminergic PPI models in identifying treatments for gating disturbances independently of their relevance to specific disorders. Both PPI and cognitive deficits in schizophrenia patients are not reversed by first generation antipsychotics but may be attenuated by clozapine. Similarly, effects of glutamate antagonists on symptoms in patients and PPI in animals appear to be reduced by clozapine. Hence, treatment-induced reversals of deficits in PPI produced by glutamate antagonists may provide animal, and human, models to aid in the discovery of treatments of cognitive deficits in patients already treated with existing antipsychotics.

A fMRI investigation of startle gating deficits in schizophrenia patients treated with typical or atypical antipsychotics

A key feature of schizophrenia is the inability to screen out irrelevant sensory input. Prepulse inhibition (PPI) of the startle response, a cross-species measure of sensorimotor gating, provides a valuable opportunity to study this feature. PPI is reliably impaired in schizophrenia. Animal models of disrupted PPI have proved valuable for the evaluation of antipsychotic substances. The cortico-striato-pallido-thalamic circuitry is primarily responsible for modulation of PPI in animals. We examined PPI and its brain correlates, using functional magnetic resonance imaging (fMRI), in men with schizophrenia treated with typical or atypical antipsychotics. Thirty men with schizophrenia on stable doses of typical antipsychotics (n=10), risperidone (n=10) or olanzapine (n=10; 9 with usable fMRI data) and 12 healthy men underwent psychophysiological testing and fMRI during a tactile PPI paradigm. The results showed reduced PPI of the eye-blink startle response in patients compared with healthy controls. Within the patient group, those on typical antipsychotics showed significantly impaired PPI but risperidone- or olanzapine-treated patients showed a milder (non-significant) deficit. Increased activity in the striatum, thalamus, insula, hippocampal, temporal, inferior frontal and inferior parietal regions occurred in association with PPI in controls. Patients treated with risperidone or olanzapine, but not with typical antipsychotics, showed significant activation in PPI-relevant regions. Our findings provide preliminary evidence that atypical antipsychotics positively influence PPI and partially restore associated brain functions in schizophrenia. Imaging data buttress the validity of PPI as a useful animal model of schizophrenia.

Exploring the short term visual store in schizophrenia using the attentional blink

Schizophrenia patients exhibit numerous deficits on visual processing tasks, ranging from very early stages of visual processing (e.g., backward masking) to the later working memory stages (e.g., delayed match-to-sample, N-back). However, little is known about deficits in an intermediate stage of visual information processing, namely short term visual memory (STVM). The attentional blink (AB) paradigm is considered to be a valid way to assess the STVM, and recent studies have reported AB deficits in schizophrenia. However, it is not clear whether the reported AB deficit in schizophrenia patients is due to their increased susceptibility to backward masking or increased vulnerability in the STVM. In this study we first found poorer performance in the AB task in 37 schizophrenia patients compared to 26 normal controls. To examine the effects of increasing and decreasing mask strength on AB performance in patients and controls, we next systematically varied the masking effect by varying the length of the distracters immediately following the targets. The manipulation had relatively little effect on the patient – control differences and patients continued to show an enhanced AB effect across conditions. The findings suggest that the enhanced AB effect in schizophrenia reflects an abnormality in their short term visual memory, as opposed to their enhanced susceptibility to visual masking.

Event-related fMRI of word classification and successful word recognition in subjects at genetically enhanced risk of schizophrenia

Verbal declarative memory is a core deficit in schizophrenia patients, seen to a lesser extent in unaffected biological relatives. Neuroimaging studies suggest volumetric differences and aberrant function in prefrontal and temporal regions in schizophrenia patients compared to controls. These deficits are also reflected in the small number of similar investigations in unaffected biological relatives. However, it is unclear the extent to which dysfunction is genetically mediated or a feature of the established illness. Event-related blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was used to measure brain activation in 68 biological relatives of schizophrenia patients (of whom 27 experienced transient or isolated psychotic symptoms) and 21 controls during verbal classification and recognition. During word classification, the high-risk group showed a greater response relative to controls in the right inferior frontal gyrus. During correct recognition (relative to correct rejection), the high-risk group showed significantly greater response relative to controls in the right cerebellum. When the high-risk group was split into those with (HR+) and without (HR-) psychotic symptoms, the increased response in the right inferior frontal gyrus was only seen when the HR+ were compared to controls. The greater cerebellar response was seen when both HR groups were compared to controls. Activation increases in the right inferior frontal gyrus and cerebellum in high-risk subjects compared to controls during a relatively low-load memory task are likely to represent compensation for genetically mediated abnormalities. This is consistent with a leftward shift of the inverted 'U' load-response model of cognitive function in schizophrenia.

Positive modulation of glutamatergic receptors potentiates the suppressive effects of antipsychotics on conditioned avoidance responding in rats

Non-competitive N-methyl- d-aspartate (NMDA) receptor antagonist administration induces a syndrome indistinguishable from schizophrenia including positive and negative symptoms and cognitive deficits. Concordantly, augmentation of the NMDA receptor function by glycine-site agonists such as d-serine and d-cycloserine has been reported to improve negative symptoms and some cognitive deficits in schizophrenia patients when added to conventional antipsychotic treatment, although they appear less effective when combined with clozapine specifically. In contrast, administration of the AMPAkine CX-516 (which positively modulate the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor) as an adjuvant to clozapine, has been shown to exert some beneficial action on the negative symptoms and cognitive deficits in schizophrenia. In the rat, selective suppression of conditioned avoidance response (CAR) behaviour has been widely reported to be a test with high predictive validity for antipsychotic efficacy. We found that d-serine and CX-516, at doses ineffective by themselves, significantly potentiated the suppression of CAR induced by threshold doses of risperidone (0.16 mg/kg, s.c.), olanzapine (0.63 mg/kg, s.c.) and clozapine (1.3 mg/kg, s.c.) without causing additional motor disturbances. Thus, the adjunct enhancement of NMDA or AMPA receptor function observed clinically, appears reflected in the present rat CAR study. Consequently, our data lend further support to the potential use of the CAR test in the investigation of augmentation strategies involving the addition of non-dopaminergic target compounds to existing atypical antipsychotics.

Compromised Memory Function in Schizophrenia and Temporal Lobe Epilepsy

Compromised Memory Function in Schizophrenia and Temporal Lobe Epilepsy

Forebrain D1 function and sensorimotor gating in rats: Effects of D1 blockade, frontal lesions and dopamine denervation

Prefrontal D1 hypoactivity is implicated in the pathophysiology of schizophrenia, and might contribute to sensorimotor gating deficits in schizophrenia patients, based on evidence that D1 blockade in the medial prefrontal cortex (MPFC) reduces prepulse inhibition of startle (PPI) in animal models. PPI is disrupted by systemic and intra-MPFC infusion of the D1 antagonist, SCH23390. We investigated the role of the MPFC in the PPI-disruptive effects of systemic SCH23390 administration, and more generally, in the dopaminergic regulation of PPI. PPI was measured in rats after forebrain manipulations, including systemic administration of SCH23390, ibotenic acid lesions of the MPFC, and 6OHDA-induced dopamine (DA) depletion from MPFC or nucleus accumbens. Systemic SCH23390 disrupted PPI; these effects were not opposed by ibotenic acid lesions of the MPFC. PPI remained intact after MPFC DA depletion, but – as predicted by Bubser and Koch [M. Bubser, M. Koch, Prepulse inhibition of the acoustic startle response of rats is reduced by 6 hydroxydopamine lesions of the medial prefrontal cortex, Psychopharmacology 113 (1994) 487–492] – a reduction in PPI from pre- to post-surgery correlated significantly with MPFC DA loss. The effects of systemic SCH23390 were not opposed by NAC DA depletion. D1 receptors regulate PPI in rats, but this effect does not appear to be mediated either by the MPFC or by increased mesolimbic DA activity.

Are cross-species measures of sensorimotor gating useful for the discovery of procognitive cotreatments for schizophrenia?

Prepulse inhibition of startle (PPI), a measure of sensorimotor gating used to identify antipsychotics, is reduced in schizophrenia patients and in rodents treated with dopamine agonists or glutamate antagonists. The National Institute of Mental Health (NIMH)-funded Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) program has initiated a new era in the development of procognitive cotreatments in schizophrenia, independently of treating positive symptoms. Although PPI is not a cognitive process per se, such abnormalities in attention may be predictive of or lead to cognitive deficits. Since first-generation antipsychotics block PPI deficits induced by dopamine agonists, this model cannot identify cognitive enhancers for use as cotreatments with antipsychotics. PPI deficits caused by glutamate antagonists, like the exacerbation of symptoms they produce in patients, are insensitive to dopamine antagonists, but reduced by clozapine. Similarly, both PPI and cognitive deficits in schizophrenia patients are insensitive to first-generation antipsychotics, but attenuated by clozapine. Hence, treatment-induced reversals of glutamate antagonist effects on PPI may provide animal and human models to identify treatments of cognitive deficits in patients already treated with existing antipsychotics.