R.M. Bilder

Reduced temporal limbic structure volumes on magnetic resonance images in first episode schizophrenia.

Pathomorphology of the limbic system has been described in post-mortem studies of schizophrenia. To determine whether this could be detected in living patients and was not secondary to the treatment or the chronicity of the disease itself, we measured the volumes of the hippocampus-amygdala complex and adjoining temporal horns of 34 patients in their first episode of schizophrenia and 25 normal volunteers using T1 weighted contiguous coronal magnetic resonance images of 3.1 mm width. The results demonstrate abnormal medial temporal lobe morphology in a subgroup of patients at the onset of their illness. There were clear laterality effects and sex differences: hippocampal tissue was significantly smaller only in the left hemisphere of male patients, whereas enlargement of the whole temporal horn or its anterior portion was present on the left side in both sexes. Dysfunction of the limbic mesiotemporal structures might explain some of the clinical features of the disease.

Brain-derived neurotrophic factor Val66met polymorphism and volume of the hippocampal formation

Magnetic resonance (MR) imaging studies have identified hippocampal structural alterations in the pathogenesis of schizophrenia. Brain-derived neurotrophic factor (BDNF) is one of the neurotrophins that is widely expressed in the hippocampal formation and has been implicated in the neurobiology of schizophrenia. Polymorphisms in the BDNF gene may therefore confer risk for schizophrenia through hippocampal pathogenesis and/or making the hippocampus more susceptible to environmental insults. In this study, we investigated whether val66met, a functional and abundant missense polymorphism in the coding region of the BDNF gene, was associated with the volume of the hippocampal formation in 19 patients with first-episode schizophrenia and 25 healthy volunteers. A total of 124 contiguous T1-weighted coronal MR images (slice thickness=1.5u2009mm) were acquired through the whole head using a 3D Fast SPGR IR Prep sequence on a 1.5u2009T GE imaging system. Volumes of the right and left hippocampal formation were measured manually by an operator blind to group status and genotype. All participants were genotyped for the BDNF val66met locus. Mixed model analyses revealed a main effect of BDNF val66met genotype such that in the combined sample of patients and healthy volunteers, val/val homozygotes (N=27) had larger volumes of the hippocampal formation compared to val/met heterozygotes (N=17). In separate analyses by group, however, val66met genotype accounted for a greater proportion of the variance in the volume of the hippocampal formation in patients compared to healthy volunteers. These findings implicate genetic involvement of BDNF in variation of human hippocampal volume and suggest that this effect may be greater among patients compared to healthy volunteers.

The neuropsychology of schizophrenic speech

Recent interest in the biological basis of schizophrenia has led to a reexamination of many symptomatic aspects of the disorder in terms of brain-behavioral models. Schizophrenic speech disturbances have traditionally been described in terms of a model of acquired aphasia. We review some of the limitations of this model and provide an alternative model for the study of some characteristics of schizophrenic speech based on neuropsychological theories of frontal lobe dysfunction in schizophrenia. The emphasis is placed on the study of productive errors noted in schizophrenic speech, most notably verbal perseverations. In a study of errors observed during a sample of 15 schizophrenics performance on a confrontation naming test, we were able to reliably identify and classify hierarchic categories of verbal perseverations occurring at both semantic and phonemic levels. These perseverations constituted 20% of the total errors. We argue that these perseverations represent a special case of executive dysfunction resulting from a disturbance of language monitoring mechanisms. We examine the implications of these findings for a hypothesis of schizophrenic speech disturbances in terms of frontal lobe dysfunction and the developmental neuropathological processes involved in the illness.

Cortical brain regions engaged by masked emotional faces in adolescents and adults: an fMRI study.

Face-emotion processing has shown signs of developmental change during adolescence. Functional magnetic resonance imaging (fMRI) was used on 10 adolescents and 10 adults to contrast brain regions engaged by a masked emotional-face task (viewing a fixation cross and a series of masked happy and masked fearful faces), while blood oxygen level dependent signal was monitored by a 1.5-T MRI scanner. Brain regions differentially engaged in the 2 age groups were mapped by using statistical parametric mapping. Summed across groups, the contrast of masked face versus fixation-cross viewing generated activations in occipital-temporal regions previously activated in passive face-viewing tasks. Adolescents showed higher maxima for activations in posterior association cortex for 3 of the 4 statistical contrasts. Adolescents and adults differed in the degree to which posterior hemisphere brain areas were engaged by viewing masked facial displays of emotion.

Working memory deficits in schizophrenia are not necessarily specific or associated with MRI-based estimates of area 46 volumes.

Despite substantial evidence that the prefrontal cortex does not function normally in patients diagnosed with schizophrenia, evidence for prefrontal structural abnormalities, as measured by magnetic resonance imaging (MRI), has been inconsistent. Additionally, evidence for relationships between prefrontal structural and functional measures has been limited. The inconsistencies in the MRI literature are, at least in part, due to a lack of standard and specific measurement protocols that allow delineation of functionally distinct cortical regions. In this study, reliable methods for measuring an estimate of area 46 (estimate referred to as area 46(e)), as defined by Cereb. Cortex 5 (1995) 323, were developed and used to examine relationships between area 46(e) volumes, working memory, and symptom severity in 23 male patients and 23 healthy male comparison subjects. Patients performed more poorly than healthy reference subjects on all cognitive measures including measures of spatial and non-spatial working memory, but showed no significant corresponding deficits in area 46(e) volumes or whole brain volumes. Moreover, there were no significant relationships between symptom severity and area 46(e) volumes. These findings suggest that the prefrontal functional abnormalities observed in schizophrenia may occur in the absence of prefrontal volume deficits, and may instead involve more widespread brain systems or prefrontal connections with other brain regions.

A reticulo-frontal disconnection syndrome

Persistent executive deficit, usually seen following prefrontal damage, is reported in a patient recovering from head trauma. Repeated neuroradidological examinations failed to reveal a lesion within the frontal lobes, but a circumscribed lesion in the ventral mesencephalic tegmentum was found. It is proposed that the observed syndrome was caused by damage to mesencephalic reticular nuclei and their projections into prefrontal cortex. The concept of a reticulo-frontal disconnection syndrome is introduced and its possible role in head trauma and schizophrenia discussed.

Incidence and correlates of tardive dyskinesia in first episode schizophrenia

BACKGROUNDnThere is controversy over whether tardive dyskinesia (TD) is solely a consequence of antipsychotic drug treatment or in part may reflect an intrinsic aspect of the disease process. Pathophysiologic factors could, independently or in concert with drug effects, lead to the development of dyskinetic signs.nnnMETHODSnWe studied prospectively 118 patients in their first episode of psychosis who were treatment-naive or had less than 12 weeks of antipsychotic drug exposure at study entry. Patients received standardized antipsychotic drug treatment and were evaluated for up to 8 1/2 years with regular assessments of psychopathologic signs and symptoms and side effects.nnnRESULTSnThe cumulative incidence of presumptive TD was 6.3% after 1 year of follow-up, 11.5% after 2 years, 13.7% after 3 years, and 17.5% after 4 years. Persistent TD had a cumulative incidence of 4.8% after 1 year, 7.2% after 2 years, and 15.6% after 4 years. Taken individually, both antipsychotic drug dose, entered as a time-dependent covariate, and poor response to treatment of the first psychotic episode were significant predicters of time to TD. When antipsychotic drug dose and treatment response were examined together, treatment responders had significantly lower hazards for presumptive TD than nonresponders (hazard ratio, 0.29; 95% confidence interval, 0.09 to 0.97). Dose was a trend-level predicter, with each 100-mg chlorpromazine equivalent unit increase in dose associated with a 5% increase in the hazard of presumptive TD (hazard ratio, 1.05; 95% confidence interval, 0.99 to 1.11).nnnCONCLUSIONnPoor response to the treatment of a first episode of psychosis and, to a lesser extent, antipsychotic drug dose are important factors in the development of TD. This suggests that there may be a disease-related vulnerability to TD manifest with antipsychotic drug exposure. Potential pathophysiologic factors might include neurodevelopmentally induced structural neuropathologic characteristics, sensitization of nigrostriatal dopamine neurons, and the induction of glutamatergically mediated neurotoxic effects.

Brain morphometric comparison of first episode schizophrenia and temporal lobe epilepsy

BACKGROUNDnConverging evidence has suggested that the abnormalities in brain morphology observed in schizophrenia are similar to those seen in temporal lobe epilepsy (TLE). The purpose of this study was to compare the features of these groups directly with measures of the brain using magnetic resonance (MR) morphometry.nnnMETHODnMorphometric measures of ventricular and hippocampal volumes obtained from FLASH MR images were studied in 32 patients with first-episode schizophrenia (FES), 39 patients with TLE (21 left, 18 right), and 42 healthy controls.nnnRESULTSnVentricular volumes in the FES and TLE groups were both significantly larger that those seen in controls and did not differ from each other. The FES group showed significantly larger temporal horns, while the TLE group had relatively larger frontal horns. Analyses of hippocampal volumes revealed a significant group by hemisphere effect. The FES group showed relative reductions in left hippocampal volume that were comparable only to TLE patients with seizures originating from the left hemisphere.nnnCONCLUSIONnThe results indicate that FES and TLE groups both show evidence of ventricular enlargement. Lateralised morphological abnormalities of the hippocampal formation in FES and left TLE are comparable, and may be specific to temporolimbic regions.

Neuropathological correlates of auditory event-related potentials in recent-onset schizophrenia

chronic schizophrenicpatientsshow deficientgenerationof the eventrelatedpotentialsmismatchnegativity(MMN),N2 and P3(MI elicitedin auditory‘oddball’paradigms.These abnormalitieshave been associated with neuroanatornical abnormalitiesin the right superiortemporalplane (h’fMN) andleftsupedortemporal gyms(P3).Weareperforminga studyto replicatethesefindingsin recent-onset patientsparticipatingin a studyof first-episodeschizophrenia. ERPsareobtainedinpassiveandactiveauditory ‘oddball’paradigms. HighresolutionMRimagesof thebrainare acquired on a 1.5TGE HorizonEchoSpeedsystem(3DFast SPGRwithII? Prep sequence;Coronalacquisition, TR = 14.5rns, TE=5.5ms,Tf=600rns,slice thickness=1.5mm).Datahavebeenobtainedin 18schizophrenic patierm (m/f= 15/3;age = 23.8t 5.1;durationof ilfness1.3~2.2y)and9 normal controls(rn/f=5/4;age = 34.* 6.7).Forpreliminaryanalysesgreyrnati volumesof bothposteriorsuperiortemporalgyri (PST@weremeasured. Aftcrcovaryingfortheagedifferencepatientshowedsmaoerarnplitudes of N2 andP3 thannormalcontrols,butnot significantlydifferentvolumesof bothpSTGs.AmplitudesofMMN,N2andP3didnotcorrelatewithPSTG greymattervolumes.Theseresultssuggestfirstfythat the observedERP abnormalitiescomparableto those seen in chronicpatientsare not explainedbymacroscopicneuroanatomicalbnormalities andsecondlythat the correlationsreportedin samplesof chronicpatientsmaybe a mrmifestationof illnesschrmricityand/orseverity.Inourpresentationmoredetailed analysesusingseparatevolumesof Hescfd’sgyri and superiortemporal planeswilfbe provided.

11. Neuropsychology I: General277 - Effects of clozapine and haloperidol on explicit memory in treatment refractory patients

Results: Changes in Verbal IQ and Fullscale IQ were significantly negatively correlated with changes in negative symptoms but not psychotic and disorganized symptom dimensions. Psychotic, negative, and disorganized symptoms significantly improved over time. Medication dosage significantly decreased over time. Although IQ measures changed significantly over time, this change was not meaningful (i.e., the change was in the range of 2-5 points) . No significant correlations were observed with Performance IQ. Conclusions: Worsening negative symptoms are associated with cognitive decline.