Marko Manninen

Spatial working memory as an endophenotype for schizophrenia

BACKGROUND Spatial working memory impairments are among the neurocognitive deficits that may mark genetic predisposition toward schizophrenia. We previously reported that impairment on the spatial span subtask of the Wechsler Adult Intelligence Scale-Revised increased in a dose-dependent manner with increasing genetic predisposition toward schizophrenia in a sample of discordant twins; however, it remains to be determined whether these deficits reflect difficulties with encoding, maintenance, manipulation, time-tagging of visual spatial information, storage capacity, or complex motor response. METHODS We developed a spatial delayed response task in which memory set size was parametrically varied, holding constant manipulation and decision processes. We then reassessed 80 of the previously studied twins (17 probands with 8 monozygotic co-twins and 13 dizygotic co-twins, and 42 healthy twins). RESULTS The spatial delayed response task was sensitive to genetic loading for schizophrenia but did not provide evidence for capacity limitations in probands or their co-twins. CONCLUSIONS The findings suggest that deficits in the encoding or storage aspects of short-term spatial mnemonic processing may be an effective endophenotypic marker for schizophrenia.

The relationship between performance and fMRI signal during working memory in patients with schizophrenia, unaffected co-twins, and control subjects

While behavioral research shows working memory impairments in schizophrenics and their relatives, functional neuroimaging studies of patients and healthy controls show conflicting findings of hypo- and hyperactivation, possibly indicating different relationships between physiological activity and performance. In a between-subjects regression analysis of fMRI activation and performance, low performance was associated with relatively lower activation in patients than controls, while higher performance was associated with higher activation in patients than controls in DLPFC and parietal cortex, but not occipital cortex, with unaffected twins of schizophrenics being intermediate between the groups. Accordingly, this supports the idea that both hyper and hypoactivation may be possible along a continuum of behavioral performance in a way consistent with a neural inefficiency model. Further, this study offers preliminary evidence that the relationship between behavior and physiology in schizophrenia may be heritable.

Maintenance and Manipulation in Spatial Working Memory: Dissociations in the Prefrontal Cortex

Two experiments were conducted to compare thec ries of the functional organization of spatial working memory within the human prefrontal cortex. In Experiment I, memory set size for locations was parametrically varied, allowing for the assessment of BOLD signal across maintenance requirements. In the sec ond experiment, manipulation of spatial information held in working memory was contrasted with simple maintenance of that information. Both experiment evoked significant activity in a distributed spatia working memory network. Although dorsolateral prefrontal activation increased monotonically with memory set size, this region was differentially engaged in task conditions involving explicit manipulation of in ternal representations. Activation in the superior frontal sulcal region was associated with maintenance of spatial information, increasing with memory se size. In contrast, ventrolateral prefrontal activation was present only at the highest memory set size, possibly due to the differential use of organizational strategies with more complex stimuli. These results sup port claims that the dorsolateral prefrontal cortex is involved in the manipulation of internal representa tions and that the superior frontal sulcal region is involved in the maintenance of spatial information but they suggest a complex role for the ventrolatera prefrontal region.

Proton MRS in twin pairs discordant for schizophrenia

Proton magnetic resonance spectroscopy (1H MRS) neurometabolite abnormalities have been detected widely in subjects with and at risk for schizophrenia. We hypothesized that such abnormalities would be present both in patients with schizophrenia and in their unaffected twin siblings. We acquired magnetic resonance spectra (TR/TE=3000/30 ms) at voxels in the mesial prefrontal gray matter, left prefrontal white matter and left hippocampus in 14 twin pairs discordant for schizophrenia (2 monozygotic, 12 dizygotic), 13 healthy twin pairs (4 monozygotic, 9 dizygotic) and 1 additional unaffected co-twin of a schizophrenia proband. In the mesial prefrontal gray matter voxel, N-acetylaspartate (NAA), creatine+phosphocreatine (Cr), glycerophosphocholine+phosphocholine (Cho) and myo-inositol (mI) did not differ significantly between patients with schizophrenia, their unaffected co-twins or healthy controls. However, glutamate (Glu) was significantly lower in patients with schizophrenia (31%, percent difference) and unaffected co-twins (21%) than in healthy controls (collapsed across twin pairs). In the left hippocampus voxel, levels of NAA (23%), Cr (22%) and Cho (36%) were higher in schizophrenia patients compared with controls. Hippocampal NAA (25%), Cr (22%) and Cho (37%) were also significantly higher in patients than in their unaffected co-twins. Region-to-region differences in metabolite levels were also notable within all three diagnosis groups. These findings suggest that 1H MRS neurometabolite abnormalities are present not only in patients with schizophrenia, but also in their unaffected co-twins. Thus, reduced mesial prefrontal cortical Glu and elevated hippocampal NAA, Cr and Cho may represent trait markers of schizophrenia risk and, when exacerbated, state markers of schizophrenia itself.

Prodromal psychosis screening in adolescent psychiatry clinics

Background: Research has identified a syndrome conferring ultra‐high risk (UHR) for psychosis, although UHR interviews require intensive staff training, time and patient burden. Previously, we developed the Prodromal Questionnaire (PQ) to screen more efficiently for UHR syndromes.

Alexithymia Is Common Among Adolescents With Severe Disruptive Behavior

This study aimed to examine alexithymic features and associations between alexithymia and psychiatric symptoms among adolescents living in a closed institution because of severe behavioral problems. Forty-seven adolescents (29 boys and 18 girls) aged 15 to 18 years completed the 20-item Toronto Alexithymia Scale (TAS-20) Questionnaire and the Youth Self-Report, whereas their foster parents completed the Child Behavior Checklist. The TAS-20 scores of the participants were compared with those of an extensive population sample (N = 6000) matched by age and birth year. Reform school adolescents are significantly more alexithymic than the control group, and the TAS-20 scores are correlated with numerous psychiatric problems, mainly in the internalizing spectrum, but also with thought problems and self-reported aggression. Promoting abilities in identifying and describing feelings is important when treating delinquent adolescents.

The relationship between psychotic-like symptoms and neurocognitive performance in a general adolescent psychiatric sample

INTRODUCTION The current criteria for detecting a Clinical High-Risk (CHR) state for psychosis do not address cognitive impairment. A first step for identifying cognitive markers of psychosis risk would be to determine which aspects of neurocognitive performance are related with more severe psychotic-like symptoms. This study assessed cognitive impairment associated with prodromal symptoms in adolescents receiving public psychiatric treatment. METHODS 189 adolescents were recruited from consecutive new patients aged 15-18 attending mainly outpatient adolescent psychiatric units in Helsinki. They had been screened for prodromal symptoms using the Prodromal Questionnaire, and all screen-positives as well as a random sample of screen-negatives were interviewed using the Structured Interview for Prodromal Symptoms (SIPS) and underwent testing using a large, standardized neurocognitive test battery. The sample included 62 adolescents who met the CHR criteria (CHR) and 112 who did not (non-CHR). A healthy control sample (n=72) was also included to provide age- and gender-matched norms. RESULTS The CHR group performed worse on visuospatial tasks than the non-CHR group. Among CHR adolescents, negative symptoms were associated with slower processing speed and poorer performance on verbal tasks. Among non-CHR adolescents, positive symptoms were associated with poorer performance on visuospatial tasks, and negative symptoms with poorer performance on verbal tasks. CONCLUSION Clinical high-risk status is associated with impaired visuospatial task performance. However, both positive, psychotic-like symptoms and negative symptoms are associated with lower levels of neurocognitive functioning among adolescents in psychiatric treatment regardless of whether CHR criteria are met. Thus, even mild positive and negative symptoms may have clinical relevance in adolescents in psychiatric care. Adolescents with both psychotic-like symptoms and neurocognitive deficits constitute a group requiring special attention.

Abnormally high EEG alpha synchrony during working memory maintenance in twins discordant for schizophrenia

BACKGROUND The present analyses aimed to test the prediction that schizophrenia patients and their non-schizophrenic co-twins would display reduced efficiency of the neurocognitive mechanisms subserving active maintenance of spatial information in working memory. METHODS Upper alpha frequency band EEG event-related desynchronization and synchronization (ERD/ERS) were calculated as percent changes in power relative to an inter-trial baseline across 4 memory loads in a spatial delayed-response task. RESULTS During the delay, the diagnostic groups showed equivalent ERD/ERS activity over posterior scalp regions at the lowest memory load; however, as memory load increased, patients, and to an intermediate degree, their non-schizophrenic co-twins (monozygotic and dizygotic pairs collapsed together), showed significantly greater increases in ERD/ERS amplitude as compared with controls. CONCLUSIONS These findings demonstrate abnormally increased ERD/ERS amplitudes with increasing memory load in patients with schizophrenia and their co-twins, consistent with inefficiency of the neurocognitive mechanisms supporting active maintenance of information across a delay.

Predicting psychosis in a general adolescent psychiatric sample.

INTRODUCTION Current psychosis risk criteria have often been studied on a pre-selected population at specialized clinics. We investigated whether the Structured Interview for Prodromal Syndromes (SIPS) is a useful tool for psychosis risk screening among adolescents in general psychiatric care. METHODS 161 adolescents aged 15-18 with first admission to adolescent psychiatric services in Helsinki were interviewed with the SIPS to ascertain Clinical High-Risk (CHR) state. The participants were followed via the national hospital discharge register, patient files, and follow-up interviews. DSM-IV Axis I diagnoses were made at baseline and 12 months. Register follow-up spanned 2.8-8.9 years, and hospital care for a primary psychotic disorder and any psychiatric disorder were used as outcomes. RESULTS CHR criteria were met by 54 (33.5%) of the adolescents. Three conversions of psychosis as defined by SIPS emerged during follow-up, two of whom belonged to the CHR group. The positive predictive value of the CHR status was weak (1.9%) but its negative predictive value was 98.0%. Using the DSM-IV definition of psychosis, there were five conversions, three of which were in the CHR group. In regression analyses, hospital admissions for primary psychotic disorder were predicted by positive symptom intensity in the baseline SIPS. In addition, CHR status and SIPS positive and general symptoms predicted hospitalization for psychiatric disorder. DISCUSSION Psychosis incidence was low in our unselected sample of adolescent psychiatric patients. CHR status failed to predict SIPS or DSM-IV psychoses significantly at 12 months. However, in a longer follow-up, CHR did predict psychiatric hospitalization.

Low verbal ability predicts later violence in adolescent boys with serious conduct problems

Abstract Background: Delinquent adolescents are a known high-risk group for later criminality. Cognitive deficits correlate with adult criminality, and specific cognitive deficits might predict later criminality in the high-risk adolescents. Aims: This study aimed to explore the neuropsychological performance and predictors of adult criminal offending in adolescents with severe behavioural problems. Methods: Fifty-three adolescents (33 boys and 20 girls), aged 15–18 years, residing in a reform school due to serious conduct problems, were examined for neuropsychological profile and psychiatric symptoms. Results were compared with a same-age general population control sample, and used for predicting criminality 5 years after the baseline testing. Results: The reform school adolescents’ neuropsychological performance was weak on many tasks, and especially on the verbal domain. Five years after the baseline testing, half of the reform school adolescents had obtained a criminal record. Males were overrepresented in both any criminality (75% vs. 10%) and in violent crime (50% vs. 5%). When cognitive variables, psychiatric symptoms and background factors were used as predictors for later offending, low verbal intellectual ability turned out to be the most significant predictor of a criminal record and especially a record of violent crime. Conclusions: Neurocognitive deficits, especially in the verbal and attention domains, are common among delinquent adolescents. Among males, verbal deficits are the best predictors for later criminal offending and violence. Clinical implications: Assessing verbal abilities among adolescent population with conduct problems might prove useful as a screening method for inclusion in specific therapies for aggression management.