Common Feature Of Schizophrenia Research Articles

Symptom attribution and frontal cortical thickness in first-episode schizophrenia.

Misattribution of symptoms is a common feature of schizophrenia, and likely involves impairment of metacognitive function that may be mediated by the frontal cortex. We aimed to compare frontal cortical thickness in first-episode schizophrenia (FES) patients with matched controls, and investigate its relationship with the symptom attribution dimension of insight in FES patients. We examined frontal cortical thickness in 92 minimally treated FES patients at baseline presentation and 93 healthy controls aged 16-45 years. We examined for correlations between symptom attribution as determined by the Birchwood Insight Scale (BIS) symptom relabeling subscale score and cortical thickness of frontal regions of interest (ROIs). We then examined for an association between symptom attribution and cortical thickness using multiple regression analysis. FES patients exhibited significantly reduced cortical thicknesses for a number of frontal regions, namely the left medial orbitofrontal, left superior frontal, left frontal pole, right rostral middle frontal, right lateral orbitofrontal and right superior frontal regions. Reduced cortical thickness in FES patients was associated with symptom misattribution for the left and right rostral middle frontal, left caudal anterior cingulate, right superior frontal, and left and right pars triangularis regions. Reduced left rostral middle frontal thickness and left anterior cingulate thickness remained significant on regression analysis. Our findings suggest that frontal neuroanatomical deficits that are present early in the disease process may be critical to the pathogenesis of symptom attribution in schizophrenia.

Theory of mind and executive functions in schizophrenia and bipolar disorder: A cross-diagnostic latent class analysis for identification of neuropsychological subtypes

ObjectiveExecutive dysfunction is a common feature of schizophrenia and bipolar disorder (BP). While deficits in social cognitive abilities, including theory of mind (ToM), have been suggested to be specific to schizophrenia, available evidence suggests that there is also a significant overlap in social cognitive performances of both disorders. However, there is significant heterogeneity of executive dysfunction and ToM deficits in BP and schizophrenia. Cross-diagnostic data-driven methods can reveal potential neurocognitive subtypes characterized by relatively selective deficits in social cognition. MethodsNeurocognitive subgroups were investigated using latent class analysis, based on executive functions and ToM, in a mixed sample of 97 clinically stable patients with schizophrenia or BP and 27 healthy controls. ResultsFour neurocognitive subgroups, including a “neuropsychologically normal” cluster, a severe global impairment cluster and two clusters of mixed cognitive profiles were found. Severe impairment cluster was characterized by particularly severe ToM deficits and predominantly included patients with schizophrenia. Schizophrenia patients in this cluster had severe negative symptoms. In contrast, individuals with BP compared to schizophrenia patients were more likely to be included in the “neuropsychologically normal” cluster. ConclusionIdentification of distinctive neurobiological subtypes of patients based on social and non-social cognitive profiles can improve classification of major psychoses. Neurocognitive subgroupings of patients might be also beneficial for intervention strategies including cognitive rehabilitation.

Serum hormone levels and cognitive functioning in male schizophrenia patients

BackgroundHormones deregulation is a common feature in schizophrenia. Among the hormones that gained increased interest are sex hormones, thyroid hormones and prolactin. However, the question whether there is an impact of the hormonal disturbances on cognitive functioning of schizophrenia patients is rarely addressed.ObjectiveTo assess the relationship between serum levels of hormones and cognitive abilities in male schizophrenic patients.Subjects and methodsIn the index group, there were 15 schizophrenia male patients, mean age 36. The control group was formed by 15 healthy volunteers, mean age 36. In the two groups, serum hormones levels were measured and neuropsychological tests were performed. Analysed hormones included thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, testosterone, progesterone and prolactin. Cognitive abilities were measured with the following tests: Trail Making Test (TMT) Part A and B, Semantic Category Fluency (SCF), Initial Letter Fluency (ILF) and Stroop Task Part 1 and 2.ResultsThe levels of FSH, LH and testosterone were lower in the index group than in the control group (3.01 mIU/mL vs 5.90 mIU/mL; 3.83 mIU/mL vs 5.28 mIU/mL; 2.76 ng/mL vs 4.69 ng/mL; accordingly) while the level of prolactin was higher in the index group (620 uIU/mL vs 118 uIU/mL). Patients performed worse that controls in all neuropsychological tests. The differences in scores of TMT Part B, ILF and Stroop Task Part 2 were found to be statistically significant.ConclusionsThere was no significant relationship between serum level of analysed hormones and performance on cognitive tasks.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Study of effectiveness of brief cognitive behavioral therapy for auditory hallucinations in schizophrenia

Introduction A growing body of evidence supports the use of cognitive behavioral therapy (CBT) for the treatment of schizophrenia. Auditory hallucinations are a common feature in schizophrenia that persists as a distressing symptom even after adequate pharmacotherapy regimen. Combining pharmacotherapy with brief CBT may reduce the severity of symptoms through decreasing the distress caused by the hallucinations. Aim The aim of this study was to evaluate the effectiveness of brief individual CBT for auditory hallucinations combined with treatment as usual (TAU) compared with TAU only in a sample of Egyptian schizophrenic patients referred to the Outpatient Clinic of El Hadara University Hospital. Patients and methods A total of 40 patients diagnosed with schizophrenia referred to the outpatient clinic of El Hadara University Hospital were randomly assigned into two groups: group I received brief CBT for auditory hallucinations combined with TAU, and group II received TAU only. Brief CBT for auditory hallucinations was delivered on eight sessions of 45 min each with a frequency of once per week. Positive and Negative Syndrome Scale (PANSS) was assessed before and after therapy in both groups and outcome was compared. Results On comparing the pre-assessment scores with the post-assessment scores of group I after 8 weeks of brief CBT for auditory hallucinations, a significant symptom reduction was observed for the PANSS positive (−18.31%, P < 0.001), negative (−16.67%, P < 0.001), general symptoms (−16.53%, P < 0.001), and total (−16.53%, P < 0.001) scores. Moreover, on comparing group I with group II after 8 weeks of brief CBT for auditory hallucinations, a significant symptom reduction was observed for the PANSS positive (P < 0.001), negative (P = 0.008), general symptoms (P < 0.001), and total (P < 0.001) scores. Conclusion Brief CBT for auditory hallucinations was found to be effective in reducing symptom severity in schizophrenia

Self-Stigma in Schizophrenia: A Concept Analysis

This study aimed to clarify the phenomenon and definition of self-stigma in schizophrenia. Self-stigma in schizophrenia affects patients' well-being and attitudes to treatment. Although stigma and self-stigma have interactive and different characteristics, theses definitions are not clearly distinguished. Mental illnesses may have different stereotypes but are treated equally in some studies. Lack of awareness of illness is a common feature in schizophrenia but has not been focused in self-stigma studies. Further studies are needed to clarify the phenomenon of self-stigma in people with schizophrenia and to develop interventions targeted at reducing self-stigma.

Premorbid functional development and conversion to psychosis in clinical high-risk youths

Deterioration in premorbid functioning is a common feature of schizophrenia, but sensitivity to psychosis conversion among clinical high-risk samples has not been examined. This study evaluates premorbid functioning as a predictor of psychosis conversion among a clinical high-risk sample, controlling for effects of prior developmental periods. Participants were 270 clinical high-risk individuals in the North American Prodrome Longitudinal Study-I, 78 of whom converted to psychosis over the next 2.5 years. Social, academic, and total maladjustment in childhood, early adolescence, and late adolescence were rated using the Cannon-Spoor Premorbid Adjustment Scale. Early adolescent social dysfunction significantly predicted conversion to psychosis (hazard ratio = 1.30, p = .014), independently of childhood social maladjustment and independently of severity of most baseline positive and negative prodromal symptoms. Baseline prodromal symptoms of disorganized communication, social anhedonia, suspiciousness, and diminished ideational richness mediated this association. Early adolescent social maladjustment and baseline suspiciousness together demonstrated moderate positive predictive power (59%) and high specificity (92.1%) in predicting conversion. Deterioration of academic and total functioning, although observed, did not predict conversion to psychosis. Results indicate early adolescent social dysfunction to be an important early predictor of conversion. As such, it may be a good candidate for inclusion in prediction algorithms and could represent an advantageous target for early intervention.

P.3.f.018 Aminotransferase levels as a predictor for the development of metabolic syndrome in patients with schizophrenia

Insomnia is a common feature in schizophrenia, and is characterized by an increase of sleep latency (SL), as well as reductions in total sleep time (TST) and sleep efficiency (SE). Regarding sleep architecture, non-rapid-eye-movement (NREM) sleep, slow wave sleep (SWS) and rapid-eye-movement (REM) sleep latency are decreased, whereas REM sleep tends to remain unchanged. According to polysomnographic studies, clozapine, olanzapine, quetiapine and ziprasidone administration increased TST and/or SE in healthy subjects. Additionally, olanzapine and ziprasidone augmented SWS, while changes corresponding to REM sleep were inconsistent. Furthermore, administration of clozapine, olanzapine and paliperidone to patients with schizophrenia was followed in most instances by a significant reduction of SL and an increase of TST and SE. In addition, olanzapine and paliperidone augmented SWS and REM sleep. By contrast, quetiapine administration further disrupted sleep as judged by the increase of SL, wake time after sleep onset (WASO) and REM sleep latency, and the reduction of SWS and REM sleep. No consistent effects on sleep variables were obtained during treatment with risperidone. To date, no polysomnographic studies have been published on the effects of aripiprazole, asenapine, iloperidone and lurasidone on sleep in either healthy subjects or patients with schizophrenia. Taken together, this evidence supports the conclusion that second generation antipsychotics (SGAs) including clozapine, olanzapine and paliperidone may ameliorate insomnia in patients with schizophrenia.

Relational memory and hippocampal function in psychotic bipolar disorder.

Recent cognitive, genetic, and histological studies have highlighted significant overlap between psychotic bipolar disorder and schizophrenia. Specifically, both bipolar disorder and schizophrenia are characterized by interneuron dysfunction within the hippocampus, an essential structure for relational memory. Relational memory impairments are a common feature of schizophrenia, but have yet to be investigated in psychotic bipolar disorder. Here, we tested the hypothesis that psychotic bipolar disorder is characterized by relational memory deficits. We used a transitive inference (TI) paradigm, previously employed to quantify relational memory deficits in schizophrenia, to assess relational memory performance in 17 patients with psychotic bipolar disorder and 22 demographically matched control participants. Functional magnetic resonance imaging was used to examine hippocampal activity during recognition memory in patients and controls. Hippocampal volumes were assessed by manual segmentation. In contrast to our hypothesis, we found similar TI performance, hippocampal volume, and hippocampal recruitment during recognition memory in both groups. Both psychotic bipolar disorder patients and controls exhibited a positive correlation between hippocampal volume and relational memory performance. These data indicate that relational memory impairments are not a shared feature of non-affective and affective psychosis.

The role of cognitive functioning in the outcome of those at clinical high risk for developing psychosis

Although it is well established that cognitive impairment is a common feature of schizophrenia, only recently has cognitive functioning been prospectively studied in individuals at clinical high risk (CHR) for developing psychosis. To date, both cross-sectional and longitudinal studies have been conducted in the CHR population and in the context of later conversion to psychosis. A comprehensive review of the literature suggests that CHR individuals have general and specific baseline cognitive deficits compared to healthy controls. As a group, their cognitive course, tends to remain stable over time and in this way does not differ from healthy controls. For those who go on to develop a full-blown psychotic illness compared to those who do not convert, there appeared to be minimal differences at baseline with respect to cognition, although over time the converters may show deterioration in certain cognitive abilities compared to the non-converters. However, for many cognitive domains results are mixed, and may result from methodological limitations.

Impaired facial emotion recognition in a ketamine model of psychosis

ObjectiveSocial cognitive disabilities are a common feature in schizophrenia. Given the role of glutamatergic neurotransmission in schizophrenia-related cognitive impairments, we investigated the effects of the glutamatergic NMDA receptor antagonist ketamine on facial emotion recognition. MethodsEighteen healthy male subjects were tested on two occasions, one without medication and one after administration with subanesthetic doses of intravenous ketamine. Emotion recognition was examined using the Ekman 60 Faces Test. In addition, attention was measured by the Continuous Performance Test (CPT), and psychopathology was rated using the Psychotomimetic States Inventory (PSI). ResultsKetamine produced a non-significant deterioration of global emotion recognition abilities. Specifically, the ability to correctly identify the facial expression of sadness was significantly reduced in the ketamine condition. These results were independent of psychotic symptoms and selective attention. ConclusionOur results point to the involvement of the glutamatergic system in the ability to recognize facial emotions.

Revisiting Thyroid Hormones in Schizophrenia

Thyroid hormones are crucial during development and in the adult brain. Of interest, fluctuations in the levels of thyroid hormones at various times during development and throughout life can impact on psychiatric disease manifestation and response to treatment. Here we review research on thyroid function assessment in schizophrenia, relating interrelations between the pituitary-thyroid axis and major neurosignaling systems involved in schizophrenia's pathophysiology. These include the serotonergic, dopaminergic, glutamatergic, and GABAergic networks, as well as myelination and inflammatory processes. The available evidence supports that thyroid hormones deregulation is a common feature in schizophrenia and that the implications of thyroid hormones homeostasis in the fine-tuning of crucial brain networks warrants further research.

Sleep disturbances in schizophrenia

Schizophrenia is often related with sleep disorders. In clinical practice insomnia is a common feature in schizophrenia. Difficulty falling asleep, maintaining or achieving a restful sleep is associated with symptoms severity and has been listed as a prodromal symptom of psychotic relapse. Sleep disturbances in schizophrenia may arise during the acute phase of illness and persists in many cases in chronic phase. The authors intend to review the main sleep disturbances observed in schizophrenia, the possible pathophysiological mechanisms, their clinical impact, and the effects of antipsychotic medication on sleep architecture. This study was carried out a systematic search of published literature from January 1965 to May 2010, through PubMed, using the following key words: sleep, REM sleep, NREM sleep, schizophrenia, polysomnography, actigraphy and antipsychotics. Most changes found in objective studies using the polysomnography, in patients with schizophrenia are: reduction of total sleep time, decrease in slow wave sleep, REM latency and sleep efficiency. Studies using actigraphy also reveal that these patients experience changes in circadian rhythm sleep disorders, specifically the irregular type and phase advance. Although some sleep disorders improve with antipsychotic treatment, in many cases, even during the remission of the disease, sleep continues fragmented , suggesting that there are physiopathologic mechanisms involved in sleep disturbance in these patients. Privation of adequate and restful sleep has a negative impact on rehabilitation strategies, quality of life of patients with schizophrenia, and may contribute to worsening of cognitive deficits.

Event-related potential correlates of suspicious thoughts in individuals with schizotypal personality features

Suspiciousness is a common feature of schizophrenia. However, suspicious thoughts are also commonly experienced by the general population. This study aimed to examine the underlying neural mechanism of suspicious thoughts in individuals with and without schizotypal personality disorder (SPD)-proneness, using an event-related potential (ERP) paradigm. Electroencephalography (EEG) was recorded when the “feeling of being seen through” was evoked in the participants. The findings showed a prominent positive deflection of the difference wave within the time window 250–400 ms after stimuli presentation in both SPD-prone and non-SPD-prone groups. Furthermore, the P3 amplitude was significantly reduced in the SPD-prone group compared to the non-SPD-prone group. The current density analysis also indicated hypoactivity in both frontal and temporal regions in the SPD-prone group, suggesting that the frontotemporal cortical network may play a role in the onset of suspicious thoughts. The P3 of difference wave was inversely correlated with the cognitive-perception factor and the suspiciousness/paranoid ideation trait, which provided preliminary electrophysiological evidence for the association of suspiciousness with SPD features.

P.3.c.003 A randomized, controlled study to evaluate quetiapine fumarate in improving sleep quality of schizophrenia

Insomnia is a common feature in schizophrenia, and is characterized by an increase of sleep latency (SL), as well as reductions in total sleep time (TST) and sleep efficiency (SE). Regarding sleep architecture, non-rapid-eye-movement (NREM) sleep, slow wave sleep (SWS) and rapid-eye-movement (REM) sleep latency are decreased, whereas REM sleep tends to remain unchanged. According to polysomnographic studies, clozapine, olanzapine, quetiapine and ziprasidone administration increased TST and/or SE in healthy subjects. Additionally, olanzapine and ziprasidone augmented SWS, while changes corresponding to REM sleep were inconsistent. Furthermore, administration of clozapine, olanzapine and paliperidone to patients with schizophrenia was followed in most instances by a significant reduction of SL and an increase of TST and SE. In addition, olanzapine and paliperidone augmented SWS and REM sleep. By contrast, quetiapine administration further disrupted sleep as judged by the increase of SL, wake time after sleep onset (WASO) and REM sleep latency, and the reduction of SWS and REM sleep. No consistent effects on sleep variables were obtained during treatment with risperidone. To date, no polysomnographic studies have been published on the effects of aripiprazole, asenapine, iloperidone and lurasidone on sleep in either healthy subjects or patients with schizophrenia. Taken together, this evidence supports the conclusion that second generation antipsychotics (SGAs) including clozapine, olanzapine and paliperidone may ameliorate insomnia in patients with schizophrenia.

Blocking Early GABA Depolarization with Bumetanide Results in Permanent Alterations in Cortical Circuits and Sensorimotor Gating Deficits

A high incidence of seizures occurs during the neonatal period when immature networks are hyperexcitable and susceptible to hypersyncrhonous activity. During development, γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in adults, typically excites neurons due to high expression of the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1). NKCC1 facilitates seizures because it renders GABA activity excitatory through intracellular Cl(-) accumulation, while blocking NKCC1 with bumetanide suppresses seizures. Bumetanide is currently being tested in clinical trials for treatment of neonatal seizures. By blocking NKCC1 with bumetanide during cortical development, we found a critical period for the development of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate synapses. Disruption of GABA signaling during this window resulted in permanent decreases in excitatory synaptic transmission and sensorimotor gating deficits, a common feature in schizophrenia. Our study identifies an essential role for GABA-mediated depolarization in regulating the balance between cortical excitation and inhibition during a critical period and suggests a cautionary approach for using bumetanide in treating neonatal seizures.

Association of HPA axis genes with suicidal behaviour in schizophrenia

Family, adoption and twin studies show that genetics influences suicidal behaviour, but do not indicate specific susceptibility variants. Stress response is thought to be mediated by the corticotrophin-releasing hormone (CRH), which is known to be a regulator of the hypothalamic-pituitary-adrenal pathway (HPA). Alterations in HPA system have been related to impulsivity, aggression and suicidal behaviour, common feature in schizophrenia. CRH is the hypothalamic factor that stimulates the pituitary gland. To search for markers conferring genetic susceptibility to suicide, we typed six HPA axis genes (CRH, CRHR1, CRHR2, CRHBP, MC2R, NC3R1) in a cohort of 231 subjects with schizophrenia in which 81 attempted suicide. The genotype analyses yielded significant association between CRH binding protein (CRHBP) and suicide attempt (P = 0.035). The genotype analysis for quantitative measures of suicidal behaviour showed no association. The interaction analysis showed a significant interaction between CRH receptor type 1 (CRHR1) and CRH binding protein (CRHBP) in influencing suicide attempt and the severity of suicidal behaviour. Current results show that genetic variation in HPA axis genes could be associated with suicidal behaviour in schizophrenia. This is to our knowledge the first study on suicidal behaviour investigating the interaction among the HPA axis genes.

Olfactory Receptor Neuron Dysfunction in Schizophrenia

Olfactory impairments are a common feature of schizophrenia. Impairments in odor detection and odor identification are present early in the course of illness and among those at risk for the disorder. These behavioral impairments have been linked to both physiological and anatomical abnormalities in the neural substrates subserving olfaction, including relatively peripheral elements of the olfactory system. The location of olfactory receptor neurons in the nasal epithelium allows noninvasive access to these neurons in living subjects. This offers a unique opportunity to directly assess neuronal integrity in vivo in patients. The peripheral olfactory receptor neuron response to odor stimulation was assessed in 21 schizophrenia patients and 18 healthy comparison subjects. The electroolfactogram, representing the electrical depolarization of the olfactory receptor neurons, was recording following stimulation with different doses and durations of hydrogen sulfide, a pure olfactory nerve stimulant. Schizophrenia patients had abnormally large depolarization responses following odor stimulation, independent of clinical symptomatology, antipsychotic medication dosage or smoking history. Although the precise pathophysiological mechanism is unknown, this olfactory receptor neuron abnormality is consistent with several lines of evidence suggesting altered proliferation or maturation of olfactory receptor neuron cell lineages in schizophrenia. It is also consistent with emerging evidence of disruptions of cyclic AMP-mediated intracellular signaling mechanisms, and may be a marker of these disruptions. It unambiguously demonstrates that neurophysiological disturbances in schizophrenia are not limited to cortical and subcortical structures, but rather include even the most peripheral sensory neurons.

POOLED ANALYSIS COMPARING NON-HIGH-DENSITY LIPOPROTEIN IN PATIENTS WITH SCHIZOPHRENIA RANDOMIZED TO ARIPIPRAZOLE OR OLANZAPINE(CN138-002/003/047EXT)

Background: Depressive symptoms are a common feature of schizophrenia and may represent a core part of the illness. Where present, it has been associated with greater overall morbidity and mortality. Monotherapy with conventional dopamine antagonists may either worsen or bestow a limited therapeutic benefit. Accordingly the use of adjunctive thymoleptics has been explored. In contrast, olanzapine (OLZ), an atypical antipsychotic agent, offers a distinctive and pleotropic pharmacology suggestive of a broader efficacy profile than conventional neuroleptic agents.Methods: In a 6-week placebo- and haloperidol (HAL)-controlled trial with 335 randomized subjects with chronic schizophrenia in an acute exacerbation, three fixed dose ranges of OLZ (5, 10, or 15 ± 2.5 mg) were evaluated versus HAL (10–20 mg) or placebo.Results: Baseline to endpoint change in the Brief Psychiatric Rating Scale including the anxiety–depression cluster (items 1, 2, 5, 9) was analyzed. Two dose ranges of OLZ (10 ± 2.5, 15 ± 2.5) were superior to placebo (p < .05) in improving mood status, whereas HAL was not.Conclusions: Contributions from a more selective mesolimbic dopaminergic profile, D1 or D4 activity, the release of dopamine/norepinephrine in the prefrontal cortex, and/or serotonin 5-HT2A,C antagonism may explain the differential benefit seen with OLZ in the treatment of comorbid anxious and depressive symptoms in schizophrenia.

The architecture of cognitive control in schizophrenia

Executive dysfunctions have long been considered a common feature of schizophrenia. However, due to their extreme heterogeneity, it is not clear whether these impairments take place at a particular level of executive functioning or non-specifically affect various aspects of behavioural control. To answer this question, we used an experimental paradigm based upon a multistage model of prefrontal executive function. This model postulates that cognitive control is organized in three hierarchically ordered control processes, operating with respect to the perceptual context (sensory and contextual controls) or the temporal episode in which the person is acting (episodic control). Twenty-four patients with schizophrenia and 24 non-psychiatric controls participated in two distinct experiments designed to separately assess each of these three levels of control. The results indicate that both sensory and episodic dimensions of cognitive control were spared in schizophrenic patients, but that they showed great difficulty in contextual conditions, as the selection of the appropriate response among competitive ones required taking into account information related to perceptual context. Contextual control can be considered as a set of executive processes mediating the hierarchical organization of behaviour. Patients' deficit in cognitive control therefore reflects a specific problem in the hierarchical control of action, leading to the selection of inappropriate behavioural representations for ongoing action plans. We also showed that this impairment was a good predictor of disorganization syndrome scores, suggesting that these clinical manifestations might result from a deficit in the combination or selection of hierarchically organized action representations.

Age-associated differences in cognitive performance in older community dwelling schizophrenia patients: Differential sensitivity of clinical neuropsychological and experimental information processing tests

Cognitive dysfunction is a common feature of schizophrenia and deficits are present before the onset of psychosis, and are moderate to severe by the time of the first episode. Controversy exists over the course of cognitive dysfunction after the first episode. This study examined age-associated differences in performance on clinical neuropsychological (NP) and information processing tasks in a sample of geriatric community living schizophrenia patients ( n = 172). Compared to healthy control subjects ( n = 70), people with schizophrenia did not differ on NP tests across age groups but showed evidence for age-associated cognitive worsening on the more complex components of an information-processing test. Age-related changes in cognitive function in schizophrenia may be a function of both the course of illness and the processing demands of the cognitive measure of interest. Tests with fixed difficulty, such as clinical NP tests, may differ in their sensitivity from tests for which parametric difficulty manipulations can be performed.