Perseverative Responses Research Articles

The Relationship of Interleukin-18 and Interleukin-6 Levels with Cognitive Functions in Bipolar Disorder

Impairment in immune functions is proposed as a key factor in the cognitive decline in bipolar disorder (BD) however there is scarcity of research on the impact of inflammation on cognitive functions. Our aim is to compare IL-18 and IL-6 levels in BD patients and controls and to study the relationship between IL-18 and IL-6 levels and cognitive impairment METHOD: Thirty-six euthymic BD-I patients and 38 age, sex and educational level matched healthy controls were enrolled in the study. All participants were evaluated with neurocognitive tests. The plasma IL-6 and IL-18 levels of both groups were measured with ELISA kits. There was no statistically significant difference between IL-6 and IL-18 levels of patient and healthy control groups. In the patient group, IL-18 level was positively correlated with completed categories score wheras there was a negative correlation with perseverative response and perseverative errors. Moreover IL-18 level was positively correlated with immediate recall, delayed recall and learning scores while there was a negative correlation with stroop interference scores. No correlation was found between IL-6 level and neuropsychological test scores in the patient group. This is the first study that investigates the relation of IL-18 with cognitive functions. Possible detrimental or protective effects of IL-18 in BD is not yet clear, however the positive association of IL-18 level and neuropsychological test scores might indicate a neuroprotective role of IL-18 in the euthymic period of BD which is the closest state to physiological condition.

Impact on cognitive functions following gamma knife radiosurgery for cerebral arteriovenous malformations.

Background:Radiosurgery is an alternative to surgical resection of arteriovenous malformation (AVM). Very few studies have addressed the concern of radiation injury to the brain and its attendant adverse effects on cognitive function.Materials and Methods:This prospective study included all patients who underwent gamma knife radiosurgery (GKRS) at our institute for cerebral AVM between 2006 and December 2008 (n = 34). All patients underwent neuropsychological evaluation before the procedure. Neuropsychological evaluation was repeated in eighteen patients 2 years following GKRS. Clinical outcome, AVM obliteration, and factors influencing outcome were analyzed in these eighteen patients.Results:Before GKRS, more than 50% had significant impairment of neuropsychological functions compared to normal population norms. 66.6% achieved the excellent radiosurgical outcome. At 2 years follow-up, patients showed varied improvement in neuropsychological function in various categories. Pretherapeutic median value for percentage perseverative responses was 26.5 and at follow-up, it reduced to 18.2 (P = 0.039). Set shifting improved in 11 patients (61.1%), remained same in 5 patients (27.7%), and deteriorated in two patients (11.1%). Patients with a higher Spetzler-Martin grade AVM demonstrated a significantly more favorable shift in follow-up test values for set shifting function (P = 0.021). Patients with postradiation imaging changes had lesser tendency to improve in neuropsychological performance at follow-up.Conclusions:GKRS has no clinically harmful effect on cognitive and neuropsychological functioning in patients with brain AVM. On the contrary, there is an improvement in majority of patients at 2 years following radiosurgery when nidus is obliterated.

Perseveration during verbal fluency in traumatic brain injury reflects impairments in working memory.

Previous studies of verbal fluency have reported higher rates of perseverative responses in both Alzheimer's disease (AD) and traumatic brain injury (TBI) relative to control groups. These perseverations could arise from a number of impairments-for example, failures in working memory, inhibitory control, or word retrieval-and different clinical populations may show an increase in perseveration because of different underlying deficits. The objective of the current report is to investigate the cause of perseveration in verbal fluency in individuals with TBI and compare those results to a recent study of individuals with AD. In a previous study, conducted by Miozzo, Fischer-Baum, and Caccappolo-van Vliet (2013), perseveration errors produced by individuals with AD were shown to have long lags between the 1st occurrence of a word and its repetition in verbal fluency, suggesting that perseverations were caused by a failure of the working memory mechanisms that control response monitoring. In the present investigation, we applied the same analysis to the perseveration errors produced during 197 administrations of the verbal fluency task with 143 individuals with TBI. The perseverations of individuals with TBI showed a lag distribution similar to that of the AD population, with the lag between the 1st occurrence of a word and its repetition systematically longer than would be expected by chance. These results suggest that the perseverations produced during verbal fluency in individuals with TBI stem from the same working memory mechanism proposed in AD, rather than inhibitory control or word retrieval deficits. (PsycINFO Database Record

Modulatory effects of psychopathy on Wisconsin Card Sorting Test performance in male offenders with Antisocial Personality Disorder

Neuropsychological deficits in executive functions (EF) have been linked to antisocial behavior and considered to be cardinal to the onset and persistence of severe antisocial and aggressive behavior. However, when psychopathy is present, prior evidence suggests that the dorsolateral prefrontal cortex is unaffected leading to intact EF. Ninety-one male offenders with Antisocial Personality Disorder (ASPD) and 24 controls completed the Wisconsin Card Sorting Test (WCST). ASPD individuals were grouped in three categories according to Psychopathy Checklist-Revised (PCL-R) scores (low, medium and high). We hypothesized that ASPD offenders with high PCL-R scores will not differ from healthy controls in EF and will show better EF performance in comparison with subjects with low PCL-R scores. Results showed that ASPD offenders with low PCL-R scores committed more perseverative errors and responses than controls and offenders with high PCL-R scores, which did not differ from healthy controls. Moreover, scores on Factor 1 and the interpersonal facet of the PCL-R were predictors of better WCST performance. Our results suggest a modulatory role of psychopathy in the cognitive performance of ASPD offenders, and provide further evidence supporting that offenders with ASPD and psychopathy are characterized by a cognitive profile different from those with ASPD without psychopathy.

Executive Function Deficits in Patients after Cerebellar Neurosurgery.

The cerebellum has long been perceived as a structure responsible for the human motor function. According to the contemporary approach, however, it plays a significant role in complex behavior regulatory processes. The aim of this study was to describe executive functions in patients after cerebellar surgery. The study involved 30 patients with cerebellar pathology. The control group comprised 30 neurologically and mentally healthy individuals, matched for sex, age, and number of years of education. Executive functions were measured by the Wisconsin Card Sorting Test (WCST), Stroop Color Word Test (SCWT), Trail Making Test (TMT), and working memory by the Digit Span. Compared to healthy controls, patients made more Errors and Perseverative errors in the WCST, gave more Perseverative responses, and had a lower Number of categories completed. The patients exhibited higher response times in all three parts of the SCWT and TMT A and B. No significant differences between the two groups were reported in their performance of the SCWT and TMT with regard to the measures of absolute or relative interference. The patients had lower score on the backward Digit Span. Patients with cerebellar pathology may exhibit some impairment within problem solving and working memory. Their worse performance on the SCWT and TMT could, in turn, stem from their poor motor-somatosensory control, and not necessarily executive deficits. Our results thus support the hypothesis of the cerebellum's mediating role in the regulation of the activity of the superordinate cognitive control network in the brain. (JINS, 2016, 22, 47-57).

Neurocognitive functioning as an intermediary variable between psychopathology and insight in schizophrenia

Based on the neuropsychological deficit model of insight in schizophrenia, we constructed exploratory prediction models for insight, designating neurocognitive measures as the intermediary variables between psychopathology and insight into patients with schizophrenia. The models included the positive, negative, and autistic preoccupation symptoms as primary predictors, and activation symptoms as an intermediary variable for insight. Fifty-six Korean patients, in the acute stage of schizophrenia, completed the Positive and Negative Syndrome Scale, as well as a comprehensive neurocognitive battery of tests at the baseline, 8-weeks, and 1-year follow-ups. Among the neurocognitive measures, the Korean Wechsler Adult Intelligence Scale (K-WAIS) picture arrangement, Controlled Oral Word Association Test (COWAT) perseverative response, and the Continuous Performance Test (CPT) standard error of reaction time showed significant correlations with the symptoms and the insight. When these measures were fitted into the model as intermediaries between the symptoms and the insight, only the perseverative response was found to have a partial mediating effect – both cross-sectionally, and in the 8-week longitudinal change. Overall, the relationship between insight and neurocognitive functioning measures was found to be selective and weak.

Compulsivity and probabilistic reversal learning in OCD and cocaine addiction

Compulsive behavior is a core symptom of both obsessive compulsive disorder (OCD) and cocaine addiction (CA). Across both pathologies, one can identify a priori goal-directed actions (purportedly anxiolytic checking or washing in OCD and pleasure-seeking drug use in addiction) that turn into rigid, ritualized and repetitive behaviors over which the patient loose control. One possible psychopathological mechanism underlying compulsivity is behavioral inflexibility, namely a deficit in the aptitude to dynamically adapt to novel contexts and changing reward rules. The probabilistic reversal learning paradigm allows to objectively assess behavioral flexibility by challenging participants with a task where they have to learn through trials-and-errors which of two stimuli is the most-often rewarded one, while adjusting to sudden inconspicuous contingency reversals. We therefore hypothesized that both OCD and CA would be associated with impaired cognitive flexibility, as measured through perseverative response rate following contingency reversals in this task. Interestingly, impulsivity may also be assessed within this task via the tendency of participants to switch from one stimulus to the other following probabilistic errors. To investigate cognitive inflexibility in relation to CA and OCD respectively, we first compared the performance in a probabilistic reversal learning task of cocaine users, ex cocaine users (abstinent for 2 months or more), and controls, as well as that of participants from the general population whose obsessive-compulsive traits were assessed using the OCI-R, a well-validated self-questionnaire. Our task yielded results similar to those found in the literature: cocaine addicts changed their responses more often, and learned less effectively. Ex-cocaine addicts performed better than addicts but worse than controls, suggesting that addicts’ poor results may be in part explained by reversible cognitive consequences of addiction. Addicts with less cognitive impairments may also be less likely to relapse. Regarding the relationship of flexibility to subclinical OCD traits, we found no link between OCI-R score and perseveration, or between impulsiveness and excessive switching.

Preference pulses and the win–stay, fix‐and‐sample model of choice

Two groups of six rats each were trained to respond to two levers for a food reinforcer. One group was trained on concurrent variable-ratio 20 extinction schedules of reinforcement. The second group was trained on a concurrent variable-interval 27-s extinction schedule. In both groups, lever-schedule assignments changed randomly following reinforcement; a light cued the lever providing the next reinforcer. In the next condition, the light cue was removed and reinforcer assignment strictly alternated between levers. The next two conditions redetermined, in order, the first two conditions. Preference pulses, defined as a tendency for relative response rate to decline to the just-reinforced alternative with time since reinforcement, only appeared during the extinction schedule. Although the pulse's functional form was well described by a reinforcer-induction equation, there was a large residual between actual data and a pulse-as-artifact simulation (McLean, Grace, Pitts, & Hughes, 2014) used to discern reinforcer-dependent contributions to pulsing. However, if that simulation was modified to include a win-stay tendency (a propensity to stay on the just-reinforced alternative), the residual was greatly reduced. Additional modifications of the parameter values of the pulse-as-artifact simulation enabled it to accommodate the present results as well as those it originally accommodated. In its revised form, this simulation was used to create a model that describes response runs to the preferred alternative as terminating probabilistically, and runs to the unpreferred alternative as punctate with occasional perseverative response runs. After reinforcement, choices are modeled as returning briefly to the lever location that had been just reinforced. This win-stay propensity is hypothesized as due to reinforcer induction.

Comparing cognitive functions in medication adherent and non-adherent patients with schizophrenia

BackgroundMedication non-adherence presents a considerable problem in patients with schizophrenia. Cognitive and executive functions can affect adherence. The association between medication non-adherence and cognitive impairment in schizophrenia is under investigated with limited and conflicting research data. Purpose of the studyTo prospectively assess the rate of drug adherence among a sample of patients with schizophrenia and to compare the cognitive and executive functions between adherent and non-adherent patients. Subjects and methods109 patients with schizophrenia diagnosed according to the DSM-IV classification were initially assessed by the Wechsler Adult Intelligence Scale (WAIS), Wechsler Memory Scale-Revised (WMS-R) and Wisconsin Card Sorting Test (WCST) and six months later by the Brief Adherence Rating Scale (BARS). Results68.8% were non-adherent to their antipsychotic medication. Adherent patients (31.2%) had significantly higher mean scores for the total, verbal and performance IQ. They had significantly higher mean scores in most of WMS subtests (orientation, information, verbal paired association, digit span, visual memory span), and higher mean scores for; total correct, conceptual level response, percentage and categories completed on the WSCT subscales (P < 0.0001). Whereas the non-adherent group had higher mean scores in; trials administered, total errors, perseverative responses, and perseverative errors (P < 0.0001). In a step regression analysis, digit span, conceptualization, total and percentage of errors were putative predictors of non-adherence. ConclusionCognitive deficits, especially verbal memory and executive functions were the strongest patients' related factors associated with non adherence to medication. Psychiatrists ought to consider possible cognitive factors influencing adherence to enable offering proper interventions.

Mice repeatedly exposed to Group-A β-Haemolytic Streptococcus show perseverative behaviors, impaired sensorimotor gating, and immune activation in rostral diencephalon.

Repeated exposure to Group-A β-Haemolytic Streptococcus (GAS) may constitute a vulnerability factor in the onset and course of pediatric motor disturbances. GAS infections/colonization can stimulate the production of antibodies, which may cross the blood brain barrier, target selected brain areas (e.g. basal ganglia), and exacerbate motor alterations. Here, we exposed developing SJL male mice to four injections with a GAS homogenate and evaluated the following domains: motor coordination; general locomotion; repetitive behaviors; perseverative responses; and sensorimotor gating (pre-pulse inhibition, PPI). To demonstrate that behavioral changes were associated with immune-mediated brain alterations, we analyzed, in selected brain areas, the presence of infiltrates and microglial activation (immunohistochemistry), monoamines (HPLC), and brain metabolites (in vivo Magnetic Resonance Spectroscopy). GAS-exposed mice showed increased repetitive and perseverative behaviors, impaired PPI, and reduced concentrations of serotonin in prefrontal cortex, a brain area linked to the behavioral domains investigated, wherein they also showed remarkable elevations in lactate. Active inflammatory processes were substantiated by the observation of infiltrates and microglial activation in the white matter of the anterior diencephalon. These data support the hypothesis that repeated GAS exposure may elicit inflammatory responses in brain areas involved in motor control and perseverative behavior, and result in phenotypic abnormalities.

Correlation between the number of antiepileptic drugs and the scores on measurements of executive functions in patients with epilepsy

The aim of this work was to evaluate the significance of the number of applied antiepileptic drugs (AEDs) in the disorder of executive function in patients with temporal lobe epilepsy (TLE). We included patients with TLE over 18 years. For the assessment of executive functions were used Wiskonsin card sorting test (WCST) with an estimate of the number of categories achieved, the number of perseverative response and the impossibility of maintaining a set and the Trail Making Test-Part B (TMT-B). The study included 32 patients with TLE with mean age 43.47 ± 10.74 years. Most patients (59.4%) were treated with two AEDs, 18.8% were on monotherapy, three AEDs were taking in 15.6% of patients, while two patients (6.25%) taking four AEDs. Most frequently used AEDs were valproate (50.00%) and lamotrigine (46.87%). Other AEDs were topiramate, carbamazepine, phenobarbital, levetiracetam, and clonazepam. We have found statistically significant correlation between the number of AEDs and number of perseverative response on the WCST. As the number of AEDs increased to the achievement of the measurements of executive function deteriorates. With the increasing number of AEDs in the treatment of patients with TLE increases the risk of developing disorder of executive function in these patients.

Verbal Fluency: Language or Executive Function Measure?

Measures of phonemic and semantic verbal fluency, such as FAS and Animal Fluency (Benton, Hamsher, & Sivan, 1989), are often thought to be measures of executive functioning (EF). However, some studies (Henry & Crawford, 2004a, 2004b, 2004c) have noted there is also a language component to these tasks. The current exploratory factor-analytic study examined the underlying cognitive structure of verbal fluency. Participants were administered language and EF measures, including the Controlled Oral Word Association Test (FAS version), Animal Fluency, Boston Naming Test (BNT), Vocabulary (Wechsler Adult Intelligence Scale-III), Wisconsin Card-Sorting Test (WCST, perseverative responses), and Trail-Making Test-Part B (TMT-B). A 2-factor solution was found with the 1st factor, language, having significant loadings for BNT and Vocabulary, while the second factor was labeled EF because of significant loading from the WCST and TMT-B. Surprisingly, FAS and Animal Fluency loaded exclusively on to the language factor and not EF. The current results do not exclude EF as a determinant of verbal fluency, but they do suggest that language processing is the critical component for this task, even without significant aphasic symptoms. Thus, the results indicated that both letter (phonemic) and category (semantic) fluency are related to language, but the relationship to EF is not supported by the results.

P48 – 2876: The evaluation of the frontal lobe function in the patients with absence epilepsy

Objective Based on earlier studies, CAE has been considered as a benign disorder with relatively easily attained seizure control and minimal involvement of cognition and behavior. However, more recent outcome studies report a varying rate of seizure control, as well as learning and cognitive difficulties. The aim of this study is the evaluation of neurocognitive function, especially frontal lobe, in the patients with typical absence epilepsy. Methods Thirty-eight (19 healthy children and 19 patients) participants were enrolled. Neurocognitive function tests such as Serial Digit Learning Test, Wisconsin Card Sorting Test, Visual Aural Digit Span Test and STROOP Test were performed to all participants. Results There was a significant difference between the groups according to Serial Digit Learning Test (SDLT) and the subgroup of Wisconsin Card Sorting Test. As for the WCST performance, there was significant difference in categories achieved, difficulty of maintaining set, perseverative errors, and perseverative responses between patient and control groups (p=0.037, p=0.010, p=0.011). In Serial Digit Learning Test and in the non-perseverative error subgroup of WCST performance, there was a significant difference in the patient group whose seizures started before the age 6 (p=0.029, p=0.041). As for the Visual-Aural Digit Span Test performance, there was a significant difference between the groups when compared to the duration response to drug treatment in categories achieved, aural-oral, visual-oral, aural-written, and visual-written. (p=0.010, p=0.025, p=0.012, p=0.034). Conclusion Long-term risk of learning impairments, failure in executive abilities, short-term memory and attention disorders can occur in children with absence epilepsy, especially in patients whose seizure started before the age of 7 years not responding to single drug, and the duration of response to drug was longer than 6 months. Our results highlight potentially detrimental effect of absence seizures on cognition.

Persistent effects of chronic Δ9-THC exposure on motor impulsivity in rats.

In humans, long-term marijuana use is associated with impaired impulse control and attentional capacity, though it has been difficult to distinguish pre-existing cognitive deficits from possible consequences of prolonged marijuana exposure. To evaluate the effects of long-term exposure to Δ9-Tetrahydrocannabinol (Δ9-THC), the primary psychoactive constituent in marijuana, on indices of impulse control and attentional capacity using the rat 5-Choice Serial Reaction Time Task (5-CSRTT). Ten 14-day cycles of Δ9-THC dosing and 5-CSRTT testing were employed, each comprised of 5-day Δ9-THC dosing (0.3 or 3 mg/kg b.i.d.) and 5-CSRTT testing during the 9 days of drug abstinence. Subsequent 5-CSRTT testing continued during 5 weeks of protracted abstinence. Dose-dependent increases in motor impulsivity (premature responses) and behavioral disinhibition (perseverative responses) emerged following 5 cycles of Δ9-THC exposure that persisted for the remaining dosing and testing cycles. Δ9-THC-related disruptions in motor impulsivity and behavioral inhibition were most pronounced during cognitively challenging 5-CSRTT sessions incorporating varying novel inter-trial intervals (ITIs), and these disruptions persisted for at least 5 weeks of Δ9-THC abstinence. Δ9-THC-related impairments in attentional capacity (response accuracy) were also evident during variable ITI challenge tests, though these attentional disruptions abated within 3 weeks of Δ9-THC abstinence. These observations demonstrate that long-term intermittent exposure to clinically meaningful Δ9-THC doses induces persistent impairments in impulse control and attentional function. If present in humans, these disruptions may impact academic and professional performance.

Markers of serotonergic function in the orbitofrontal cortex and dorsal raphé nucleus predict individual variation in spatial-discrimination serial reversal learning.

Dysfunction of the orbitofrontal cortex (OFC) impairs the ability of individuals to flexibly adapt behavior to changing stimulus-reward (S-R) contingencies. Impaired flexibility also results from interventions that alter serotonin (5-HT) and dopamine (DA) transmission in the OFC and dorsomedial striatum (DMS). However, it is unclear whether similar mechanisms underpin naturally occurring variations in behavioral flexibility. In the present study, we used a spatial-discrimination serial reversal procedure to investigate interindividual variability in behavioral flexibility in rats. We show that flexibility on this task is improved following systemic administration of the 5-HT reuptake inhibitor citalopram and by low doses of the DA reuptake inhibitor GBR12909. Rats in the upper quintile of the distribution of perseverative responses during repeated S-R reversals showed significantly reduced levels of the 5-HT metabolite, 5-hydroxy-indoleacetic acid, in the OFC. Additionally, 5-HT2A receptor binding in the OFC of mid- and high-quintile rats was significantly reduced compared with rats in the low-quintile group. These perturbations were accompanied by an increase in the expression of monoamine oxidase-A (MAO-A) and MAO-B in the lateral OFC and by a decrease in the expression of MAO-A, MAO-B, and tryptophan hydroxylase in the dorsal raphé nucleus of highly perseverative rats. We found no evidence of significant differences in markers of DA and 5-HT function in the DMS or MAO expression in the ventral tegmental area of low- vs high-perseverative rats. These findings indicate that diminished serotonergic tone in the OFC may be an endophenotype that predisposes to behavioral inflexibility and other forms of compulsive behavior.

Reduced striatal dopamine transporter density associated with working memory deficits in opioid-dependent male subjects: a SPECT study.

Research on the effects of repeated opioid use on striatal dopamine transporters has yielded inconsistent results, possibly confounded by a history of methamphetamine or methadone exposure in opioid-dependent individuals. Previous studies have shown that striatal dopamine transporter density is positively correlated with the cognitive performance of healthy volunteers. This study aimed to investigate changes in striatal dopamine transporter density and their functional significance in opioid-dependent individuals. Single-photon emission computed tomography with [(99m) Tc]TRODAT-1 as a ligand was used to measure striatal dopamine transporter levels in 20 opioid-dependent individuals and 20 age- and sex-matched healthy controls. Opioid-dependent individuals had no history of methamphetamine or methadone use. The Wisconsin Card Sorting Test (WCST) was performed to assess neurocognitive function. We found that compared with healthy controls, opioid-dependent individuals showed a significant reduction in striatal dopamine transporter density. They also showed poorer performance on the WCST in terms of the trials administered, total errors, perseverative responses, perseverative errors, and non-perseverative errors. Striatal dopamine transporter levels negatively correlated with non-perseverative errors not only in opioid-dependent individuals but also in healthy controls. These findings suggest that in human, repeated opioid exposure reduces striatal dopamine transporter density, which can be associated with non-perseverative errors. Non-perseverative errors may be one of the more sensitive parameters in WCST to identify working memory deficits associated with striatal dopamine transporter reduction. Moreover, we suggest that whether opioid-associated neurotoxicity is reversible depends on the brain region.

Prenatal Ethanol Exposure Impairs Executive Function in Mice into Adulthood

Despite evidence that prenatal alcohol exposure (PAE) can lead to a wide range of impairments in cognitive, social, and emotional behaviors, drinking during pregnancy remains common. Although there is a general understanding that high levels of drinking during pregnancy are unsafe, conflicting evidence regarding the impact of low intake may account for the persistence of this behavior. To investigate the effects of PAE on learning and executive control, we utilized a voluntary paradigm where pregnant mice had access to a saccharin-sweetened 10% alcohol solution for 4hours, during the dark cycle, throughout gestation. Male and female offspring were tested as adults on a touch-screen discrimination and reversal task mediated by corticostriatal circuits. Consistent with previous findings, PAE did not lead to gross morphological, motor, or sensory alterations in offspring. Both PAE and saccharin control female mice were slower to acquire the discrimination than males, but PAE did not impair associative learning in either sex. During reversal, PAE led to a specific and significant impairment in the early phase, where cortical control is most required to flexibly alter choice behavior. PAE mice showed a significant increase in maladaptive perseverative responses but showed intact learning of the new association during late reversal. Previously, data from clinical studies have suggested that executive control deficits may underlie cognitive, as well as social, problems seen in adolescents with documented PAE. These data demonstrate that even more moderate alcohol exposure during development can lead to impaired cognitive functioning well into adulthood.

Frontostriatal dysexecutive syndrome: a core cognitive feature of myotonic dystrophy type 2.

The aim of this study was to assess cognitive status in a large group of patients with myotonic dystrophy type 2 (DM2) compared to type 1 (DM1) subjects matched for gender and age, using a comprehensive battery of neuropsychological tests. Thirty-four genetically confirmed adult DM2 patients were recruited and matched for gender and age with 34 adult-onset DM1 subjects. All patients underwent detailed classic pen and pencil neuropsychological investigation and also computerized automated battery-CANTAB. More than half of DM2 patients had abnormal results on executive tests [Intra/Extradimensional Set Shift (IED), Stockings of Cambridge (SOC)] and verbal episodic memory (Ray Auditory Verbal Learning Test). Regarding DM1, abnormal results in more than 50 % of subjects were achieved in even ten tests, including visuospatial, language, executive, cognitive screening and visual memory tests. Direct comparison between patient groups showed that lower percentage of DM2 patients had abnormal results on following tests: Addenbrooke's Cognitive Examination-Revised, Raven Standard Progressive Matrices, Block Design, copy and recall of Rey-Osterieth Complex Figure, number of categories and perseverative responses on Wisconsin Card Sorting Test and Boston Naming Test (p < 0.01), as well as Trail Making Test-B and Spatial Span (p < 0.05). Our results showed significant dysexecutive syndrome and certain impairment of episodic verbal memory in DM2 patients that are reflective of frontal (especially frontostriatal) and temporal lobe dysfunction. On the other hand, dysexecutive and visuospatial/visuoconstructional deficits predominate in DM1 which correspond to the frontal, parietal (and occipital) lobe dysfunction.

Antidepressant efficacy of theta-burst transcranial magnetic stimulation in treatment of first-episode depression: a randomized, double blind controlled trial

Objective To evaluate the antidepressant efficacy, cognitive effect and safety of theta-burst transcranial magnetic stimulation (TBS) in treatment of first-episode depression. Methods 43 hospitalized patients with first-episode depression meeting with Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) were randomly divided into theta-burst stimulation group(TBS group, n=21)and sham-stimulation group(sham group, n=22). All patients were treated at left dorsolateral prefrontal cortex (DLPFC) for 4 weeks, and were concomitantly taking venlafaxine (150-300)mg/d. Hamilton Depression Scale-24 was used to assess the severity of depression before treatment, at week 2 and week 4 in both groups. Wisconsin Card Sorting Test (WCST) and Continuous Performance Test (CPT) were used to estimate cognitive function of depression before and after treatment. Results There was no difference on HAMD score before treatment between two groups((38.2±7.1)vs.(37.5±6.8), t=0.314, P=0.754). The reduction of HAMD score in TBS group showed significantly faster than that in sham group at week 2 ((20.5±4.8)vs.(16.1±5.9), t=2.547, P=0.015) and week 4((30.3±5.2)vs.(26.0±6.3), t=2.318, P=0.026). After 2-week stimulation, the response rate was higher in TBS group than that in sham group (57.9%vs. 25%, χ2 =4.358, P=0.037). The response and remission rates were significantly higher in TBS group than those in sham group after 4-week stimulation period (94.7%vs.65%, χ2 =5.284, P=0.021; 78.9%vs.45%, χ2=4.744, P=0.029). The improvements on WCST and CPT after treatment in TBS group, such as categories completed, correct responses, error responses, perseverative responses errors, nonperseverative responses errors, CPT1, CPT2 and CPT3, were significant than those in sham group (P<0.05). Conclusions Theta-burst stimulation of the left dorsolateral prefrontal cortex is safe and well-tolerated, while offering the potential to enhance early effects and modulate cognition in first-episode depressive patients. Key words: Theta-burst stimulation; Transcranial magnetic stimulation; Depression

Contributions of β2 subunit-containing nAChRs to chronic nicotine-induced alterations in cognitive flexibility in mice.

Deficits in executive functions underlie compulsive drug use, and understanding how nicotine influences these cognitive processes may provide important information on neurobiological substrates of nicotine addiction. Accumulating evidence suggests that β2 subunit-containing nicotinic receptors (nAChRs) are involved in the reinforcing process of nicotine addiction. Whether these nAChRs also contributes to the detrimental effects of chronic nicotine on flexible decision-making is not known. In the present study, the effects of chronic nicotine were assessed in mice with partial or complete deletion of the β2 subunit-containing nAChR gene (β2+/- or β2-/-) performing an operant cognitive flexibility task. Visual discrimination learning was not affected in saline-treated β2 nAChR mutants as compared to the wild-type (β2+/+) mice; yet, chronic nicotine facilitated acquisition of visual discrimination in all genotypes. The acquisition of new egocentric response strategy set-shifting remained similar in all genotypes, and there was no effect of treatment. Chronic nicotine treatment impaired reversal learning in β2+/+ mice by increasing response perseveration to the previously rewarded stimulus. Moreover, the acquisition of inverted stimulus-reward contingencies did not differ between β2+/+ and β2-/- mice exposed to chronic nicotine. Interestingly, nicotine-induced reversal learning deficits were not observed in β2+/- mice. Collectively, these findings suggest that β2 subunit-containing nAChRs are not critical for visual discrimination learning and extra dimensional rule shift. However, sustained activation of these nAChRs with nicotine may interfere with inhibitory control processes influencing affective shifts in stimulus-reward contingencies.