Endophenotypic Marker Research Articles

Pediatric bipolar disorder: evidence for prodromal states and early markers.

Childhood bipolar disorder remains a controversial but increasingly diagnosed disorder that is associated with significant impairment, chronic course and treatment resistance. Therefore, the search for prodromes or early markers of risk for later childhood bipolar disorder may be of great importance for prevention and/or early identification. Literature searches were conducted to identify reviews, case reports and empirical papers addressing the issue of prodromes of childhood bipolar disorder. A total of 54 articles were found that related to bipolar prodromes, risk factors for later childhood bipolar disorder, childhood risk for adult bipolar disorder, mania manifestations in early childhood, and neuropsychological and biological markers of childhood bipolar disorder. A review of articles suggest (a) childhood bipolar prodromes may be detectable prior to the onset of the disorder, (b) prodromal symptoms may display episodicity during childhood, (c) there is evidence of possible endophenotypic markers such as deficits in executive function, sustained attention, and emotion labeling, (d) there is a potential association with functional, structural, and biochemical alterations evident in brain structures involved in mood regulation, (e) a link between childhood bipolar disorder with early tempermental markers, such as emotional regulation and behavioral disinhibition and (f) there is some early but promising evidence of effective psychotherapeutic preventions. There has been very limited investigation of early prodromes of childhood bipolar disorder. Based on the promising findings of prodromes as well as high-risk states and possible endophenotypic markers, more controlled and targeted investigations into the early markers of bipolar disorder appear warranted and potentially fruitful. Until such longitudinal studies with appropriate controls are conducted, specific markers for bipolar prodromes will remain elusive, although evidence suggests they are manifest in at least some subgroups. The finding of promising psychotherapeutic prevention programs underscores the need to find specific and sensitive markers of bipolar prodromes in childhood.

Olfactory function and schizophrenia: an update

Olfaction is a field of growing interest in schizophrenia research. This article reviews recent studies on olfactory functions in schizophrenia. The current literature provides additional insights into olfactory deficits, abnormalities, and olfactory hedonic dysfunction in schizophrenia. Recent findings reinforce particular associations with negative symptoms and deficit syndrome schizophrenia. Studies indicate that abnormalities in patients with schizophrenia extend to more peripheral olfactory structures and functions, including olfactory receptor neuron dysfunction. Olfactory identification ability was found to relate to prodromal disorganization symptoms in young high-risk patients. Further support for the notion of a genetic contribution to olfactory dysfunction in schizophrenia derives from studies reporting physiological olfactory dysfunction (olfactory event-related potentials) in unaffected relatives, and an odor-specific hyposmia, present in both patients with schizophrenia and family members. Further research is needed to improve our understanding of olfactory dysfunction in schizophrenia. Recent encouraging findings underscore that the olfactory system is a field of research that holds promise for advancing our understanding of the pathophysiology of schizophrenia and possibly as a useful endophenotypic marker of neurodevelopmental vulnerability.

Mismatch negativity in treatment-resistant depression and borderline personality disorder

Cognitive dysfunctions, such as attentional impairment, are central features of both treatment-resistant depression (TRD) and borderline personality disorder (BPD). The treatment failure of TRD due to its comorbidity with BPD is debated in the literature. The mismatch negativity (MMN) of the event-related potentials provides an objective marker of involuntary stimulus selective processing, which might help shed light on this issue and provide an avenue for investigating a possible endophenotypic marker for TRD. We investigated MMN in 22 patients with TRD, 19 with BPD, and 22 with TRD cormorbid with BPD (TRD+BPD), as well as in 32 healthy volunteers, by employing an acoustic frequency deviance paradigm. In addition, we measured the depressive mood using the Plutchik-van Praag (PVP) depression inventory. There was no significant between-group difference for the N1 latencies/amplitudes, both to the standard and deviant stimuli, and no significant between-group difference for MMN latencies. However, MMN amplitudes were higher in the TRD group than those in the other three groups. PVP scores were highest in TRD+BPD, then TRD, BPD patients, and lowest in healthy subjects. The higher MMN was not correlated with PVP score, nor with the duration of life-long depression, which can be considered as a neurophysiological marker for TRD. An atypical lack of inhibition on the irrelevant stimuli or increased cortical neuronal activity, especially frontal area, or both, might be responsible for the finding.

Abnormal dose-response melatonin suppression by light in bipolar type I patients compared with healthy adult subjects.

Among potential endophenotypes proposed for bipolar affective disorder focusing on circadian abnormalities associated with the illness has particularly high face validity. Melatonin sensitivity to light is one circadian endophenotype proposed as useful in bipolar disorder. The aim of this study was to investigate melatonin sensitivity to light over a range of light intensities in order to compare and contrast responses in bipolar I patients with those of healthy adult volunteers. The study included seven patients (4 females, 3 males) with bipolar I disorder and 34 control participants (22 females, 12 males) with no personal or family history of affective illness. Melatonin sensitivity to light was determined in all patients and participants across a range of light intensities (0, 200, 500 and 1000 lux). The results indicated that patients showed melatonin super-sensitivity to light in comparison with controls, a response that was consistent across the entire light intensity range investigated. The study provides further evidence for a super sensitive response in bipolar I patients and suggests that its potential usefulness as an endophenotypic marker of the illness is deserving of further research.

Fear of harm, a possible phenotype of pediatric bipolar disorder: A dimensional approach to diagnosis for genotyping psychiatric syndromes

Background In a prior concordance study of affected sibling pairs with a community diagnosis of pediatric bipolar disorder (PBD) a behavioral phenotype termed Fear of Harm (FOH) was found to have one of the strongest concordance coefficients (rho) between probands and siblings, and the widest contrasts between the rho-estimates for the proband/sibling vs. proband/comparison pairs [Papolos, D., Hennen, J., Cockerham, M.S, Lachman, H., 2007]. A strategy for identifying phenotypic subtypes: concordance of symptom dimensions between sibling pairs who met screening criteria for a genetic linkage study of childhood-onset bipolar disorder using the Child Bipolar Questionnaire (CBQ) was employed. J. Affect. Disord. 99, 27–36.]. We used the Child Bipolar Questionnaire (OUT) (CBQ) to further elucidate this behavioral phenotype of PBD. We hypothesized that selective factors including parent reported symptoms of mania and depression, would be distinguishing features of impairment between groups defined by 1) the magnitude of their score on a continuous measure of FOH, and 2) the high FOH group would have significantly greater levels of severity on course of illness variables. These measures included earlier age of onset of first psychiatric symptoms, first hospitalization, and frequency of psychiatric hospitalizations, as well as, degree of social impairment as determined by exposure to the juvenile justice system and school performance problems. Methods The sample was comprised of children with community diagnoses of bipolar disorder or at risk for the illness based on enriched family history with multiple first degree relatives diagnosed with BPD ( N = 5335). Included were all subjects who had > 40 positively endorsed CBQ symptom items at frequencies of very often, almost always, and always. This group was divided randomly into two groups, the exploratory group ( N = 2668) and the hypothesis testing (study) group ( N = 2666). The exploratory group was used for the development of hypotheses and the study group was used to test these hypotheses on a new set of data. All results reported here derive from the latter group. In subsequent analyses, we classified each child as having a high degree of FOH, low FOH, or no FOH. We examined a subset of the sample for differences in age of onset of first psychiatric symptoms, course of illness and measures of symptom severity. These groups were compared using the chi-square procedure for categorical data and the Analysis of Variance (ANOVA) with Scheffe pair wise tests for continuous variables. The Child Bipolar Questionnaire V.2.0, the Yale-Brown Obsessive Compulsive Scale (YBOCS) and the Overt Aggression Scale (OAS) were the principal instruments used to obtain diagnostic information for this study. Results We found that children representative of the FOH phenotype when compared to children with PBD who lack this trait had higher indices of severity of mania and depression, as well as other indices that reflect severity and course of illness. Trait factors were derived from a factor analysis of CBQ in a large population of children diagnosed with or at risk for PBD, and used to further elucidate trait features of children with FOH. Children with the FOH traits were also more likely to be defined by six CBQ factors; Sleep/Arousal, Harm to Self and Others, Territorial Aggression, Anxiety, Self-esteem, Psychosis/Parasomnias/Sweet Cravings/Obsessions (PPSO). Limitations This data is derived from samples enriched with bipolar disorder cases. Further validation is needed with samples in which childhood-onset BD is rarer and diagnoses more diverse. Clinician diagnosis was not validated via research interview. Conclusions The FOH phenotype, as defined by a metric derived from combining items from the YBOCS/OAS, is a clinically homogeneous behavioral phenotype of PBD with early age of onset, severe manic and depressive symptoms, and significant social impairment that is strongly associated with 6 CBQ factors and can be easily identified using the CBQ. Through the examination of dimensional features of PBD in an enriched sample of large size, we were able to further refine a phenotype and identify clinical dimensions potentially linked to endophenotypic markers that may prove fruitful in differential diagnosis, treatment and etiological studies of PBD. The nature of the sets of specific symptoms that comprise the FOH factors enabled us to propose a biological model for the phenotype (OUT) that involves a complex orexigenic circuit which links hypothalamic, limbic, and other brain nuclei primarily responsible for the regulation of behavioral and proposed physiological features of the FOH phenotype.

Enhanced Visual Motion Perception in Major Depressive Disorder

Major depressive disorder (MDD) is a mood disorder that is not traditionally considered to affect the visual system. However, recent findings have reported decreased cortical levels of the inhibitory neurotransmitter GABA in occipital cortex. To explore possible functional consequences of MDD on visual processing, we applied a psychophysical visual motion processing task in which healthy young adults typically exhibit impaired perceptual discrimination of large high-contrast stimuli. It has been suggested that this phenomenon, spatial suppression, is mediated by GABAergic center-surround antagonism in visual pathways. Based on previous findings linking MDD to occipital GABA dysfunction, we hypothesized that MDD patients would exhibit decreased spatial suppression, leading to the counterintuitive hypothesis of better psychophysical performance. Indeed, motion perception for typically suppressed stimuli was enhanced in patients with MDD compared with age-matched controls. Furthermore, the degree of spatial suppression correlated with an individual's illness load; patients with greater lifetime duration of depression exhibited the least spatial suppression and performed the best in the high-contrast motion discrimination task. Notably, this decrease in spatial suppression persisted beyond recovery and without the confound of acute illness or treatment; all patients had been clinically recovered and unmedicated for several months at the time of testing, suggesting that depression has ubiquitous consequences that may persist long after mood symptoms have receded. This finding raises the possibility that spatial suppression may represent a sensitive endophenotypic marker of trait vulnerability in MDD.

Patterns of neurocognitive impairment in first-episode bipolar disorder and schizophrenia

Researching psychotic disorders in unison rather than as separate diagnostic groups is widely advocated, but the viability of such an approach requires careful consideration from a neurocognitive perspective. To describe cognition in people with bipolar disorder and schizophrenia and to examine how known causes of variability in individual's performance contribute to any observed diagnostic differences. Neurocognitive functioning in people with bipolar disorder (n = 32), schizophrenia (n = 46) and healthy controls (n = 67) was compared using analysis of covariance on data from the Northern Ireland First Episode Psychosis Study. The bipolar disorder and schizophrenia groups were most impaired on tests of memory, executive functioning and language. The bipolar group performed significantly better on tests of response inhibition, verbal fluency and callosal functioning. Between-group differences could be explained by the greater proclivity of individuals with schizophrenia to experience global cognitive impairment and negative symptoms. Particular impairments are common to people with psychosis and may prove useful as endophenotypic markers. Considering the degree of individuals' global cognitive impairment is critical when attempting to understand patterns of selective impairment both within and between these diagnostic groups.

Nocturnal Enuresis: A Suggestive Endophenotype Marker for a Subgroup of Inattentive Attention-Deficit/Hyperactivity Disorder

Attention-deficit/hyperactivity disorder (ADHD) and enuresis co-occur at a higher rate than expected; the cause for this is unclear. Diagnostic and demographic variables were compared in 344 children ages 6 to 12 years, with and without enuresis, recruited in an ADHD genetic study. Sleep variables were investigated in a subgroup of 44 enuretic children with age- and sex-matched nonenuretic controls. The association of enuresis with single nucleotide polymorphisms located in regions reported in linkage with enuresis was explored. The prevalence rate of nocturnal enuresis was 16.9% for the entire cohort. There were no differences in sex, age, socioeconomic status, intelligence quotient, medication treatment, or comorbidities. The enuresis group had a higher likelihood of inattentive symptoms than the nonenuretic group. Night wakings and ability of children to wake themselves in the morning were both significantly decreased in children with enuresis compared with control children in the Child Sleep Habits Questionnaire Night Wakings subscale. No significant association was found with chromosomal regions previously reported in linkage with enuresis. Deficits in arousal may contribute to both enuresis and inattentive ADHD. Nocturnal enuresis may be a useful clinical marker in identifying a subgroup of the inattentive phenotype in ADHD genetic studies.

Genetic and Environmental Covariations Among Obsessive–Compulsive Symptoms, Neuroticism, and Extraversion in South Korean Adolescent and Young Adult Twins

A growing literature suggests that personality traits may be endophenotype markers for psychiatric illnesses. Although the phenotypic relationships between obsessive-compulsive disorder (OCD) and high neuroticism and low extraversion have been well documented, underlying genetic and environmental contributions to these associations have not been explored previously. Five hundred and twenty-four monozygoitc (MZ) and 228 dizygotic (DZ) pairs of adolescent and young adult twins (aged 13-24 years) drawn from the South Korean Twin Registry completed the Maudsley Obsessive Compulsive Inventory (MOCI) and the Neuroticism and Extraversion scale of the Eysenck Personality Scale by mail. The total score of MOCI (MOCIT) was significantly and positively correlated with Neuroticism (r = .44), but only weakly and negatively related to Extraversion (r = -.10). A trivariate Cholesky model was applied to the data. The additive genetic correlations in the best-fitting model were .51 between Neuroticism and MOCIT and -.17 between Extraversion and MOCIT, suggesting that additive genetic factors that lead to high neuroticism and low extraversion overlap with those genetic factors influencing high OC symptoms. These findings add to the cumulative evidence of the shared genetic etiology for the associations between a personality profile of high neuroticism and low extraversion and mental illnesses.

Explicit identification and implicit recognition of facial emotions: II. Core domains and relationships with general cognition

Both general and social cognition are important in providing endophenotypic markers and predicting real-world functional outcomes of clinical psychiatric disorders. However, to date, focus has been on general cognition, rather than on core domains of social/emotional cognition. This study sought to determine core domains of emotion processing for both explicit identification and implicit recognition and their relationships with core domains of general cognition. Age effects and sex differences were also investigated. A sample of 1,000 healthy individuals (6 to 91 years, 53.5% female) undertook the WebNeuro tests of emotion identification and recognition and tests of general cognitive function. Factor analysis revealed seven core domains of emotion processing: speed of explicit emotion identification, speed of implicit emotion recognition, implicit emotion recognition accuracy, “threat” processing, sadness–disgust identification, “positive emotion” processing, and general “face perception.” Seven corresponding core domains of general cognition were identified: information-processing speed, executive function, sustained attention/vigilance, verbal memory, working-memory capacity, inhibition/impulsivity, and sensorimotor function. Factors of emotion processing generally showed positive associations with those of general cognitive function, suggesting commonality in processing speed in particular. Moreover, age had a consistent nonlinear impact on both emotion processing and general cognitive factors, while sex differences were more specific. These findings contribute to a normative and standardized structure for assessment of emotional and general cognition in clinical groups.

Cognitive endophenotypes in OCD: A study of unaffected siblings of probands with familial OCD

Background Impairments in executive functions and non-verbal memory are considered potential endophenotype markers of obsessive–compulsive disorder (OCD). For the neuropsychological deficits to be considered endophenotypes, they should be demonstrable in unaffected family members. Aim To compare the neuropsychological performance in unaffected siblings of probands with familial OCD with that of individually matched healthy controls. Methods Twenty-five unaffected siblings of OCD probands with familial OCD, and 25 individually matched healthy controls were assessed with tests of attention, executive function, memory and intelligence. Results Unaffected siblings showed significant deficits in tests of decision making and behavioural reversal i.e., the Iowa Gambling Task (IGT) and the Delayed Alternation Test (DAT) respectively, but performed adequately in other tests. Conclusions Our study suggests that the deficits in decision making and behavioural reversal could be potential endophenotypes in OCD. These deficits are consistent with the proposed neurobiological model of OCD involving the orbitofrontal cortex. Future studies could couple cognitive and imaging strategies to identify neurocognitive endophenotypes in homogenous samples of OCD.

Memory functioning in familial bipolar I disorder patients and their relatives

The aim of this study was to compare the memory function of patients with familial bipolar I disorder (BD I) who had shown psychotic features, their non-psychotic, non-bipolar first-degree relatives, and normal controls. We assessed 38 patients with a lifetime diagnosis of BD I who had experienced psychotic symptoms, 49 of their non-psychotic, non-bipolar first-degree relatives, and 44 controls. Patients and relatives were from families multiply affected with functional psychotic illness. A five-subtest short form of the Wechsler Adult Intelligence Scale-Revised and three Wechsler Memory Scale subtests were administered to all participants. BD I patients showed deficits in verbal memory and verbal learning but not in visual memory. Compared to controls, relatives showed worse verbal learning at a statistically significant or suggestive level and performed significantly worse in both immediate and delayed verbal memory. Similar to patients, there were no differences between the relatives and control group for visual memory. Impaired verbal memory and learning were found in patients and their relatives. These deficits may represent candidate endophenotypic markers for bipolar disorder.

Block design reconstruction skills: not a good candidate for an endophenotypic marker in autism research

Superior performance on block design tasks is reported in autistic individuals, although it is not consistently found in high-functioning individuals or individuals with Asperger Syndrome. It is assumed to reflect weak central coherence: an underlying cognitive deficit, which might also be part of the genetic makeup of the disorder. We assessed block design reconstruction skills in high-functioning individuals with autism spectrum disorders (ASD) from multi-incidence families and in their parents. Performance was compared to relevant matched control groups. We used a task that was assumed to be highly sensitive to subtle performance differences. We did not find individuals with ASD to be significantly faster on this task than the matched control group, not even when the difference between reconstruction time of segmented and pre-segmented designs was compared. However, we found individuals with ASD to make fewer errors during the process of reconstruction which might indicate some dexterity in mental segmentation. However, parents of individuals with ASD did not perform better on the task than control parents. Therefore, based on our data, we conclude that mental segmentation ability as measured with a block design reconstruction task is not a neurocognitive marker or endophenotype useful in genetic studies.

Fronto-temporal alterations within the first 200 ms during an attentional task distinguish major depression, non-clinical participants with depressed mood and healthy controls: a potential biomarker?

Attentional impairment in depression is a cardinal feature of depression and has been proposed as a candidate endophenotype for major depressive disorder. Event-related potentials (ERPs) elicited by oddball signal detection tasks provide objective markers of selective stimulus processing, and are pertinent endophenotypic markers for depression. While previous studies have sought to determine objective markers for attentional impairment in depression, evidence is inconsistent and may involve heterogeneity in relatively small samples. Here, we brought together oddball ERP recording with source localization of neural correlates of selective attention in outpatients with major depressive disorder (MDD; n = 78) and participants with depressed mood (PDM; n = 127) relative to healthy controls (CTL; n = 116). The key finding was a dimensional exaggeration of the P200 (140-270 ms) to both target (signal) and non-target (noise) stimuli, most pronounced in MDD, followed by PDM, relative to CTL. This exaggeration was coupled with slower and more variable response times, suggesting that neural systems are attempting to compensate for a difficulty in discriminating signal from noise. P200 alterations were localised to limbic (hippocampal), temporal and ventral prefrontal regions, key components of the signal detection network. A subsequent reduction and delay in the P300 was also revealed for MDD indicating that the pronounced lack of discrimination in clinical depression may also lead to impaired stimulus evaluation. This P200 increase in depression could provide a potential mechanism for the attentional impairment frequently observed in depression and consequent alterations in the P300 may differentiate clinically significant depression.

Executive and verbal working memory dysfunction in first-degree relatives of patients with bipolar disorder

The authors aimed to investigate cognitive performance of first-degree relatives of probands with bipolar disorder (BD). They hypothesized that the relatives of BD patients would have impaired performance on cognitive tests of frontal-executive functions. A neuropsychological battery was administered to 34 first-degree relatives of BD probands and 25 control subjects. Relatives showed significant impairment in verbal working memory and executive function. Verbal memory and psychomotor performances of relatives were not different from control subjects. One particular component of executive function, cognitive flexibility, was associated with family history of mood episodes with psychotic features. Verbal working memory and executive function deficits may be useful endophenotypic markers of genetic vulnerability to BD.

Neuropsychological correlates of N400 anomalies in patients with schizophrenia: A preliminary report

We investigated N400 anomalies and their relationship with neuropsychological disturbance of schizophrenia. Twelve patients with schizophrenia and 12 normal controls, matched for age, sex, education and handedness underwent both the neuropsychological test and the electrophysiological recordings employing semantic violation sentence paradigm. The patients with schizophrenia showed a reduced N400 amplitude and worse performance in the frontal lobe function test compared to healthy participants. Furthermore, statistically significant positive correlations were found between N400 amplitude and neuropsychological performances on the Stroop Task and Wisconsin Card Sorting Test in patients with schizophrenia. Our results suggest the possibility that N400 anomalies reflect the disturbed integrity of the fronto-temporal network in schizophrenia evidenced by neuropsychological deficits. In addition, we concluded that the N400 amplitude is a candidate for an endophenotype marker of schizophrenia by revealing its relationship to neuropsychological deficits.

The Afrikaner and schizophrenia: A Genetic study

An overview is given on the genetics of schizophrenia in an Afrikaner founder population. This research has been done over a period of ten years. Founder populations hold tremendous promise for mapping genes for complex traits, as they offer less genetic and environmental heterogeneity and greater potential for genealogical research. Not all founder populations are equally valuable, however. The Afrikaner population meets several criteria that make it an ideal population for mapping complex traits. These include founding by a small number of initial founders that likely allowed for a relatively restricted set of mutations and a large current population size that allows identification of a sufficient number of cases. Since a large number of patients was traced to an original founder couple, the genealogical data of the research support the hypothesis that a substantial portion of the schizophrenia cases the researchers have identified will share the same or a small number of susceptibility alleles. Results further show that genetic variation at the 22q11 locus enhances the risk to develop schizophrenia. More than one gene in this region can independently or synergistically increase the risk of schizophrenia in non-deleted patients. In three independent samples, evidence was provided for a contribution of the PRODH/DGCR6 locus in 22q11 associated schizophrenia. One of these samples was from South Africa as part of an ongoing collection of schizophrenia patients of Afrikaner origin. An unusual pattern of PRODH2 gene variation that mimics the sequence of a linked pseudogene was uncovered. Several of the pseudo gene-like variants identified, resulted in missense changes at conserved residues and may prevent synthesis of a fully functional enzyme. The results have implications for understanding the genetic basis of the 22q11-associated psychiatric phenotype and provide further insight into the genomic instability of this region. It was shown in an independent sample of Afrikaner schizophrenia patients that the frequency of 22q11 deletion syndrome was 2%, as suggested in earlier studies. Early deviant behaviour before 10 years of age was the most important factor related to the onset of illness. Early deviant childhood behaviour was grouped into three clusters: social functioning impairment cluster, mood/anxiety cluster and cognitive impairment cluster. Some of these factors are important in male schizophrenia patients and maybe used as endophenotypic markers. The LRRTM1 gene is implicated in the paternal transmission of schizophrenia. This gene may be implicated in the development of specific forebrain structures. It influences neuronal differentiation and connections. Male users of cannabis suffering from schizophrenia; with prominent early deviant behaviour have the lowest age of onset of illness, namely 18.4 years. Approximately half of the male schizophrenia patients and a quarter of the female schizophrenia patients used or abused cannabis. These figures are high and make cannabis use/abuse an important part of the management strategy of these patients. It was stated that in male patients with a specific subtype of schizophrenia (where early deviant behaviour was present) the use of cannabis triggers an illness with earlier onset and a poor prognosis. The prevalence of obsessive-compulsive disorder and obsessive-compulsive symptoms in Afrikaner patients suffering from schizophrenia was 13.25%. This finding differs from those in another ethnic group in South Africa suggesting the possible role of genetic and cultural factors in the prevalence of co-morbid OCD/OCS in this patient population. The most common obsession reported was contamination followed by religious obsession. The most common compulsion was checking behaviour. Clinical characteristics of Afrikaner schizophrenia and schizo-affective disorder patients with and without co-morbid OCD/OCS are the same; both groups were associated with significant psychopathology and a poor prognosis.

Autism: Face-Processing Clues to Inheritance

When reading faces, autistic individuals gain considerably less information from the eyes and more from the mouth. A new study reports that some parents of autistic children use strikingly similar strategies, providing a crucial clue as to what might be inherited in autism.

Effects of topiramate and levetiracetam vs placebo on habituation of contingent negative variation in migraine patients

Migraine is characterized by reduced habituation of multimodal evoked potentials, which in turn reflects an abnormal pattern of cortical excitability. We assessed the effects of a 2-month treatment with topiramate or levetiracetam vs placebo on contingent negative variation (CNV) habituation and amplitude in a cohort of migraine without aura (MO) patients. Forty-five MO patients were selected from a university-based outpatient clinic and randomly assigned to 100mg topiramate or 1000mg levetiracetam or placebo in a double-blind design. Twenty-four control subjects were also recruited. The initial CNV (iCNV) amplitude and habituation were assessed by Cz/A1-A2 derivation recordings in the basal condition (T0) and after 2 months of treatment (T1). Both topiramate and levetiracetam produced a significant reduction in migraine frequency compared to placebo, they also reversed the abnormal iCNV habituation pattern which characterized the MO patients in the basal condition and which was not present in controls. For migraine patients, the reduced migraine frequency and habituation index following treatment were significantly correlated. A lack of habituation of evoked responses is an interictal endophenotypic marker in migraine, the reversion of which may improve disease outcome. These results suggest a role for neurophysiological methods in the management of migraine.

Are neuropsychological deficits trait markers in OCD?

Objective Neuropsychological deficits are potential endophenotype markers. In obsessive–compulsive disorder (OCD), there is impairment in executive functions and nonverbal memory. However, studies have largely examined neuropsychological functioning in patients during the symptomatic phase. The state independent nature of neuropsychological deficits in OCD is not established. For neuropsychological deficits to be endophenotype markers, they have to be state-independent. We compared neuropsychological functions in recovered OCD patients with matched healthy controls. Method We assessed 30 recovered DSM-IV OCD patients without any concurrent comorbidity or lifetime history of schizophrenia, bipolar disorder, tics and alcohol/substance abuse and 30 healthy controls individually matched for age, sex and education. They were assessed on different neuropsychological dimensions: attention, executive function, memory and intelligence. For between-group comparisons, we employed univariate analyses, and to identify neuropsychological variables that differentiate cases and controls, we used backward conditional logistic regression for matched case-control design. Results Patients in the recovered phase of the illness had significant deficits in tests of set-shifting ability, alternation, response inhibition and nonverbal memory but had intact performance in other tests. In the logistic regression, scores on the Wisconsin Card Sorting Test ‘categories completed’ and the Rey's Complex Fig. Test ‘delayed recall’ were significant after controlling for the possible confounding effects of age and education. There was no correlation between illness-related variables and neuropsychological deficits. Conclusions Deficits in certain executive functions and nonverbal memory are possibly state independent. Neuropsychological deficits are possibly candidate endophenotype markers for OCD and may help clarify genetic contributions. Future studies should evaluate unaffected siblings to establish deficits are endophenotype markers. Prospective studies with serial measurements of cognitive deficits are also needed to assess whether these deficits are cumulative with the progression of illness.