Emergence of social behavior deficit, blunted corticolimbic activity and adult depression-like behavior in a rodent model of maternal maltreatment.

Disrupted social behavior is a core symptom of multiple psychiatric and neurodevelopmental disorders. Many of these disorders are exacerbated by adverse infant experiences, including maltreatment and abuse, which negatively affect amygdala development. Although a link between impaired social behavior, abnormal amygdala function and depressive-like behavior following early adversity has been demonstrated in humans and animal models, the developmental emergence of maltreatment-related social deficits and associated amygdala neural activity are unknown. We used a naturalistic rodent model of maternal maltreatment during a sensitive period, postnatal days 8-12 (PN8-12), which produces social behavior deficits that precede adolescent depressive-like behavior and amygdala dysfunction, to examine social behavior in infancy, periweaning and adolescence. Neural activity in response to the social behavior test was assessed via c-Fos immunohistochemistry at these ages. A separate group of animals was tested for adult depressive-like behavior in the forced swim test. Maltreatment spared infant (PN16-18) social behavior but disrupted periweaning (PN20-22) and adolescent (PN42-48) social behavior. Maltreated rats exhibited blunted neural activation in the amygdala and other areas implicated in social functioning, including the medial prefrontal cortex and nucleus accumbens, at these ages and increased adult depressive-like behavior. These findings may suggest corticolimbic involvement in the emergence of maltreatment-induced social deficits that are linked to adult depressive-like behavior, thereby highlighting potential targets for therapeutic intervention. Understanding how infant experiences influence social behavior and age-specific expression across development may provide insights into basic neural mechanisms of social behaviors and disease-relevant social dysfunction exacerbated by early-life stress.

Brain and behaviour phenotyping of a mouse model of neurofibromatosis type-1: an MRI/DTI study on social cognition.

Neurofibromatosis type-1 (NF1) is a common neurogenetic disorder and an important cause of intellectual disability. Brain-behaviour associations can be examined in vivo using morphometric magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) to study brain structure. Here, we studied structural and behavioural phenotypes in heterozygous Nf1 mice (Nf1(+/-) ) using T2-weighted imaging MRI and DTI, with a focus on social recognition deficits. We found that Nf1(+/-) mice have larger volumes than wild-type (WT) mice in regions of interest involved in social cognition, the prefrontal cortex (PFC) and the caudate-putamen (CPu). Higher diffusivity was found across a distributed network of cortical and subcortical brain regions, within and beyond these regions. Significant differences were observed for the social recognition test. Most importantly, significant structure-function correlations were identified concerning social recognition performance and PFC volumes in Nf1(+/-) mice. Analyses of spatial learning corroborated the previously known deficits in the mutant mice, as corroborated by platform crossings, training quadrant time and average proximity measures. Moreover, linear discriminant analysis of spatial performance identified 2 separate sub-groups in Nf1(+/-) mice. A significant correlation between quadrant time and CPu volumes was found specifically for the sub-group of Nf1(+/-) mice with lower spatial learning performance, suggesting additional evidence for reorganization of this region. We found strong evidence that social and spatial cognition deficits can be associated with PFC/CPu structural changes and reorganization in NF1.

Schizophrenia and reelin: a model based on prenatal stress to study epigenetics, brain development and behavior

Schizophrenia is a severe psychiatric disorder that results in a significant disability for the patient. The disorder is characterized by impairment of the adaptive orchestration of actions, a cognitive function that is mainly dependent on the prefrontal cortex. This behavioral deficit, together with cellular and neurophysiological alterations in the prefrontal cortex, as well as reduced density of GABAergic cells and aberrant oscillatory activity, all indicate structural and functional deficits of the prefrontal cortex in schizophrenia. Among the several risk factors for the development of schizophrenia, stress during the prenatal period has been identified as crucial. Thus, it is proposed that prenatal stress induces neurodevelopmental alterations in the prefrontal cortex that are expressed as cognitive impairment observed in schizophrenia. However, the precise mechanisms that link prenatal stress with the impairment of prefrontal cortex function is largely unknown. Reelin is an extracellular matrix protein involved in the development of cortical neural connectivity at embryonic stages, and in synaptic plasticity at postnatal stages. Interestingly, down-regulation of reelin expression has been associated with epigenetic changes in the reelin gene of the prefrontal cortex of schizophrenic patients. We recently showed that, similar to schizophrenic patients, prenatal stress induces down-expression of reelin associated with the methylation of its promoter in the rodent prefrontal cortex. These alterations were paralleled with altered prefrontal cortex functional connectivity and impairment in prefrontal cortex-dependent behavioral tasks. Therefore, considering molecular, cellular, physiological and behavioral evidence, we propose a unifying framework that links prenatal stress and prefrontal malfunction through epigenetic alterations of the reelin gene.

Trastorno del espectro autista y trastorno específico del lenguaje ¿Dos entidades diferentes o un continuo de manifestaciones neuropsicológicas? / [Autism spectrum disorder and specific language disorder. Are two different entities or a continuum of neuropsychological manifestations?].

Follow-up of children with delayed language development underscores the fact that, in several cases, language difficulties coexist with other symptoms such as social behavior changes. Autism spectrum disorder (ASD) and language specific disorder (LSD) are developmental disorders that are defined differently, but have some common language and social behavior characteristics which impose diagnostic difficulties. For this reason it is believed that they may share not only symptomatic but also ethiological aspects. With that in mind, we performed a literature search of works that discussed and, with their results, clarified this issue. Although several studies have allowed clearer and frequent diagnosis of both ASD and LSD, many cases persist in which the question in this article’s title cannot be clearly answered, especially in children younger than two years of age.

Geissoschizine methyl ether, an alkaloid in Uncaria hook, is a potent serotonin 1A receptor agonist and candidate for amelioration of aggressiveness and sociality by yokukansan.

Yokukansan (YKS), a traditional Japanese medicine, is composed of seven kinds of dried herbs. It is widely prescribed in clinical situation for treating psychiatric disorders such as aggressiveness in patients with dementia. We previously demonstrated that YKS and Uncaria hook (UH), which is a constituent herb of YKS, had a partial agonistic effect to 5-HT(1A) receptors in vitro. However, it has still been unclear whether this in vitro effect is reflected in in vivo, and what the active ingredients are. The purpose of the present study is to find the active ingredient in YKS and to demonstrate the effect in in vivo. In the present study, we first studied the effect of YKS and UH on aggressiveness and sociality in socially isolated mice. YKS and UH ameliorated the isolation-induced increased aggressiveness and decreased sociality, and these ameliorative effects were counteracted by coadministration of 5-HT(1A) receptor antagonist WAY-100635, or disappeared by eliminating UH from YKS. These results suggest that the effect of YKS is mainly attributed to UH, and the active ingredient is contained in UH. To find the candidate ingredients, we examined competitive binding assay and [(35)S] guanosine 5'-O-(3-thiotriphosphate) (GTPγS) binding assay of seven major alkaloids in UH using Chinese hamster ovary cells expressing 5-HT(1A) receptors artificially. Only geissoschizine methyl ether (GM) among seven alkaloids potently bound to 5-HT(1A) receptors and acted as a partial agonist. This in vitro result on GM was further demonstrated in the socially isolated mice. As did YKS and UH, GM ameliorated the isolation-induced increased aggressiveness and decreased sociality, and the effect was counteracted by coadministration of WAY-100635. These lines of results suggest that GM in UH is potent 5-HT(1A) receptor agonist and a candidate for pharmacological effect of YKS on aggressiveness and sociality in socially isolated mice.

Evaluation of bilateral cingulotomy and anterior capsulotomy for the treatment of aggressive behavior.

BACKGROUND: Agressiveness is a psychiatric symptom that may be part of schizophrenia, mental retardation, drug abuse and other conditions. Surgical treatment remains controversial and few therapeutic options are available. We undertook this study to perform a prospective analysis on the efficacy and safety of bilateral cingulotomy and anterior capsulotomy in the treatment of aggressiveness behavior. METHODS: We studied 25 patients with a primary diagnosis of aggressiveness refractory to conventional treatment. Subjects were clinically evaluated with the Mayo-Portland adaptability inventory and the Global Assessment of Functioning score. Lesions were placed stereotactically in both targets and confirmed by postoperative magnetic resonance imaging. Significant changes were evaluated with Wilcoxon test after 3 and 6 months. RESULTS: According to inclusion and exclusion criteria, only 12 patients were finally included and surgical treated. Lesions significantly decreased using the Mayo-Portland adaptability inventory and the Global Assessment of Functioning score (p <0.002) at 3 and 6 months follow-up. Only five patients showed either mild or transitory postsurgical complications. CONCLUSIONS: Combined bilateral anterior capsulotomy and cingulotomy successfully reduced aggressiveness behavior and improved clinical evaluations. These effects were obtained with fewer complications than previously described targets.

Of brain and bone: the unusual case of Dr. A.

Frontotemporal dementia (FTD) is a clinical syndrome characterized by progressive decline in social conduct and a focal pattern of frontal and temporal lobe damage. Its biological basis is still poorly understood but the focality of the brain degeneration provides a powerful model to study the cognitive and anatomical basis of social cognition. Here, we present Dr. A, a patient with a rare hereditary bone disease (hereditary multiple exostoses) and FTD (pathologically characterized as Pick's disease), who presented with a profound behavioral disturbance characterized by acquired sociopathy. We conducted a detailed genetic, pathological, neuroimaging and cognitive study, including a battery of tests designed to investigate Dr. A's abilities to understand emotional cues and to infer mental states and intentions to others (theory of mind). Dr. A's genetic profile suggests the possibility that a mutation causing hereditary multiple exostoses, Ext2, may play a role in the pattern of neurodegeneration in frontotemporal dementia since knockout mice deficient in the Ext gene family member, Ext1, show severe CNS defects including loss of olfactory bulbs and abnormally small cerebral cortex. Dr. A showed significant impairment in emotion comprehension, second order theory of mind, attribution of intentions, and empathy despite preserved general cognitive abilities. Voxel-based morphometry on structural MRI images showed significant atrophy in the medial and right orbital frontal and anterior temporal regions with sparing of dorsolateral frontal cortex. This case demonstrates that social and emotional dysfunction in FTD can be dissociated from preserved performance on classic executive functioning tasks. The specific pattern of anatomical damage shown by VBM emphasizes the importance of the network including the superior medial frontal gyrus as well as temporal polar areas, in regulation of social cognition and theory of mind. This case provides new evidence regarding the neural basis of social cognition and suggests a possible genetic link between bone disease and FTD.

Early onset problem behavior, young adult psychopathology, and contextual risk.

A prospective study of 692 male twins was undertaken to investigate the relationships among early adolescent problem behavior, contextual risk, and disinhibitory psychopathology. Early adolescent problem behavior was assessed by the number of the following behaviors engaged in by the time of the age-14 assessment: (1) tobacco use, (2) alcohol use, (3) marijuana use, (4) other illicit drug use, (5) sexual intercourse, and (6) police contact. Contextual risk was assessed as a composite of measures of peer models, parent-offspring conflict, and academic engagement from the age-14 assessment. Disinhibitory psychopathology was assessed by symptoms of nicotine dependence, alcohol dependence, drug dependence, and adult antisocial behavior at the age-18 assessment. Early adolescent problem behavior and contextual risk were strongly correlated (r = .53) and both were strongly and independently associated with symptoms of disinhibitory psychopathology (r from .35 to .60). The association of early adolescent problem behavior with both contextual risk and disinhibitory psychopathology was mediated entirely by genetic factors while the association between contextual risk and disinhibitory psychopathology was mediated by both genetic and nonshared environmental factors. The results are discussed in the context of emerging research on the prognostic significance of early adolescent problem behavior for risk of adult psychopathology.

Prenatal drug exposure effects on subsequent vulnerability to drug abuse.

Research has shown that both prenatal alcohol and tobacco exposure are associated with increased risk of significant adverse medical, developmental, and behavioral outcomes including substance abuse. Research on the outcomes of prenatal exposure to illicit drugs (PNDE) has also found increased physical and behavioral problems for gestationally drug-exposed children. However, a clear picture has not emerged on whether the consequences of PNDE are independent from those associated with having a substance abusing parent and whether PNDE increases vulnerability to drug abuse. Because of its typical co-occurrence with factors inherent in having a drug-abusing parent, PNDE is at least a marker of significant increased risk for a range of negative outcomes including greater vulnerability to substance abuse. Although a review of the relevant research literatures indicates that the direct consequences of PNDE appear to be generally both subtle and nonglobal, PNDE does appear to have negative developmental and behavioral outcomes, and there is evidence that it is a modest direct contributor to increased substance abuse vulnerability.

Cognitive and behavioural effects of chronic stimulation of the subthalamic nucleus in patients with Parkinson's disease.

OBJECTIVE: To investigate cognitive and behavioural effects of bilateral lead implants for high frequency stimulation (HFS) of the subthalamic nucleus in patients with Parkinson's disease; and to discriminate between HFS and the effects of surgical intervention on cognitive function by carrying out postoperative cognitive assessments with the stimulators turned on or off. METHODS: Motor, cognitive, behavioural, and functional assessments were undertaken in 20 patients with Parkinson's disease before implantation and then at three, six, and 12 months afterwards. Nine patients were also examined 18 months after surgery. Postoperative cognitive assessments were carried out with stimulators turned off at three and 18 months, and turned on at six and 12 months. RESULTS: Cognitive assessment showed a significant postoperative decline in performance on tasks of letter verbal fluency (across all postoperative assessments, but more pronounced at three months) and episodic verbal memory (only at three months, with stimulators off). At three, six, and 12 months after surgery, there was a significant improvement in the mini-mental state examination and in a task of executive function (modified Wisconsin card sorting test). On all postoperative assessments, there was an improvement in parkinsonian motor symptoms, quality of life, and activities of daily living while off antiparkinsonian drugs. A significant postoperative decrease in depressive and anxiety symptoms was observed across all assessments. Similar results were seen in the subgroup of nine patients with an 18 month follow up. Following implantation, three patients developed transient manic symptoms and one showed persistent psychic akinesia. CONCLUSIONS: Bilateral HFS of the subthalamic nucleus is a relatively safe procedure with respect to long term cognitive and behavioural morbidity, although individual variability in postoperative cognitive and behavioural outcome invites caution. Stimulation of the subthalamic nucleus does not per se appear to impair cognitive performance in patients with Parkinson's disease and may alleviate the postoperative decline in verbal fluency.

The role of 5-HT1A receptors in mediating the anxiogenic effects of nicotine following lateral septal administration.

The purpose of the present study was to determine the role of the 5-HT1A receptors in the lateral septum in the mediation of the anxiogenic effects of nicotine in the social interaction and elevated plus maze tests of anxiety in the rat. Bilateral infusion of (-)-nicotine (4 and 8 microg) and of the 5-HT1A receptor agonist 8-OH-DPAT (200 and 500 ng) into the lateral septum decreased the time spent in social interaction, indicating anxiogenic effects. The anxiogenic effect of 8-OH-DPAT (500 ng) was completely reversed by coadministration of a behaviourally inactive dose of the 5-HT1A receptor antagonist, WAY 100635 (200 ng). The anxiogenic effect of the lower dose of (-)-nicotine (4 microg) was completely reversed by WAY 100635 (200 ng), but the reversal was only partial following administration of 8 microg nicotine. In a second test of anxiety, the elevated plus maze, lateral septal administration of 8-OH-DPAT (500 ng) and nicotine (4 microg) induced anxiogenic effects. In this test, the anxiogenic effect of nicotine (4 microg) was completely reversed by coadministration of WAY 100635 (200 ng). The effects of 8-OH-DPAT demonstrate that stimulation of 5-HT1A receptors in the lateral septum has anxiogenic effects in two animal tests and that the anxiogenic effects of nicotine are mediated at least in part by these 5-HT1A receptors.

Neurologic evaluation of violent juveniles.

Any juvenile who has acted violently requires a systematic, meticulous neurologic evaluation. There is no substitute for an adequate medical, family, and social history, the latter focusing on abuse and neglect. Evaluation should include a full physical and a conventional neurologic examination. Additionally, the physical, neurologic examination must include tests of cerebral-cortical function. The history and physical examination usually will indicate the diagnosis. A neuropsychologic evaluation of higher cerebral functions, including tests of frontal functions, should also be done in most cases. Some specific causes of brain disease can be identified by appropriate blood and urine tests, waking and sleep EEGs, and neuroimaging investigations. In general, positive findings are more significant than negative findings. If the physical examination and psychological tests are negative and the MR imaging shows a brain tumor, the patient has a brain tumor. If the neurologic or neuropsychological examinations demonstrate brain dysfunction, the patient has brain dysfunction, even if MR imaging is normal.

Leukotomy revisited: late cognitive and behavioral effects in chronic institutionalized schizophrenics.

BACKGROUND: In the 1940s and 1950s, prefrontal lobotomy was widely used to treat aggressive, disruptive and psychotic behavior in schizophrenics. Subsequent observations have confirmed its ineffectiveness in schizophrenia. Few studies have addressed its long-term consequences. METHODS: We conducted tests of frontal function, behavior (Frontal Behavioral Inventory), psychopathology (PANSS), neurological examinations and CT scans in 19 chronically institutionalized schizophrenic patients (mean age 74) who had undergone orbitofrontal leukotomy between 1948 and 1972 and 11 controls (mean age 74) matched for age, length of hospitalization, education, and diagnosis. RESULTS: There were no significant differences between leukotomized patients and controls on: Folstein Mini-Mental score (leuko 22.13+/-5.66; controls 23.55+/-5.93), utilization behavior, Luria alternating written and motor sequences, verbal fluency, imitation behavior, motor impersistence, primitive reflexes, or psychopathology. Significant differences were found on clock drawing and on the go/no-go test, which may reflect the presence of an orbitofrontal lesion in the leukotomized group. There was a tendency for the leukotomized group to have fewer indices of frontal behavioral dysfunction. Both groups showed comparable impairment on the Stroop test and cognitive rigidity on the Odd Man Out test of category shifting. CONCLUSIONS: With few exceptions, elderly leukotomized and nonleukotomized schizophrenic patients show varying degrees of distractibility, difficulty in set shifting, poor planning and organization, susceptibility to interference, primitive reflexes and signs of global cognitive impairment. Allowing for the small sample size, variability in the surgical frontal lesion, and the long interval from surgery to testing, these observations likely reflect the long-term consequences of severe schizophrenia in both groups.

Neurobiological factors in aggressive behavior.

OBJECTIVE: The author's aim was to review literature in the neurosciences and psychiatric clinical research reports about biological factors in aggression and the pathophysiological mechanisms that accompany aggression in neuropsychiatric syndromes. METHOD: Studies were located through computer searches of relevant experimental reports and review articles mainly from the last 25 years. RESULTS: Several studies using neuroimaging and neurophysiological and neuropathological research techniques have identified lesions in the limbic structures, temporal lobes, and frontal lobes of the brain in abnormally aggressive individuals. Several reports have associated deficiency or dysregulation of serotonin with homicidal, suicidal, and impulsive behavior. However, few studies have focused on polypeptides or second messenger systems, although abnormalities in these systems have been reported in patients with neuropsychiatric syndromes who have shown aggressive behavior. Even fewer studies focus on the correlation of brain structures and metabolic markers. CONCLUSIONS: The understanding of aggressive behavior in psychiatric patients is fragmented. Some explanations are speculative and extrapolated to clinical psychiatric syndromes from experimental data on the neurophysiology of cats, rats, and other mammals. Identification of biochemical markers that can be used in predicting patients' response to pharmacological interventions may be the next step in developing more rational treatment of violent patients.