The cerebellar role in Executive Functions:new insights from behavioral and structural neuroimaging data

“Executive functions” (EFs) are a set of cognitive processes that allow to select and monitor behaviours to achieve specific goals. Although it has been proposed that the cerebellum is involved in EFs by means of specific anatomical connections with the lateral prefrontal cortex, its specific role in these processes needs to be clarified. Aim of the present study was to investigate the EFs in subject with cerebellar pathology to characterize their profile of executive impairment. Twenty-three patients with cerebellar atrophy (CA), 18 patients with focal cerebellar damage (FCD), and 43 matched healthy controls (CT) were enrolled in the study and underwent an extensive evaluation of the EFs. A one-way Anova and Tukey’s post hoc test were performed. Moreover a principal components analysis with 3 factors (Planning, Set shifting and Cognitive Inhibition) was executed to identify possible shared process among impaired EFs tasks. Finally, in order to investigate the link between executive impairment and the pattern of cerebellar structural alterations, T1 weighted scans were also collected for voxel-based morphometry analysis and cerebellar lesion characterization. The neuropsychological assessment evidenced that CA was significantly impaired in planning tasks while FCD was significantly impaired in set shifting tasks. By using the neuroimaging analysis, the damaged cerebellar regions have been identified in CA and FCD. The structural alteration patterns have been related to the executive impairment patterns. The hypothesis that, in presence of a cerebellar pathology, different profiles of EFs alteration depend on cerebellar damage localization will be discussed

O cerebelo e os transtornos psiquiátricos

OBJECTIVE: The objective of this update article is to report structural and functional neuroimaging studies exploring the potential role of cerebellum in the pathophysiology of psychiatric disorders. METHOD: A non-systematic literature review was conducted by means of Medline using the following terms as a parameter: cerebellum, cerebellar vermis, schizophrenia, bipolar disorder, depression, anxiety disorders, dementia and attention deficit hyperactivity disorder. The electronic search was done up to April 2008. DISCUSSION: Structural and functional cerebellar abnormalities have been reported in many psychiatric disorders, namely schizophrenia, bipolar disorder, major depressive disorder, anxiety disorders, dementia and attention deficit hyperactivity disorder. Structural magnetic resonance imaging studies have reported smaller total cerebellar and vermal volumes in schizophrenia, mood disorders and attention deficit hyperactivity disorder. Functional magnetic resonance imaging studies using cognitive paradigms have shown alterations in cerebellar activity in schizophrenia, anxiety disorders and attention deficit hyperactivity disorder. In dementia, the cerebellum is affected in later stages of the disease. CONCLUSION: Contrasting with early theories, cerebellum appears to play a major role in different brain functions other than balance and motor control, including emotional regulation and cognition. Future studies are clearly needed to further elucidate the role of cerebellum in both normal and pathological behavior, mood regulation, and cognitive functioning.OBJETIVO: Este artigo de atualização tem como objetivo avaliar estudos em neuroimagem estrutural e funcional a fim de explorar o papel do cerebelo na patofisiologia dos transtornos psiquiátricos. MÉTODO: Uma revisão não sistemática foi realizada através do Medline utilizando-se como parâmetro os seguintes termos: cerebellum, cerebellar vermis, schizophrenia, bipolar disorder, depression, anxiety disorders, dementia e attention deficit hyperactivity disorder. A busca eletrônica foi feita até abril de 2008. DISCUSSÃO: Anormalidades cerebelares estruturais e funcionais têm sido relatadas em muitos transtornos psiquiátricos, entre eles a esquizofrenia, transtorno bipolar, transtorno depressivo, transtornos ansiosos, demências e transtorno de déficit de atenção e hiperatividade. Estudos utilizando imagem por ressonância magnética estrutural relataram a diminuição do volume total do cerebelo e do vermis cerebelar na esquizofrenia, transtornos do humor e transtorno de falta de atenção com hiperatividade. Estudos utilizando ressonância magnética funcional e paradigmas cognitivos têm demonstrado alterações na atividade cerebelar na esquizofrenia, transtornos ansiosos e transtorno de falta de atenção com hiperatividade. Nas demências, o cerebelo é afetado nos estágios mais avançados dessas doenças. CONCLUSÃO: Contrastando com as primeiras teorias, o cerebelo parece apresentar um papel mais importante em diferentes funções cerebrais além do controle motor e do equilíbrio, incluindo a regulação emocional e cognição. Futuros estudos são necessários para melhor elucidar o papel do cerebelo em ambos os comportamentos, normal e patológico, na regulação do humor e nas funções cognitivas.Universidade Federal de São Paulo (UNIFESP) Departamento de Psiquiatria Laboratório Interdisciplinar de Neurociências ClínicasIrmandade da Santa Casa de São Paulo Centro de Atenção Integrada à Saúde MentalUniversidade Federal do TocantinsInstituto Sinapse de Neurociências ClínicasCentro de Pesquisa e Ensaios Clínicos Sinapse-BairralUNIFESP, Depto. de Psiquiatria Laboratório Interdisciplinar de Neurociências ClínicasSciEL

Characterisation of genetic risk factors for mental illness in rodent models, impact of Map2k7+/- and Fxyd6-/- mice on neural systems and working memory

Even in wealthy and seemingly prosperous countries like the United Kingdom, the spectre of mental illness and psychiatric disorders remains highly prevalent. These disorders present a huge economic burden to societies, where in the UK alone, mental disorders cost the economy an estimated €134 billion a year; along with the unmeasurable societal and human costs. This has led to an intense debate over the past few decades just as to what factors contribute to these illnesses. It is now understood that a number of biological and non-biological factors contribute. These include socio-economic pressures, early-life trauma, gestational and peri-natal infections; genetic and familial factors, and molecular and cellular factors. However, while the definitions and diagnostic criteria of mental disorders remain based in the subjective realms of the DSM and ICD, treatment and understanding of psychiatric illness has had little chance to progress over the last fifty years. As a result, neuroscientists are starting to direct psychiatric disorder research from the bottom-up; where genetic, cognitive and neuroconnectivity factors are being investigated to serve as a future basis for diagnosis and treatment. One of the most complex and debilitating psychiatric disorders, schizophrenia, exhibits a complex array of genetic, cognitive and neuroconnectivity abnormalities. Current challenges in schizophrenia research is to understand how identified genetic abnormalities contribute to neuroconnectivity and cognitive impairments which are prominent in schizophrenia. Recently, genetic association studies have implicated two genes as risk factors for schizophrenia - FXYD6 and MAP2K7. Currently it is unclear exactly how these genes contribute to schizophrenia pathology, particularly cognitive symptoms and neural circuitry.;This thesis investigates these two genes by utilising two mouse models, first a heterozygous mouse line of Map2k7+/- and second, a gene knock-out line of Fxyd6-/-. MAP2K7 is a gene that expresses a kinase that is involved in the c-Jun N-terminal kinase (JNK) pathway, which is implicated in neuronal activity, receptor function, and cortical and hippocampal plasticity. Recent studies have found a decreased expression of MA2PK7 in the PFC, ACC and hippocampal regions in schizophrenia patients; regions associated with memory and decision making. A component of the cognitive profile of MAP2K7 was therefore investigated using Map2k7+/- mouse lines in a working memory paradigm in the radial arm maze. This test is known as the n-back test or the retention interval test. For the first time this investigation reveals that Map2k7+/- mice exhibit a subtle yet significant spatial working memory deficit compared to WT mice; as judged by their average performance over the whole experiment. WT mice exhibited an overall average performance of 70% and MAP2K7+/- mice 66% (p<0.001). This indicates that MAP2K7 may play a subtle role in working memory function in rodents, and may represent a component of the aberrations in the genetic architecture that gives rise to working memory impairments in psychiatric disorders, particularly schizophrenia. This experiment also backs up previous evidence for this radial arm maze paradigm as a robust behavioural test for testing rodent working memory.;FXYD6 belongs to a group of proteins that are known to be involved in modulating NaKATPase activity. Previously, NaKATPase has been associated with bipolar disorder and depression, but has now also been implicated in schizophrenia. Previous studies have found that FXYD6 is also abnormally expressed in the PFC of schizophrenia patients, and therefore may contribute to the cognate symptoms of the disorder. This experiment, therefore, investigated how Fxyd6 contributes to local brain activation, particularly in neural systems relevant to cognition, using gene knockout Fxyd6-/- mouse models and semi quantitative 2DG autoradiographic imaging. Three regions showed a significant deviation in activity in Fxyd6-/- mice compared to WT mice. The subiculum, medial septum and lateral septum all exhibited significant reductions in activity in Fxyd6-/- mice compared to WT mice. Notably the subiculum is heavily implicated with memory functions, particularly working memory and disambiguation of previously learned memory. Indicating a possible role for FXYD6 and NaKATPase in working memory processing and memory disambiguation in the subiculum. Finally, the role of glutamate in relation to FXYD6 function and brain activity was assessed by administering the NMDA receptor antagonist ketamine and analysing regional brain activity using semi quantitative 2DG autoradiographic imaging. Generally, regions which were affected by ketamine in WT mice including PFC, thalamic and septal regions, were not affected in Fxyd6-/- mice. It is hypothesized that this may be down to a compensatory effect that knocking-out Fxyd6 may have on glutamate reuptake. Because NaKATPase is involved in glutamate reuptake into glia and neurons, the blockage of NMDA receptors may have less effect due to a reduction in glutamate reuptake, and therefore higher than normal postsynaptic glutamate concentrations. In conclusion, this investigation highlights two genes which may have roles in working memory functioning and neural circuitry that contribute to cognitive processes. While the evidence from this investigation does not explicitly associate these genes with symptoms of schizophrenia and other psychiatric disorders; the evidence does provide indication that they are involved in cognitive processes in rodents, and possibly humans. This investigation provides an interesting path of investigation for the potential roles of these genes regardless of their relationship to psychiatric disorders and will inform future research into the genetic architecture of neural circuits and cognition.Even in wealthy and seemingly prosperous countries like the United Kingdom, the spectre of mental illness and psychiatric disorders remains highly prevalent. These disorders present a huge economic burden to societies, where in the UK alone, mental disorders cost the economy an estimated €134 billion a year; along with the unmeasurable societal and human costs. This has led to an intense debate over the past few decades just as to what factors contribute to these illnesses. It is now understood that a number of biological and non-biological factors contribute. These include socio-economic pressures, early-life trauma, gestational and peri-natal infections; genetic and familial factors, and molecular and cellular factors. However, while the definitions and diagnostic criteria of mental disorders remain based in the subjective realms of the DSM and ICD, treatment and understanding of psychiatric illness has had little chance to progress over the last fifty years. As a result, neuroscientists are starting to direct psychiatric disorder research from the bottom-up; where genetic, cognitive and neuroconnectivity factors are being investigated to serve as a future basis for diagnosis and treatment. One of the most complex and debilitating psychiatric disorders, schizophrenia, exhibits a complex array of genetic, cognitive and neuroconnectivity abnormalities. Current challenges in schizophrenia research is to understand how identified genetic abnormalities contribute to neuroconnectivity and cognitive impairments which are prominent in schizophrenia. Recently, genetic association studies have implicated two genes as risk factors for schizophrenia - FXYD6 and MAP2K7. Currently it is unclear exactly how these genes contribute to schizophrenia pathology, particularly cognitive symptoms and neural circuitry.;This thesis investigates these two genes by utilising two mouse models, first a heterozygous mouse line of Map2k7+/- and second, a gene knock-out line of Fxyd6-/-. MAP2K7 is a gene that expresses a kinase that is involved in the c-Jun N-terminal kinase (JNK) pathway, which is implicated in neuronal activity, receptor function, and cortical and hippocampal plasticity. Recent studies have found a decreased expression of MA2PK7 in the PFC, ACC and hippocampal regions in schizophrenia patients; regions associated with memory and decision making. A component of the cognitive profile of MAP2K7 was therefore investigated using Map2k7+/- mouse lines in a working memory paradigm in the radial arm maze. This test is known as the n-back test or the retention interval test. For the first time this investigation reveals that Map2k7+/- mice exhibit a subtle yet significant spatial working memory deficit compared to WT mice; as judged by their average performance over the whole experiment. WT mice exhibited an overall average performance of 70% and MAP2K7+/- mice 66% (p<0.001). This indicates that MAP2K7 may play a subtle role in working memory function in rodents, and may represent a component of the aberrations in the genetic architecture that gives rise to working memory impairments in psychiatric disorders, particularly schizophrenia. This experiment also backs up previous evidence for this radial arm maze paradigm as a robust behavioural test for testing rodent working memory.;FXYD6 belongs to a group of proteins that are known to be involved in modulating NaKATPase activity. Previously, NaKATPase has been associated with bipolar disorder and depression, but has now also been implicated in schizophrenia. Previous studies have found that FXYD6 is also abnormally expressed in the PFC of schizophrenia patients, and therefore may contribute to the cognate symptoms of the disorder. This experiment, therefore, investigated how Fxyd6 contributes to local brain activation, particularly in neural systems relevant to cognition, using gene knockout Fxyd6-/- mouse models and semi quantitative 2DG autoradiographic imaging. Three regions showed a significant deviation in activity in Fxyd6-/- mice compared to WT mice. The subiculum, medial septum and lateral septum all exhibited significant reductions in activity in Fxyd6-/- mice compared to WT mice. Notably the subiculum is heavily implicated with memory functions, particularly working memory and disambiguation of previously learned memory. Indicating a possible role for FXYD6 and NaKATPase in working memory processing and memory disambiguation in the subiculum. Finally, the role of glutamate in relation to FXYD6 function and brain activity was assessed by administering the NMDA receptor antagonist ketamine and analysing regional brain activity using semi quantitative 2DG autoradiographic imaging. Generally, regions which were affected by ketamine in WT mice including PFC, thalamic and septal regions, were not affected in Fxyd6-/- mice. It is hypothesized that this may be down to a compensatory effect that knocking-out Fxyd6 may have on glutamate reuptake. Because NaKATPase is involved in glutamate reuptake into glia and neurons, the blockage of NMDA receptors may have less effect due to a reduction in glutamate reuptake, and therefore higher than normal postsynaptic glutamate concentrations. In conclusion, this investigation highlights two genes which may have roles in working memory functioning and neural circuitry that contribute to cognitive processes. While the evidence from this investigation does not explicitly associate these genes with symptoms of schizophrenia and other psychiatric disorders; the evidence does provide indication that they are involved in cognitive processes in rodents, and possibly humans. This investigation provides an interesting path of investigation for the potential roles of these genes regardless of their relationship to psychiatric disorders and will inform future research into the genetic architecture of neural circuits and cognition

The contribution of executive dysfunction to memory impairment and confabulation in schizophrenia

Study 1. Using a cognitive-process approach, 25 schizophrenic patients were matched with 25 healthy volunteers and compared on tests of memory and executive function. The schizophrenia group was found to have a significant impairment in immediate memory with relatively spared long-delay and recognition memory. Memory deficits were irrespective of the encoding strategies used and were unrelated to chronicity. In addition, the schizophrenic patients performed worse than controls on tests of executive function which was supported by some significant correlations between aspects of memory and executive function. The pattern of performance resembled that found in patients with subcortical or frontal lesions. Study 2. To examine further executive aspects of memory, an attempt to demonstrate confabulation in schizophrenia was made. Twelve schizophrenic patients were matched with 12 volunteers, 8 of whom were normal healthy subjects, with the remained being depressed patients. The subjects were asked to recall a set of experimental narratives, with confabulation being defined as the recall of ideas not present in the narrative. Subjects were also examined on a number of neuropsychological tests and the patients were assessed on the Krawiecka scale. Variable amounts of confabulation were observed in all the schizophrenic patients while only one control subject confabulated. The form of confabulation differed from those observed in other patients in that the original ideas were spontaneously rearranged to produce new ones. Confabulation was found to be related to difficulties in suppressing inappropriate responses and formal thought disorder. Study 3. Three schizophrenic patients previously identified as confabulators, were intensively studied to establish the mechanisms of narrative confabulation in schizophrenia. Patients were administered experimental tasks as well as standard neuropsychological tests of memory and executive function. Assessment of current symptoms was made using the SANS and SAPS scales. The severity of cognitive impairment was found to reflect the severity of confabulation, but memory impairment was neither nor sufficient to account for confabulation. Within the spectrum of executive deficits, impairments in response suppression and response monitoring, but not planning or generation were consistently associated with confabulation. The findings from the experimental tasks suggest that faults occur at both input and output. At the input stage, narrative material is encoded in a disorganised manner while at the output stage, this disorganisation is compounded by faulty editing processes. Study 4. Four schizophrenic patients who were known confabulators with narrative material, were subjected to an experimental autobiographical questionnaire designed to establish whether schizophrenic patients confabulate in response to questions calling on the recollection of personal facts and events. In addition, a number of neuropsychological tests were administered and current symptoms was assessed with the SANS and SAPS scales. All patients were observed to confabulate to varying degrees, particularly in response to questions relating to personal episodes rather than facts. For two patients, personal delusional systems were found to play a role in confabulation by providing a framework on which to base certain confabulatory recollections. Memory impairment was not found to be a necessary component to autobiographical confabulation but deficits in response suppression and response monitoring were observed to be related to the verification process performed during this task. Study 5. In an attempt to establish which anatomical regions may be at fault in schizophrenia when patients are engaged in response suppression tasks, six normal subjects were studied using positron emission tomography (PET) to identify anatomical regions involved when performing the Hayling Test. Subjects were also required to perform a control condition in which they had to read out the last word of given sentences. Compared to the control task, response initiation was associated with left sided activation of the frontal operculum, inferior frontal gyrus, middle temporal gyrus and right anterior cingulate gyrus, whereas response suppression was associated with left frontal operculum, inferior frontal gyrus and right anterior cingulate gyrus activation only. The difference between the two parts of the Hayling Test was in the increased activation of the left middle temporal gyrus and the left inferior frontal region (Brodmann's area 44/6) during response initiation

Neuropsychological assessment and functional magnetic resonance imaging of verbal declarative memory performance in relatives of schizophrenia patients and controls

BACKGROUND: While the aetiology of schizophrenia has yet to be established, genetic liability is currently the most robust determinant of propensity for the development of schizophrenia, with a risk rate of between 15 and 20% in first-degree relatives of schizophrenia patients. Unaffected relatives of schizophrenics have shown similar, but less severe neuropsychological impairments, to those seen in schizophrenia patients, which are stable over time in individuals beyond the age of risk for the disorder. Such deficits may be reflective of a genetic vulnerability to the disorder (Byrne et al 2003; (Faraone et al 1999). Declarative memory has emerged as a core cognitive impairment in schizophrenia (Cirillo and Seidman 2002) and evidence shows functional brain response differences between patients and controls in frontal, temporal, and parietal areas during tests of memory (Ragland et al 2004). Nonetheless, it is unclear how far behavioural and functional deficits reflect increased risk, at what stage, if at all, these deteriorate in those who develop the disorder, or whether pre-morbid impairments in those who go on to develop schizophrenia could be predictive of psychosis. The Edinburgh High Risk Study recruited 162 individuals (16-25 years) with at least one first or second degree relative with schizophrenia and 43 closely matched controls. A broad neuropsychological and clinical assessment battery was administered every 18-24 months over 10 years, while participants underwent between 1 and 3 functional magnetic resonance imaging (fMRI) scans during a verbal memory and executive function task over 5 years. | | METHODS: Baseline predictors of schizophrenia, performance changes over 2 neuropsychological assessments, and the influence of genetic liability were examined in high risk participants with (HR+) and without psychotic symptoms (HR-), those who are now ill (Scz) and controls (C), using one-way ANOVAs and repeated measures ANCOVAs. Aspects of verbal and non-verbal learning and memory were also compared between the HR and C in the first 100 participants to undergo a functional MRI scan using one-way ANOVAs. In the same participants, differences between groups in blood oxygen level dependent (BOLD) fMRI brain responses during an event related verbal encoding (word classification) and retrieval task were investigated using fixed and random effects general linear models. | | RESULTS: On a test of verbal learning at baseline, Scz performed significantly less well than HR However, there were no significant interactions of time by group, and HR showed stable impairments relative to controls on immediate and delayed prose recall, delayed list recall and response suppression across both assessments before and after controlling for IQ. A measure of quantitative genetic liability was inversely correlated with delayed prose recall over time. HR showed poorer cued delayed recall, and less word retention between short and long delay recall trials on a verbal learning test. A visual recognition test also significantly discriminated between HR and C. Behavioural analysis of the fMRI verbal encoding and retrieval task revealed no differences between groups in reaction time or accuracy. However, during a word classification task (encoding) there was a greater BOLD response in the right inferior frontal lobe (BA45/44) in HR relative to C and in the right inferior parietal lobule (BA7/40) in HR+ relative to C and HR-. A greater bilateral cerebellar and left inferior frontal response was also apparent in HR relative to C, and an increased ventral anterior thalamus response in HR- relative to HR+, during correct recognition compared to correct rejection responses. | | CONCLUSIONS: Stable differences in NP performance over time suggest a trait deficit, which is relatively unaffected by the presence of psychotic symptoms and schizophrenia onset, although small numbers might have precluded detection of significant time by group interactions. Poorer verbal memory performance overall in Scz suggests that this deficit is more pronounced in those who go on to develop schizophrenia. Non-verbal learning impairments reflect encoding deficits, while verbal learning impairments reflect encoding and retention difficulties in the HR group. Increased BOLD response in frontal and cerebellar areas in the HR group could be due to a requirement for greater effort to perform the task equivalently to C, and may reflect a biological trait deficit in the brains of relatives of schizophrenia patients. Subtle differences in the inferior parietal lobe between HR+ and HR- and C may be indicative of state related functional abnormalities, which possibly herald the onset of schizophrenia

Imaging genetic risk and episodic memory in psychosis

A key feature of many psychiatric disorders, including schizophrenia and bipolar disorder, are pervasive deficits in several domains of cognition. Episodic memory is one of the most consistently observed cognitive deficits exhibited by patients with schizophrenia, and can be a predictor of overall functional outcome. Several neuroimaging studies have assessed episodic memory in psychosis, however the neural mechanisms underlying this deficit remain somewhat unclear. Studying the impact of rare genetic variants of large effect can offer a powerful method to further our understanding of the pathophysiology of psychiatric disorders. One such gene, DISC1 (Disrupted in Schizophrenia 1) is a putative susceptibility gene for a spectrum of major psychiatric disorders such as schizophrenia, bipolar disorder and major depression. DISC1 was originally identified in a large Scottish pedigree, in which it is disrupted by a balanced translocation between chromosomes 1 and 11, and this translocation confers a dramatically increased risk of major psychiatric disorder. However, the impact of this translocation on brain imaging measures is largely unknown. The rarity of this variation results in small group numbers for analysis, however rare variants are likely to have large neural effects. This thesis offers a unique investigation into the effects of the t(1;11) translocation, by examining fMRI of members of the original Scottish pedigree. Four groups of participants; 19 family members (8 with the translocation, 11 without), 30 patients with schizophrenia, 11 patients with bipolar disorder and 40 healthy controls underwent a functional MRI episodic memory encoding and recognition paradigm. Data processing and statistical analyses were performed using the standard approach in SPM8. The primary aim of this work was to investigate functional activation during episodic memory in individuals with and without the translocation, to examine the impact of the t(1;11) translocation. Analyses were also performed to examine differences between controls and patients with schizophrenia and bipolar disorder, to compare the effects of the translocation to the effects of a having a psychotic illness. During encoding of neutral scenes, translocation carriers showed greater activation of the left posterior cingulate, right fusiform gyrus and right superior frontal gyrus compared to non-carriers. During recognition, carriers showed greater activation in the right fusiform gyrus, left posterior cerebellum, right superior temporal gyrus, left anterior cingulate, right ventrolateral prefrontal cortex (VLPFC) and right dorsolateral prefrontal cortex (DLPFC). For both contrasts, no regions were found to be more active in family members without the translocation when compared to carriers. There were no significant differences between the groups in terms of their performance or reaction time on encoding and recognition conditions. Compared to healthy controls, patients with schizophrenia demonstrated increased activation during encoding in the inferior parietal lobe bilaterally, and decreased activation during recognition in a region encompassing the caudate nucleus and anterior cingulate cortex. Patients with bipolar disorder showed no difference in activation compared to controls during encoding, and increased activation during recognition in a region encompassing the caudate and anterior cingulate, extending to the inferior frontal lobe and insula. There was also a significant difference between patients with schizophrenia and bipolar disorder during recognition, with patients with bipolar disorder again showing increased activation in the caudate extending to the anterior cingulate cortex. These findings support previous research suggesting overactivation of fronto-limbic and striatal structures including the anterior cingulate and caudate in bipolar disorder, with a relative underactivation in schizophrenia. This thesis presents the first evidence of functional alterations during episodic memory in association with the translocation, primarily in fronto-temporal regions. Brain regions that were over activated in translocation carriers have been shown to be involved in memory encoding and recognition, and are known to be affected in patients with major psychiatric disorders and unaffected relatives. Family members with the translocation demonstrated a more similar pattern of activation during recognition to patients with bipolar disorder compared to schizophrenia, perhaps due to the fact that most diagnoses in the carriers were of an affective disorder rather than a schizophrenia-related psychosis. Based on these findings it can be argued that the translocation has an influence on brain activations in areas associated with episodic memory processes. These findings begin to provide a better understanding of the neural effects of the t(1;11) translocation, and highlight the significance of rare but biologically informative genetic variants in understanding psychosis

Functional neuroimaging in subjects at high genetic risk of schizophrenia

Schizophrenia is an incapacitating psychiatric disorder characterized by hallucinations and delusions with a lifetime risk of around 1% worldwide. It is a highly heritable disorder which generally becomes manifest in early adult life. The established condition has been associated with structural and functional brain abnormalities, principally in prefrontal and temporal lobes, but it is unclear whether such abnormalities are related to inherited vulnerability, medication effects, or the presence of symptoms. Furthermore, the mechanisms by which the pre-morbid state switches into florid psychosis are unknown. The Edinburgh High Risk Study is designed to address these issues. The first phase (1994-1999) employed repeated clinical, neuropsychological assessments and structural imaging. In the current phase (1999-2004) functional magnetic resonance imaging (fMRI) has been added to the tests used previously.As part of the Edinburgh High Risk Study, this study used a covert verbal initiation fMRI task (the Hayling Sentence Completion Test) known to elicit frontal and temporal activation, to examine a large number of young participants at high risk of developing schizophrenia for genetic reasons, in comparison with a matched group of healthy controls. Subjects were scanned at baseline, and after approximately one year. At the time of the baseline scan none of the participants met criteria for any psychiatric disorder, however, a number of subjects reported isolated psychotic symptoms on direct questioning. Over the course of the entire study (1994-2004), 21 individuals developed schizophrenia according to standard diagnostic criteria. Four of these subjects made the transition over the course of the current study (1999-2004), i.e. subsequent to the baseline functional scanThere were three main aims of the current study (i) to use fMRI to identify the neural correlates of state and trait effects in high risk individuals, (ii) to determine ifit is possible to distinguish those who subsequently become ill from those who remain well using functional imaging, and (iii) to determine if patterns of brain activity change with the transition to illness, or vary with changes in symptomatic status of these individuals.Regarding the first aim, group differences of apparent genetic origin were found in prefrontal, thalamic, cerebellar regions, and differences in activation in those with symptoms were found in the parietal lobe. Functional connectivity analysis examining interactions between these regions also indicated similar abnormalities. These results may therefore reflect inherited deficits, and the earliest changes associated with the psychotic state, respectively. Although only a small number of subjects became ill over the course of the current study («=4), initial findings suggested abnormalities in medial prefrontal and medial temporal regions (with an indication of parietal lobe dysfunction) were able to distinguish those who later became ill versus those that remained well. Finally, there were also indications of changes in activation patterns over time in a subgroup of subjects with varying symptomatic status.To conclude, these results are consistent with previous findings in the Edinburgh High Risk Study - what is inherited by the high risk individuals is a state of heightened vulnerability manifesting, in the case of functional imaging, as abnormalities in activation and/or connectivity in preffontal-thalamiccerebellar and prefrontal-parietal regions. These finding also suggest that there are additional differences seen in those with psychotic symptoms, and to some extent in those who subsequently go on to develop the disorder. These results are not confounded by anti-psychotic medication since all subjects were anti-psychotic naive at the time of assessment. The lack of findings traditionally associated with the established illness (dorsolateral prefrontal cortex and lateral temporal lobe) indicate these may be specifically associated with the established state, or when performance differences become manifest. Overall therefore these findings reveal information regarding the pathophysiology of the state of vulnerability to the disorder and about the mechanisms involved in the development of schizophrenia or schizophrenic symptomatology

Examining Patterns of Executive Functioning Across Dimensions of Psychopathology

Executive functioning is a multifaceted collection of higher-order cognitive processes used to perform goal-oriented tasks. Although this construct is heavily researched, a major issue regarding the current literature stems from the influence of task impurity, which interferes with how executive functioning performance is interpreted. Additionally, while executive functioning has been previously explored in clinical populations, less work has evaluated this topic measuring dimensional psychopathology. The present study sought to examine the role of executive functioning, as it relates to dimensional psychopathology. Data was analyzed from a total of 731 individuals between the age of 18-59 years who took part in the Nathan Kline Institute (NKI)-Rockland project. A three-factor model of executive functioning (i.e., inhibition, shifting, and fluency) proposed by Karr et al. (2018) using scores primarily from the Delis-Kaplan Executive Function System (D-KEFS) and an original three-factor model of dimensional psychopathology (i.e., internalizing, externalizing, and thought disorder symptoms) using the Adult Self-Report (ASR) and Peter’s et al. Delusions Inventory (PDI) were constructed with confirmatory factor analyses and then compared using structural equation modeling. Results supported both three-factor models as having adequate fit for this sample and indicated that internalizing and externalizing psychopathology had positive and negative relationships with different factors of executive functioning, while thought disorders traits were not related to executive functioning. Implications for future work are discussed