Impact of long-acting injectable antipsychotics vs. oral medication on relapses of patients with psychosis and bipolar disorder.

Relapse associated with multiple hospital readmissions of patients with chronic and severe mental disorders, such as psychosis and bipolar disorder, is frequently associated with non-adherence to treatment. The primary aim of the study was to compare the effectiveness of long-acting injectable (LAI) treatment, vs. oral medication in reducing readmissions of patients with psychotic or bipolar disorder in a community sample of 164 patients with psychosis and 29 patients with bipolar disorder (n = 193), with poor adherence to oral medication. The mean follow up period was 5.6 years and the number of readmissions were compared for an equal-length period of oral treatment preceding the onset of LAI administration. We observed a significant decrease of 45.2 % in total hospital readmissions after receiving LAIs treatment. The effect was significant both for patients with a pre-LAI treatment history of predominantly voluntary hospitalizations and with predominantly involuntary admissions. In addition, we observed equal effectiveness of first- vs. second-generation LAIs in reducing total hospital readmissions regardless of type of pre-treatment admission history (voluntary vs. involuntary). LAIs appear to be effective in reducing both voluntary and involuntary hospital readmissions in patients with psychosis and bipolar disorder with a history of poor adherence to treatment.

Multisubject Task-Related fMRI Data Processing via a Two-Stage Generalized Canonical Correlation Analysis.

Functional magnetic resonance imaging (fMRI) is one of the most popular methods for studying the human brain. Task-related fMRI data processing aims to determine which brain areas are activated when a specific task is performed and is usually based on the Blood Oxygen Level Dependent (BOLD) signal. The background BOLD signal also reflects systematic fluctuations in regional brain activity which are attributed to the existence of resting-state brain networks. We propose a new fMRI data generating model which takes into consideration the existence of common task-related and resting-state components. We first estimate the common task-related temporal component, via two successive stages of generalized canonical correlation analysis and, then, we estimate the common task-related spatial component, leading to a task-related activation map. The experimental tests of our method with synthetic data reveal that we are able to obtain very accurate temporal and spatial estimates even at very low Signal to Noise Ratio (SNR), which is usually the case in fMRI data processing. The tests with real-world fMRI data show significant advantages over standard procedures based on General Linear Models (GLMs).

Preserved visuospatial abilities in absence of the right hemisphere: A case of cerebral hemiatrophy with minimal cognitive impairment.

Cerebral hemiatrophy is a rare neurological condition, usually resulting in severe and diffuse cognitive impairment. In this paper we present a 69-year old woman with notable congenital hemiatrophy with strikingly preserved cognitive functions. Cognitive assessment indicated that although her executive functions were found impaired, the remaining cognitive domains were relatively unaffected. We argue that this unexpected cognitive profile may be explained by anomalous hemispheric lateralization, driven by neuroplasticity along the developmental course.

Action Observation Responses Are Influenced by Movement Kinematics and Target Identity.

In order to inform the debate whether cortical areas related to action observation provide a pragmatic or a semantic representation of goal-directed actions, we performed 2 functional magnetic resonance imaging (fMRI) experiments in humans. The first experiment, involving observation of aimless arm movements, resulted in activation of most of the components known to support action execution and action observation. Given the absence of a target/goal in this experiment and the activation of parieto-premotor cortical areas, which were associated in the past with direction, amplitude, and velocity of movement of biological effectors, our findings suggest that during action observation we could be monitoring movement kinematics. With the second, double dissociation fMRI experiment, we revealed the components of the observation-related cortical network affected by 1) actions that have the same target/goal but different reaching and grasping kinematics and 2) actions that have very similar kinematics but different targets/goals. We found that certain areas related to action observation, including the mirror neuron ones, are informed about movement kinematics and/or target identity, hence providing a pragmatic rather than a semantic representation of goal-directed actions. Overall, our findings support a process-driven simulation-like mechanism of action understanding, in agreement with the theory of motor cognition, and question motor theories of action concept processing.

Improving the Sensitivity of Task-Related Functional Magnetic Resonance Imaging Data Using Generalized Canonical Correlation Analysis.

General Linear Modeling (GLM) is the most commonly used method for signal detection in Functional Magnetic Resonance Imaging (fMRI) experiments, despite its main limitation of not taking into consideration common spatial dependencies between voxels. Multivariate analysis methods, such as Generalized Canonical Correlation Analysis (gCCA), have been increasingly employed in fMRI data analysis, due to their ability to overcome this limitation. This study, evaluates the improvement of sensitivity of the GLM, by applying gCCA to fMRI data after standard preprocessing steps. Data from a block-design fMRI experiment was used, where 25 healthy volunteers completed two action observation tasks at 1.5T. Whole brain analysis results indicated that the application of gCCA resulted in significantly higher intensity of activation in several regions in both tasks and helped reveal activation in the primary somatosensory and ventral premotor area, theoretically known to become engaged during action observation. In subject-level ROI analyses, gCCA improved the signal to noise ratio in the averaged timeseries in each preselected ROI, and resulted in increased extent of activation, although peak intensity was considerably higher in just two of them. In conclusion, gCCA is a promising method for improving the sensitivity of conventional statistical modeling in task related fMRI experiments.

Multi-subject Task-related fMRI Data Analysis via Generalized Canonical Correlation Analysis.

Functional magnetic resonance imaging (fMRI) is one of the most popular methods for studying the human brain. It measures brain activity, by detecting local changes of Blood Oxygen Level Dependent (BOLD) signal in the brain, over time, and can be used in both task-related and resting-state studies. In task-related studies, our aim is to determine which brain areas are activated when a specific task is performed. Various unsupervised multivariate statistical methods are being increasingly employed in fMRI data analysis. Their main goal is to extract information from a dataset, often with no prior knowledge of the experimental conditions. Generalized canonical correlation analysis (gCCA) is a well known statistical method that can be considered as a way to estimate a linear subspace, which is "common" to multiple random linear subspaces. We propose a new fMRI data generating model which takes into consideration the existence of common task-related and resting-state components. We estimate the common spatial task-related component via a two-stage gCCA. We test our theoretical results using real-world fMRI data. Our experimental findings corroborate our theoretical results, rendering our approach a very good candidate for multi-subject task-related fMRI processing.Clinical Relevance-This work provides a set of methods for amplifying and recovering commonalities across subjects that appear in data from multi-subject task-related fMRI experiments.

The auditory and association cortex and language evaluation methods.

This chapter presents a summary of current notions regarding cortical specialization for language and a description of the methods employed for the assessment of that specialization. We distinguish between the "canonical" model of language specialization as it evolved from the early observations of Broca and Wernicke, implicating the inferior frontal gyrus and the posterior temporal cortex of the speech dominant hemisphere (usually the left) and its modern variants that are based on both detailed studies of lesion-symptom correlations and on the results of functional brain mapping methods. The latter fall into two categories. The first includes the invasive ones, namely the Wada procedure for assessing hemispheric dominance for speech and cortical stimulation mapping (whether intraoperative or extraoperative) for identifying cortical nodes or "hubs" of the neuronal network for language. The second category includes the noninvasive methods of functional magnetic resonance imaging, magnetoencephalography, and transcranial magnetic stimulation used for both assessment of hemispheric dominance for language and for localization of the cortical nodes of the language network. The advantages and the shortcomings of all methods are juxtaposed to facilitate selection of particular methods of assessment of the locus of the language network in particular cases.

Age-related deep white matter changes in myelin and water content: A T2 relaxometry study.

BACKGROUND: According to the retrogenesis hypothesis, the rate of age-related changes in white matter (WM) myelin content varies between early myelinating (parietal, occipital) and late myelinating (prefrontal, lateral-posterior temporal) areas. The multiecho spin echo (MESE), PD-to-T2 -weighted sequence provides an index of myelin content (myelin water fraction [MWF]) derived from measurements of myelin water (via the short T2 component [10-50 msec]) and intra- and extracellular water (via the long T2 component [>50-200 msec]). PURPOSE: To assess the shape and regional variations in the rate of age-related myelin and water content changes in deep WM regions using the MESE sequence. STUDY TYPE: Prospective, cross-sectional. POPULATION: In all, 90 healthy adults aged 22-81 years. FIELD STRENGTH/SEQUENCE: 1.5T/ T1 w, T2 w, fluid attenuated inversion recovery (FLAIR), MESE sequences. ASSESSMENT: Short T2 , long T2 , and MWF values were measured in prefrontal, parietal, lateral-posterior temporal, and occipital normal-appearing WM (NAWM) areas. STATISTICAL TESTS: Linear and quadratic effects of age on long T2 and MWF were assessed through regression analyses. Regional variations in the effect of age on long T2 and MWF values at both the individual and group level were examined, using regression and analysis of covariance (ANCOVA) analyses, respectively, controlling for total WM volume. RESULTS: The rate of age-related changes in long T2 and MWF was higher for older persons and a significant increase or decline, respectively, was first noted at 60-69 years (P < 0.0033). MWF values peaked earlier (at 30 years of age) and displayed a steeper age-related reduction in prefrontal and lateral-posterior temporal NAWM as compared with the occipital lobes (P < 0.05). The opposite pattern of age-related effect was found for long T2 values. DATA CONCLUSION: Significant age-related reductions in myelin content were closely followed by corresponding increases in intra- and extracellular water content. These changes were more pronounced among elderly people and followed an anterior-posterior pattern. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1393-1404.

Typical and Aberrant Functional Brain Flexibility: Lifespan Development and Aberrant Organization in Traumatic Brain Injury and Dyslexia.

Intrinsic functional connectivity networks derived from different neuroimaging methods and connectivity estimators have revealed robust developmental trends linked to behavioural and cognitive maturation. The present study employed a dynamic functional connectivity approach to determine dominant intrinsic coupling modes in resting-state neuromagnetic data from 178 healthy participants aged 8-60 years. Results revealed significant developmental trends in three types of dominant intra- and inter-hemispheric neuronal population interactions (amplitude envelope, phase coupling, and phase-amplitude synchronization) involving frontal, temporal, and parieto-occipital regions. Multi-class support vector machines achieved 89% correct classification of participants according to their chronological age using dynamic functional connectivity indices. Moreover, systematic temporal variability in functional connectivity profiles, which was used to empirically derive a composite flexibility index, displayed an inverse U-shaped curve among healthy participants. Lower flexibility values were found among age-matched children with reading disability and adults who had suffered mild traumatic brain injury. The importance of these results for normal and abnormal brain development are discussed in light of the recently proposed role of cross-frequency interactions in the fine-grained coordination of neuronal population activity.

In Search of Executive Impairment in Pathological Gambling: A Neuropsychological Study on Non-treatment Seeking Gamblers.

Pathological gambling is characterized by a persisting maladaptive and recurrent behavior with severe social and psychological consequences. There is evidence of strong comorbidity with psychiatric manifestations as well as cognitive mainly involving executive functions. This study aimed to investigate impairment in executive functions and working memory, and personality traits in a sample of Greek gamblers. Twenty-four men involved in various gambling activities were recruited from ecological settings as probable pathological gamblers. They were assessed with a comprehensive neuropsychological battery involving several executive tasks, the Zuckerman-Kuhlman Personality Questionnaire, the Hospital Anxiety Depression Scale, and the Difficulties in Emotion Regulation Scale. An age- and education-level matched group of 21 men without history of habitual gambling served as controls. As a group, gamblers displayed significantly lower scores on indices of inhibition, decision making and self-reported emotional awareness, and scored higher on impulsivity/sensation seeking personality traits. Notably, gamblers scored similarly or significantly higher on measures of verbal and visuospatial working memory, cognitive flexibility, processing speed, verbal fluency, and sustained attention. Overall, we argue that gamblers do present with specific cognitive deficits, but there is no evidence for a generalized executive impairment, and further stress the importance of investigating cognitive, personality, and psychiatric aspects of gambling on the basis of an ecologically valid sampling.

Aberrant resting-state functional brain networks in dyslexia: Symbolic mutual information analysis of neuromagnetic signals.

Neuroimaging studies have identified a variety of structural and functional connectivity abnormalities in students experiencing reading difficulties. The present study adopted a novel approach to assess the dynamics of resting-state neuromagnetic recordings in the form of symbolic sequences (i.e., repeated patterns of neuromagnetic fluctuations within and/or between sensors). Participants were 25 students experiencing severe reading difficulties (RD) and 27 age-matched non-impaired readers (NI) aged 7-14 years. Sensor-level data were first represented as symbolic sequences in eight conventional frequency bands. Next, dominant types of sensor-to-sensor interactions in the form of intra and cross-frequency coupling were computed and subjected to graph modeling to assess group differences in global network characteristics. As a group RD students displayed predominantly within-frequency interactions between neighboring sensors which may reflect reduced overall global network efficiency and cost-efficiency of information transfer. In contrast, sensor networks among NI students featured a higher proportion of cross-frequency interactions. Brain-reading achievement associations highlighted the role of left hemisphere temporo-parietal functional networks, at rest, for reading acquisition and ability.

Myelin content changes in probable Alzheimer's disease and mild cognitive impairment: Associations with age and severity of neuropsychiatric impairment.

BACKGROUND: Existing indices of white matter integrity such as fractional anisotropy and magnetization transfer ratio may not provide optimal specificity to myelin content. In contrast, myelin water fraction (MWF) derived from the multiecho T2 relaxation time technique may serve as a more direct measure of myelin content. PURPOSE/HYPOTHESIS: The goal of the present study was to identify markers of regional demyelination in patients with probable Alzheimer's disease (AD) and mild cognitive impairment (MCI) in relation to age and severity of neuropsychiatric impairment. POPULATION: The sample included patients diagnosed with probable AD (n = 25) or MCI (n = 43), and cognitively intact elderly controls (n = 33). FIELD STRENGTH/SEQUENCE ASSESSMENT: Long T2 , short T2 , and MWF values were measured with a 1.5T scanner in periventricular and deep normal-appearing white matter (NAWM), serving as indices of intra/extracellular water content and myelin content. A comprehensive neuropsychological and neuropsychiatric assessment was administered to all participants. STATISTICAL TESTS, RESULTS: AD patients displayed higher age-adjusted long and short T2 values and reduced MWF values in left temporal/parietal and bilateral periventricular NAWM than controls and MCI patients (P < 0.004; one-way analysis of covariance [ANCOVA] tests). Short T2 /MWF values in temporal, frontal, and periventricular NAWM of controls and/or MCI patients were significantly associated with episodic and semantic memory performance and depressive symptomatology (P < 0.004; partial correlation indices). The impact of age on memory performance was significantly (P < 0.01; mediated linear regression analyses) mediated by age-related changes in short T2 and MWF values in these regions. DATA CONCLUSION: Age-related demyelination is associated with memory impairment (especially in prodromal dementia states) and symptoms of depression in an anatomically specific manner. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1359-1372.

Assessment and conceptual remediation of basic calculation skills in elementary school students.

The specific domain model for math disabilities postulates a core number deficit which presents a prime target for remedial interventions. This longitudinal study identified two groups of Grade 3 students based on their basic calculation abilities: students with persistent difficulties through Grade 4 (PD group) and students whose performance improved into the average range (IP group). Baseline data revealed a distinct cognitive profile for students in the PD group featuring predominant deficits in symbolic number processing. A conceptual intervention based on explicit teaching of basic arithmetic procedures was implemented when students attended Grade 5 or 6. Students in the PD group benefited more from the programme, especially in performing written calculations and in multiplication speed. Statement of contribution What is already known on this subject? Most interventions focus on young students' basic arithmetical skills to prevent serious math problems in future. Few interventions target older students who often face persistent math difficulties. These interventions are usually procedural and focus on age-appropriate math skills. What does this study add? A conceptual intervention was implemented to remediate basic calculation deficits at the end of elementary school. The aim was to help students compensate for their gaps in knowledge and motivate them to engage in math activities. Neuropsychological testing of arithmetic abilities revealed difficulties in symbolic number processing.

Cognitive screening tools for primary care settings: examining the 'Test Your Memory' and 'General Practitioner assessment of Cognition' tools in a rural aging population in Greece.

BACKGROUND: Under conditions of high demand for primary care services in a setting of low financial resources, there is need for brief, easily administered cognitive screening tools for use in the primary care setting, especially in rural areas. However, interpretation of these cognitive tests' results requires knowledge on their susceptibility to cultural, educational and demographic patient characteristics. OBJECTIVES: To assess the clinical validity of the 'Test Your Memory' (TYM) and 'General Practitioner assessment of Cognition' (GPCog) which was specifically designed for primary care practice, in a rural primary care setting in Greece, utilizing the 'Mini Mental State Examination' (MMSE) as a reference standard. METHODS: The MMSE, TYM, and GPCog were administered to a random sample of 319 community dwelling Greek adults aged 60 to 89 years in 11 rural Primary Healthcare Centres of the Prefecture of Heraklion on the island of Crete, Greece. Analyses examined (a) The association of each instrument with demographic factors and MMSE and (b) optimal cut-off scores, sensitivity and specificity against MMSE-based cognitive impairment risk using ROC analyses with the MMSE 23/24 point cut-off as a reference standard. RESULTS: We found a sensitivity of 80% and a specificity of 77% for TYM (35/36 or 38/39 cut-off, depending on education). Corresponding values were 89% and 61% for GPCog (7/8 cut-off), respectively. CONCLUSION: The TYM and GPCog instruments appear to be suitable for routine use in the primary care setting as tools for cognitive impairment risk detection in elderly rural populations.

Neural foundations of overt and covert actions.

We used fMRI to assess the human brain areas activated for execution, observation and 1st person motor imagery of a visually guided tracing task with the index finger. Voxel-level conjunction analysis revealed several cortical areas activated in common across all three motor conditions, namely, the upper limb representation of the primary motor and somatosensory cortices, the dorsal and ventral premotor, the superior and inferior parietal cortices as well as the posterior part of the superior and middle temporal gyrus including the temporo-parietal junction (TPj) and the extrastriate body area (EBA). Functional connectivity analyses corroborated the notion that a common sensory-motor fronto-parieto-temporal cortical network is engaged for execution, observation, and imagination of the very same action. Taken together these findings are consistent with the more parsimonious account of motor cognition provided by the mental simulation theory rather than the recently revised mirror neuron view Action imagination and observation were each associated with several additional functional connections, which may serve the distinction between overt action and its covert counterparts, and the attribution of action to the correct agent. For example, the central position of the right middle and inferior frontal gyrus in functional connectivity during motor imagery may reflect the suppression of movements during mere imagination of action, and may contribute to the distinction between 'imagined' and 'real' action. Also, the central role of the right EBA in observation, assessed by functional connectivity analysis, may be related to the attribution of action to the 'external agent' as opposed to the 'self'.

The unbridged gap between clinical diagnosis and contemporary research on aphasia: A short discussion on the validity and clinical utility of taxonomic categories.

Even if the traditional aphasia classification is continuously questioned by many scholars, it remains widely accepted among clinicians and included in textbooks as the gold standard. The present study aims to investigate the validity and clinical utility of this taxonomy. For this purpose, 65 left-hemisphere stroke patients were assessed and classified with respect to aphasia type based on performance on a Greek adaptation of the Boston Diagnostic Aphasia Examination. MRI and/or CT scans were obtained for each patient and lesions were identified and coded according to location. Results indicate that 26.5% of the aphasic profiles remained unclassified. More importantly, we failed to confirm the traditional lesion-to-syndrome correspondence for 63.5% of patients. Overall, our findings elucidate crucial vulnerabilities of the neo-associationist classification, and further support a deficit-rather than a syndrome-based approach. The issue of unclassifiable patients is also discussed.

Greater Repertoire and Temporal Variability of Cross-Frequency Coupling (CFC) Modes in Resting-State Neuromagnetic Recordings among Children with Reading Difficulties.

Cross-frequency, phase-to-amplitude coupling (PAC) between neuronal oscillations at rest may serve as the substrate that supports information exchange between functionally specialized neuronal populations both within and between cortical regions. The study utilizes novel algorithms to identify prominent instantaneous modes of cross-frequency coupling and their temporal stability in resting state magnetoencephalography (MEG) data from 25 students experiencing severe reading difficulties (RD) and 27 age-matched non-impaired readers (NI). Phase coherence estimates were computed in order to identify the prominent mode of PAC interaction for each sensor, sensor pair, and pair of frequency bands (from δ to γ) at successive time windows of the continuous MEG record. The degree of variability in the characteristic frequency-pair PAC(f1-f2) modes over time was also estimated. Results revealed a wider repertoire of prominent PAC interactions in RD as compared to NI students, suggesting an altered functional substrate for information exchange between neuronal assemblies in the former group. Moreover, RD students showed significant variability in PAC modes over time. This temporal instability of PAC values was particularly prominent: (a) within and between right hemisphere temporo-parietal and occipito-temporal sensors and, (b) between left hemisphere frontal, temporal, and occipito-temporal sensors and corresponding right hemisphere sites. Altered modes of neuronal population coupling may help account for extant data revealing reduced, task-related neurophysiological and hemodynamic activation in left hemisphere regions involved in the reading network in RD. Moreover, the spatial distribution of pronounced instability of cross-frequency coupling modes in this group may provide an explanation for previous reports suggesting the presence of inefficient compensatory mechanisms to support reading.

Frontotemporal Dysfunction in Amyotrophic Lateral Sclerosis: A Discriminant Function Analysis.

BACKGROUND: There is growing evidence for extramotor dysfunction (EMd) in amyotrophic lateral sclerosis (ALS), with a reported prevalence of up to 52%. OBJECTIVE: In the present study, we explore the clinical utility of a brief neuropsychological battery for the investigation of cognitive, behavioral, and language deficits in patients with ALS. METHODS: Thirty-four consecutive ALS patients aged 44-89 years were tested with a brief neuropsychological battery, including executive, behavioral, and language measures. Patients were initially classified as EMd or non-EMd based on their scores on the frontal assessment battery (FAB). RESULTS: Between-group comparisons revealed significant differences in all measures (p < 0.01). Discriminant analysis resulted in a single canonical function, with all tests serving as significant predictors. This function agreed with the FAB in 13 of 17 patients screened as EMd and identified extramotor deficits in 2 additional patients. Overall sensitivity and specificity estimates against FAB were 88.2%. CONCLUSIONS: We stress the importance of discriminant function analysis in clinical neuropsychological assessment and argue that the proposed neuropsychological battery may be of clinical value, especially when the option of extensive and comprehensive neuropsychological testing is limited. The psychometric validity of an ALS-frontotemporal dementia diagnosis using neuropsychological tests is also discussed.

In Search of Matthew Effects in Reading.

The concept of Matthew effects in reading development refers to a longitudinally widening gap between high achievers and low achievers. Various statistical approaches have been proposed to examine this idea. However, little attention has been paid to psychometric issues of scaling. Specifically, interval-level data are required to compare performance differences across performance ranges, but only ordinal-level data are available with current literacy measures. To demonstrate the interpretability problems of contrasting growth slopes, we use data from a longitudinal study of literacy development. We explore the possibility of comparing across ages, matched for performance, and we examine the consequences of nonlinear growth, temporal lag estimates, and individual differences in developmental progression. We conclude that, although conceptually appealing, the widening gap prediction is not empirically testable.

Age-related decline in verbal learning is moderated by demographic factors, working memory capacity, and presence of amnestic mild cognitive impairment.

Age-related memory changes are highly varied and heterogeneous. The study examined the rate of decline in verbal episodic memory as a function of education level, auditory attention span and verbal working memory capacity, and diagnosis of amnestic mild cognitive impairment (a-MCI). Data were available on a community sample of 653 adults aged 17-86 years and 70 patients with a-MCI recruited from eight broad geographic areas in Greece and Cyprus. Measures of auditory attention span and working memory capacity (digits forward and backward) and verbal episodic memory (Auditory Verbal Learning Test [AVLT]) were used. Moderated mediation regressions on data from the community sample did not reveal significant effects of education level on the rate of age-related decline in AVLT indices. The presence of a-MCI was a significant moderator of the direct effect of Age on both immediate and delayed episodic memory indices. The rate of age-related decline in verbal episodic memory is normally mediated by working memory capacity. Moreover, in persons who display poor episodic memory capacity (a-MCI group), age-related memory decline is expected to advance more rapidly for those who also display relatively poor verbal working memory capacity.