Abnormal hippocampal subfields are associated with cognitive impairment in Essential Tremor.

Multi-domain cognitive impairment (CI) has been frequently described in patients with essential tremor (ET). However, the exact neuroanatomical basis for this impairment is uncertain. This study aims to ascertain the role of the hippocampal formation in cognitive impairment in ET. Forty patients with ET and 40 age, gender and education matched healthy controls (HC) were enrolled. Cognition was assessed using a structured neuropsychological battery and patients were categorized as ET with CI (ETCI) and ET without CI (ETNCI). Automatic segmentation of hippocampal subfields was performed using FreeSurfer 6.0. The obtained volumes were correlated with scores of neuropsychological tests. Significant atrophy of the left subiculum, CA4, granule-cell layer of dentate gyrus, right molecular layer, and hypertrophy of bilateral parasubiculum, right hippocampus-amygdala-transition-area, bilateral hippocampal tail (HT) and widening of right hippocampal fissure was observed in ET. Trends toward atrophy of right subiculum, and widening of left HF was also observed. Comparison of HC and ETCI revealed atrophy of right subiculum, hypertrophy of bilateral parasubiculum, HT, and widening of left HF. ETCI showed a trend toward widening of right HF. ETNCI had isolated left parasubicular hypertrophy and in comparison, to ETNCI the ETCI subgroup had atrophy of bilateral fimbria. Significant correlations were observed between the volumes of HT, HF, fimbria and scores of tests for executive function, working and verbal memory. Patients with ET have significant volumetric abnormalities of several hippocampal subfields and these abnormalities may be important contributors for some forms of cognitive impairment observed in ET.

Abnormalities of white and grey matter in early multiple system atrophy: comparison of parkinsonian and cerebellar variants.

OBJECTIVE: Multiple system atrophy (MSA) is a neurodegenerative disorder with progressive motor and autonomic dysfunction. There is a paucity of information on the early neurostructural changes in MSA, especially its subtypes, MSA-P (patients with predominant parkinsonism) and MSA-C (patients with predominant cerebellar signs). This study investigates the abnormalities of grey matter (GM) and white matter (WM) in early MSA and its subtypes using multi-modal voxel-based analysis. MATERIALS AND METHODS: Twenty-six patients with MSA with duration of symptoms ≤ 2.5 years (mean duration: 1.6 ±0.9 years) were assessed clinically and with 3T MRI. Voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) were performed to identify the structural changes in MSA and its subtypes. The GM changes and diffusion parameters of WM tracts were correlated with the clinical scores. The results were compared with MRI of 25 age- and gender-matched healthy controls. RESULTS: The early structural changes in MSA included GM loss of the cerebellum and subcallosal gyrus with widespread involvement of supratentorial and infratentorial WM fibres. In MSA-C, GM loss was limited to the cerebellum with WM changes predominantly affecting the infratentorial WM and association tracts. In contrast, MSA-P did not demonstrate any GM loss and the WM involvement was mainly supratentorial. There was no significant correlation between structural changes and clinical severity score. CONCLUSION: In early MSA, WM microstructure was more affected than GM. These changes were greater in MSA-C than in MSA-P, suggesting variable deterioration in the subtypes of MSA. KEY POINTS: • Structural changes in early multiple system atrophy were evaluated using multi-modal neuroimaging. • White matter was more affected than grey matter in early MSA. • Clinical variables did not correlate with early structural changes.

A Multimodal Structural and Functional Neuroimaging Study of Amnestic Mild Cognitive Impairment.

Examination of brain structural and functional abnormalities in amnestic mild cognitive impairment (aMCI) has the potential to enhance our understanding of the initial pathophysiological changes in dementia. We examined gray matter volumes and white matter microstructural integrity, as well as resting state functional connectivity (rsFC) in patients with aMCI (N = 48) in comparison to elderly cognitively healthy comparison subjects (N = 48). Brain volumetric comparisons were carried out using voxel-based morphometric analysis of T1-weighted images using the FMRIB Software Library. White matter microstructural integrity was examined using whole-brain tract-based spatial statistics analysis of fractional anisotropy maps generated from diffusion tensor imaging data. Finally, rsFC differences between the samples were examined by Multivariate Exploratory Linear Optimised Decomposition into Independent Components of the resting state functional magnetic resonance imaging time series, followed by between-group comparisons of selected networks using dual regression analysis. Patients with aMCI showed significant gray matter volumetric reductions in bilateral parahippocampal gyri as well as multiple other brain regions including frontal, temporal, and parietal cortices. Additionally, reduced rsFC in the anterior subdivision of the default mode network (DMN) and increased rsFC in the executive network were noted in the absence of demonstrable impairment of white matter microstructural integrity. We conclude that the demonstrable neuroimaging findings in aMCI include significant gray matter volumetric reductions in the fronto-temporo-parietal structures as well as resting state functional connectivity disturbances in DMN and executive network. These findings differentiate aMCI from healthy aging and could constitute the earliest demonstrable neuroimaging findings of incipient dementia.

Resting-State Functional Connectivity Changes Associated with Visuospatial Cognitive Deficits in Patients with Mild Alzheimer Disease.

BACKGROUND/AIMS: Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive disconnection of various brain networks leading to neuropsychological impairment. Pathology in the visual association areas has been documented in presymptomatic AD and therefore we aimed at examining the relationship between brain connectivity and visuospatial (VS) cognitive deficits in early AD. METHODS: Tests for VS working memory, episodic memory and construction were used to classify patients with AD (n = 48) as having severe VS deficits (n = 12, female = 4) or mild deficits (n = 11, female = 4). Resting-state functional magnetic resonance imaging and structural images were acquired as per the standard protocols. Between-group differences in resting-state functional connectivity (rsFC) were examined by dual regression analysis correcting for age, gender, and total brain volume. RESULTS: Patients with AD having severe VS deficits exhibited significantly reduced rsFC in bilateral lingual gyri of the visual network compared to patients with mild VS deficits. CONCLUSION: Reduced rsFC in the visual network in patients with more severe VS deficits may be a functional neuroimaging biomarker reflecting hypoconnectivity of the brain with progressive VS deficits during early AD.

Multivariate associations between cognition and neighborhood geospatial characteristics in schizophrenia.

Cognitive impairment contributes to functional impairment in schizophrenia. Yet, little is known about how environmental characteristics are related to cognition in schizophrenia. By examining how cognition and the environment are intertwined, it may be possible to identify modifiable risk and protective factors that can improve cognitive outcomes in schizophrenia. We aimed to identify multivariate associations between cognition and three geospatial characteristics (built-space density, habitable green spaces, and public spaces for social interaction) within one's immediate neighborhood among individuals with schizophrenia. We recruited participants with schizophrenia from three sites - an urban metropolitan and two towns in southern India. We administered standard cognitive assessments and performed a principal axis factoring to identify episodic memory, cognitive control, and social inference-making factors for use in further analyses. We estimated geospatial characteristics of an individual's neighborhood, i.e., up to 1 km2 around the residence, by sourcing data from Google Earth. We performed unconditional and conditional (to examine the effect of clinical covariates) canonical correlation analyses to understand the multivariate relationship between cognition and geospatial characteristics. We analyzed data from 208 participants; the first canonical cognitive variate (higher social inference-making and poorer cognitive control) shared 24% of the variance (r = 0.49; P < 0.001) with the first geospatial variate (lower built density and poorer access to public spaces). Years of education, age at onset, and place of residence significantly modulated this relationship. We observe differential associations of the built environment with social and non-social cognition in schizophrenia, and highlight the clinical and demographic characteristics that shape these associations.

Impairment of verbal learning and memory and executive function in unaffected siblings of probands with bipolar disorder.

OBJECTIVES: Impairments in executive function and memory have been reported in relatives of patients with bipolar disorder, suggesting that they could be potential endophenotypes for genetic studies, but the findings are inconsistent. In this study, neuropsychological performance in unaffected siblings of probands with family loading for bipolar disorder is compared to that of individually matched healthy controls. We hypothesized that performance on tests of executive functions and memory would be impaired in unaffected siblings of probands with bipolar disorder compared to matched healthy controls. METHODS: We evaluated 30 unaffected siblings of probands with bipolar I disorder and 30 individually matched healthy controls using tests of attention, executive function, and memory. Unaffected siblings and healthy control subjects did not differ with respect to gender, age, and years of education. RESULTS: Unaffected siblings performed poorly on the Tower of London test (TOL), the Rey's auditory verbal learning test (RAVLT), and the Rey's complex figure test. In the multivariate analysis, significance was noted for the TOL, total number of moves (p = 0.007) and the RAVLT total learning score (p = 0.001). CONCLUSIONS: Our study suggests that the deficits in verbal learning and memory and executive functions (planning) could be potential endophenotypes in bipolar disorder. These deficits are consistent with the proposed neurobiological model of bipolar disorder involving the frontotemporal and subcortical circuits. Future studies could couple cognitive and imaging strategies and genomics to identify neurocognitive endophenotypes in bipolar disorder.

Integrated intervention program for alcoholism improves impulsiveness and disadvantageous reward processing/risk-taking.

BACKGROUND: Impulsivity and aberrant reward processing are the core features of substance use disorders, including alcoholism. The present study examined the effects of an Integrated Intervention Program for Alcoholism (IIPA) on impulsiveness and disadvantageous reward processing/risk-taking in persons with alcoholism. MATERIALS AND METHODS: The study adopted age- and education-matched (±1 year) randomized control design with the pre-post comparison. The sample comprised 50 persons with alcoholism. They were allotted randomly into two groups, the intervention (IIPA) group and treatment as usual (TAU) group (n = 25 in each). Participants were assessed at pre-intervention on impulsivity (Barratt's Impulsiveness Scale) and decision-making task, which reflects reward processing deficits (modified Iowa gambling task [mIGT]). The TAU group received usual treatment for alcoholism (i.e., pharmacotherapy; three sessions in a week group therapy on relapse prevention and six sessions in week yoga) for 18 days. The intervention group received IIPA along with usual treatment (except yoga). Outcome assessment was repeated after 18 days of intervention. RESULTS: Both groups were comparable at pre-intervention (baseline). However, the intervention (IIPA) group showed a significant reduction in impulsivity and selection from disadvantageous decks on mIGT at post-intervention, while the TAU group had no significant change. CONCLUSION: The findings suggest that IIPA could improve impulsivity and disadvantageous reward processing/risk-taking in persons with alcoholism. These are core features of substance use disorders and could pose a high chance for relapse after treatment. Further studies may examine improving these characteristics with IIPA and its impact on treatment outcomes such as relapse rate and maintaining sobriety.

Effectiveness of an Integrated Intervention Program for Alcoholism (IIPA) for enhancing self-regulation: Preliminary evidence.

OBJECTIVE: Alcoholism could be a core problem of self-regulatory failure. Several neurocognitive theories have hypothesized hypo-functioning or dysfunction of reflective (executive) system and heightened functioning of reactive (impulsive) system in self-regulatory failure implicated in drug addiction. Similarly, stress and affect dysregulation may breakdown self-regulation. The present study aimed to develop an Integrated Intervention Program for Alcoholism (IIPA) to enhance self-regulation and to test its effectiveness in the treatment of alcoholism. METHOD: Individuals with early onset alcoholism (n = 50) were recruited after getting written informed consent. The study used randomized case control design. The participants were matched on age (+/-1 year) and education (+/-1 year). The TAU group received usual treatment for alcoholism which included pharmacotherapy, 6 sessions/week yoga and 3 sessions/week group therapy on relapse prevention. The intervention group received IIPA for 18 days along with usual treatment (except yoga sessions). The IIPA included several cognitive remediation tasks and mind-body exercise (Qigong and Tai Chi Chuan). Both groups were assessed on executive function tests and affect regulation scale at pre and post-intervention. The subjects were also followed up for 6 months to compare the abstinence between groups. RESULTS: Both groups were comparable at baseline. At post-intervention, the IIPA group showed a significant improvement compared to the TAU group on executive functioning and affect regulation. Follow-up results showed lower relapses in six months in the IIPA group. CONCLUSION: Preliminary evidence showed that IIPA is effective in facilitating self-regulation. Further study may examine its utility and feasibility in other clinical conditions.

Differentiation of Early Alzheimer's Disease, Mild Cognitive Impairment, and Cognitively Healthy Elderly Samples Using Multimodal Neuroimaging Indices.

Brain resting-state functional connectivity (rsFC), white matter (WM) integrity, and cortical morphometry, as well as neuropsychological performance, have seldom been studied together to differentiate Alzheimer's disease (AD), mild cognitive impairment (MCI), and elderly cognitively healthy comparison (eCHC) samples in the context of the same study. We examined brain rsFC in samples of patients with mild AD (n = 50) and MCI (n = 49) in comparison with eCHC samples (n = 48) and then explored whether rsFC abnormalities can be linked to underlying gray matter (GM) volumetric and/or WM microstructural abnormalities. The mild AD sample showed significantly increased rsFC in the executive control network (ECN) and dorsal attention network (DAN) compared with the eCHC sample, and increased rsFC in ECN compared with MCI. Brain regions corresponding to both these resting-state networks (RSNs) showed significant reduction in fractional anisotropy in mild AD in comparison with eCHC. Significant GM volumetric reductions were observed in brain regions corresponding to both RSNs in the mild AD sample compared with MCI as well as eCHC samples. The association of default mode network-DAN anticorrelation with cognitive performances differentiated mild AD and MCI from eCHC sample. These findings highlight the association between brain structural and functional abnormalities as well as cognitive impairment that enables differentiation between early AD, MCI, and eCHC samples.

Are neuropsychological deficits trait markers in OCD?

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

Trait Impulsivity in Alcohol-naïve Offspring at High Risk for Alcoholism.

BACKGROUND: Impulsivity is considered to be a vulnerability marker for substance use disorders, including alcoholism, in offspring with familial alcoholism. However, it is not adequately explored whether different age groups offspring at high risk for alcoholism differ in their impulsivity. The present study examined trait impulsivity in offspring at high risk for alcoholism, and further examined impulsivity by categorizing these offspring into different age groups. The study also examined the association between impulsivity and age, and the association of executive functions with age and education. MATERIALS AND METHODS: Sample consisted of alcohol-naïve offspring at high (n = 34) and low (n = 34) risk for alcoholism. Participants were matched on age (±1 year), education (±1 year), and gender. The measures included were: Mini-international neuropsychiatric interview, family interview for genetic studies, sociodemographic data sheet, Annett's handedness questionnaire, Barratt's Impulsiveness Scale-version 11, and tests assessing executive functions. RESULTS: Offspring at high risk for alcoholism demonstrated significantly high impulsivity. Furthermore, offspring at high risk were categorized into three subgroups with age. Results showed no significant difference between the subgroups with respect to impulsivity. Correlation analysis revealed no significant association between impulsivity and age. However, executive functions (concept formation, working memory, and safe decision-making) showed significant positive association, while perseveration and risky decision-making showed a negative association with age and education in both the groups. CONCLUSION: The present study demonstrates high impulsivity trait in offspring at high risk for alcoholism. The high impulsivity could pose a risk for addiction and may require preventive intervention.

Clinical and neuropsychological profile of persons with mild cognitive impairment, a hospital based study from a lower and middle income country.

Mild Cognitive impairment (MCI) is an important pre-dementia stage to be identified towards prevention. We screened a large number of older adults seeking help at hospital and community towards a diagnosis of MCI and this study describe their clinical and neuropsychological profile. Older adults aged 60 years & above seeking help at NIMHANS outpatient & community services were screened for early cognitive deficits. Persons were diagnosed to have MCI according to Petersen's criteria, after detailed clinical and neuropsychological assessments. Age, gender and education matched healthy controls were recruited for comparison. A total of 7469 older adults were screened during the study period (July 2012-December 2014). Less than 1% (n=56) were diagnosed with MCI. Majority were males, from urban background with an average of 13 years of education. They presented mainly with memory disturbances, more than 75% (n=43) were found to have amnestic type of MCI (aMCI). Of the aMCI subjects, majority (80%) had deficits in more than one cognitive domain. They performed significantly worse (p<0.001) on tests of episodic memory, logical memory, attention and executive functions. Neuropsychiatric symptoms were prevalent in 55% of MCI group and influenced their cognitive scores. The findings suggest that persons with MCI perform worse not only on memory tasks but also on some of the attention and executive functions tasks. As observed in earlier studies, amnestic multiple-domain MCI was the most common type of MCI in this study population. Indigenous assessment tools were of significant value in distinguishing MCI from normal ageing.

Neuropsychological profile of schizophrenia with and without obsessive compulsive disorder.

Neuropsychological profile of schizophrenia with obsessive compulsive disorder (OCD) in comparison with that of schizophrenia without OCD is understudied and the results are inconsistent. We hypothesize that patients having schizophrenia with OCD ('schizo-obsessive disorder') may have unique neuropsychological deficits in comparison with those with schizophrenia alone, particularly with respect to executive functions. Thirty patients with schizo-obsessive disorder and 30 individually matched patients with schizophrenia without any obsessive-compulsive symptoms formed the sample of the study. Neuropsychological assessment included tests for attention, executive functions and memory. Patients with schizo-obsessive disorder did not differ from those with schizophrenia alone with respect to measures of attention, executive functions and memory. Our findings do not support unique neuropsychological profile of schizo-obsessive disorder. Studying a larger sample of drug-naive patients in a longitudinal design may provide us more insights in to this.

Neurocognitive predictors of social cognition in remitted schizophrenia.

Knowledge of how specific neurocognition (NC) abilities predict social cognition (SC) in schizophrenia has potential to guide novel integrated cognitive-remediation therapies. The scope of studies conducted in this field is limited as they have not examined a comprehensive set of SC domains and they employ small sample sizes of heterogeneous patient groups. We studied a broad range of NC (sustained attention, processing speed, verbal/visual memory and visual processing/encoding, cognitive flexibility and planning) and SC [different levels of theory of mind (ToM)], attributional bias, emotion recognition and social perception] abilities in 170 remitted schizophrenia patients. Multivariate regression analyses revealed attention and planning as predictors of 1st order ToM. Memory encoding was the strongest predictor of 2nd order ToM. Faux-pas recognition, social perception and emotion recognition were influenced by a combination of cognitive flexibility and memory encoding abilities. Overall, NC predicted anywhere between ~4% and 40% of variance observed in specific SC sub-dimensions of attributional bias (4%), 1st order (19%) and 2nd order (12%) theory of mind, faux-pas recognition (28%), social perception (29%) and emotion recognition (39%). Individual SC abilities are predicted by distinctive as well as shared NC abilities. These findings have important implications for integrated cognitive remediation.

Neuropsychological performance in OCD: a study in medication-naïve patients.

BACKGROUND: Obsessive-compulsive disorder (OCD) is associated with impairments in multiple neuropsychological domains but the findings are rather inconsistent across studies. One potential reason for poor replication is the confounding influence of medications. There is limited research on neuropsychological performance in medication-naïve, never treated OCD patients. METHODS: In this study, we assessed 31 medication-naïve, never-treated, DSM-IV OCD patients free of comorbid major depression and 31 healthy controls individually matched for age, gender and years of education, with tests of attention, executive function, memory reasoning and visuo-spatial function. RESULTS: Medication-naïve OCD patients did not significantly differ from healthy controls on most neuropsychological tests. Patients performed somewhat poorly only on the highest goal hierarchy of the Tower of London (TOL) test (p=0.001, effect size=0.68). CONCLUSIONS: It is intriguing to find that symptomatic, drug-naïve OCD patients did not significantly differ from healthy controls on most neuropsychological tests. Our finding of medium effect size on TOL highest goal hierarchy test suggests that brain regions outside the affective orbitofrontal loop may also be perhaps involved in OCD. This finding however needs replication because of modest effect size. Future studies should focus on studying medication-naïve, co-morbidity-free patients and relatives using symptom dimensions for consistent and robust findings.

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

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