Graph analysis uncovers an opposing impact of methylphenidate on connectivity patterns within default mode network sub-divisions.

BACKGROUND: The Default Mode Network (DMN) is a central neural network, with recent evidence indicating that it is composed of functionally distinct sub-networks. Methylphenidate (MPH) administration has been shown before to modulate impulsive behavior, though it is not yet clear whether these effects relate to MPH-induced changes in DMN connectivity. To address this gap, we assessed the impact of MPH administration on functional connectivity patterns within and between distinct DMN sub-networks and tested putative relations to variability in sub-scales of impulsivity. METHODS: Fifty-five right-handed healthy adults underwent two resting-state functional MRI (rs-fMRI) scans, following acute administration of either MPH (20 mg) or placebo, via a randomized double-blind placebo-controlled design. Graph modularity analysis was implemented to fractionate the DMN into distinct sub-networks based on the impact of MPH (vs. placebo) on DMN connectivity patterns with other neural networks. RESULTS: MPH administration led to an overall decreased DMN connectivity, particularly with the auditory, cinguloopercular, and somatomotor networks, and increased connectivity with the parietomedial network. Graph analysis revealed that the DMN could be fractionated into two distinct sub-networks, with one exhibiting MPH-induced increased connectivity and the other decreased connectivity. Decreased connectivity of the DMN sub-network with the cinguloopercular network following MPH administration was associated with elevated impulsivity and non-planning impulsiveness. CONCLUSION: Current findings highlight the intricate effects of MPH administration on DMN rs-fMRI connectivity, uncovering its opposing impact on distinct DMN sub-divisions. MPH-induced dynamics in DMN connectivity patterns with other neural networks may account for some of the effects of MPH administration on impulsive behavior.

The Two-Track Model of Dementia Grief and spousal response to illness and death.

This cross-sectional study examined the experiences of healthy spouses caring for their partners via the Two-Track Model of Dementia Grief thereby broadening our understanding of the functional and relational aspects of this process. The 122 participating older adults had spouses drawn from four groups: mild to moderate cognitive-impairment; advanced cognitive-impairment; deceased following dementia; and, healthy controls. They completed a battery of self-report measures. Results showed elevated scores on both tracks of the model for all affected groups. Assisting spouses of those living with cognitive-impairment begins with the earliest symptoms of decline and continues after the death of the loved one.

Cognitive dysfunction following COVID-19 infection.

The coronavirus (COVID-19) pandemic is still evolving, causing hundreds of millions of infections around the world. The long-term sequelae of COVID-19 and neurologic syndromes post COVID remain poorly understood. The present study aims to characterize cognitive performance in patients experiencing cognitive symptoms post-COVID infection. Patients evaluated at a post COVID clinic in Northern Israel who endorsed cognitive symptoms were referred for neurologic consultation. The neurologic work-up included detailed medical history, symptom inventory, neurological examination, the Montreal Cognitive Assessment (MoCA), laboratory tests and brain CT or MRI. Between December 2020 and June 2021, 46 patients were referred for neurological consultation (65% female), mean age 49.5 (19-72 years). On the MoCA test, executive functions, particularly phonemic fluency, and attention, were impaired. In contrast, the total MoCA score, and memory and orientation subscores did not differ from expected ranges. Disease severity, premorbid condition, pulmonary function tests and hypoxia did not contribute to cognitive performance. Cognitive decline may affect otherwise healthy patients post-COVID, independent of disease severity. Our examination identified abnormalities in executive function, attention, and phonemic fluency. These findings occurred despite normal laboratory tests and imaging findings.

Spousal Mourning for Partners Living with Cognitive Impairment: The Interplay of Attachment and the Two-Track Model of Dementia Grief.

The aim of the present research was to study the interplay of Attachment Theory and the Two-Track Model of Dementia Grief. To examine the research hypotheses, a cross-sectional study was designed and included 122 participants (Mean age = 72.77) drawn from four groups: spouses of people living with mild to moderate cognitive impairment, spouses of people living with advanced cognitive impairment, widowed spouses of deceased dementia patients, and a control group. Participants completed a battery of self-report questionnaires. Results showed that secure attachment constitutes a significant protective factor with regard to bio-psycho-social symptomatology (Track I) as well as difficulties in the relational bond with the spouse and grief over their deterioration (Track II). The results of the research support integrating attachment-based insights into clinical work with spouses coping with the losses accompanying cognitive decline and the grief processes that are operant in these losses.

[ADHD IN THE AGING POPULATION: A NEW DIFFERENTIAL DIAGNOSIS?]

INTRODUCTION: During midlife and aging, subjective reports regarding cognitive decline increase in frequency. Age-associated cognitive impairment, mild cognitive impairment and dementia, increase in prevalence and are frequently diagnosed. Background medical conditions and risk factors are often regarded as contributing to the cognitive decline. The contribution of prior undiagnosed ADHD (Attention Deficit Hyperactive Disorder) is seldom considered. The aim of the current study was to examine whether childhood or adult ADHD should be considered relevant in the differential diagnosis of cognitive complaints during midlife and aging. METHODS: Thirty-six subjects, aged 50-70 years, diagnosed with probable ADHD (pADHD) and 29 controls participated in the present study. The pADHD group included 12 individuals self-referred due to self-complaints regarding cognitive decline or memory impairment, previously undiagnosed with ADHD (ADHD-A) but with lifelong symptomatology of ADHD and fulfilling ADHD criteria and 24 individuals, parents of diagnosed ADHD children and reporting ADHD symptoms (ADHD-B) , without complaints regarding recent cognitive decline. The neuropsychological evaluation included the Conners' Adult ADHD Rating Scale-SL, Beck Depression Inventory, and the following cognitive tests: logical memory subscale (LM- WMS), California Verbal study was conducted at the Cognitive Neurology Clinic - Rambam Health Care Campus and was granted the approval of the local IRB committee. RESULTS: ADHD-A were impaired on attention parameters while memory and executive functions were intact. ADHD-B did not present measurable attention or other neuropsychological deficits as compared to the control group. Neither group fulfilled criteria for MCI or dementia. CONCLUSIONS: ADHD should be considered as a new/additional entity in the differential diagnosis of subjective cognitive complaints among middle-aged and older persons. The recognition of the specific cognitive and behavioral profiles of ADHD should contribute to the ability to reach optimal differentiation from pre-dementia conditions in order to tailor appropriate therapies. The pathophysiology and future trajectory of the emerging ADHD symptomatology in older patients fulfilling lifelong ADHD symptomatology remains to be clarified. When examining older adults, ADHD should be considered as a differential diagnosis.

Cognitive impairment in hodgkin lymphoma survivors.

Cancer-related cognitive impairment (CRCI) is commonly reported post-chemotherapy in adults with solid tumours. Hodgkin lymphoma (HL) mostly affects young adults. Data regarding CRCI in HL survivors (HLS) are scarce. The current study aimed to objectively assess CRCI incidence and characteristics in HLS. HLS, who completed first-line (chemotherapy ± radiation) therapy and remained in complete remission for 6 months to 5 years from therapy end, were evaluated. Age- and education-matched healthy individuals served as controls (n = 14). Test results were compared to population norms and healthy controls. Study participants completed self-reported questionnaires evaluating fatigue, depression, anxiety, quality of life and cognitive function. Subjects underwent neurocognitive evaluation, assessing processing speed, memory, attention, executive functions and intelligence domains. The present study included 51 HLS with a median age of 28 years, mean education of 14·5 ± 2·5 years. Complaints related to cognitive deterioration and fatigue were significantly more severe and frequent in HLS compared to healthy controls. Objective neurocognitive evaluation demonstrated that 30% of HLS were impaired in ≥2 cognitive domains. In conclusion, the present study demonstrates that fatigue and cognitive impairment, predominantly in executive functions and memory, constitute frequent and alarming findings in HLS. These adverse effects can persist and exert an impact on all aspects of life.

Risk, Resilience, and the Two-Track Model of Dementia Grief Among Spouses of People Living With Cognitive Decline.

Pre-death grief in the context of dementia caregiving is a significant risk factor for depression, burden, anxiety, and adjustment difficulties. The Two-Track Model of Dementia Grief (TTM-DG) provides a bifocal perspective addressing the nature of the emotional attachment to a loved one living with cognitive impairment, along with a medico-psychiatric perspective associated with stress, trauma, and change in life. The aims of the present study were to empirically validate the components of the model as to identify salutary and risk factors for maladaptive grief responses. Participants were 62 spouses of people living with cognitive impairment, and a control group of 32 spouses. All completed a battery of self-report questionnaires. Structural Equation Modeling yielded six variables consistent with the TTM-DG: partner's behavioral disorders; caregiver's burden; social support; physical health; attachment anxiety; and dementia grief as an outcome measure. Additional findings addressed participants at risk for grief difficulties. The findings provide empirical support for the utility of the TTM-DG in the identification of risk factors associated with maladaptive responses and pre-death grief following a spousal cognitive decline. The TTM-DG can assist in the formulation of evidence-based evaluations and interventions to assist spouses caring for their loved ones living with dementia.

Fronto-striatal connectivity patterns account for the impact of methylphenidate on choice impulsivity among healthy adults.

Choice impulsivity depicts a preference towards smaller-sooner rewards over larger-delayed rewards, and is often assessed using a delay discounting (DD) task. Previous research uncovered the prominent role of dopaminergic signaling within fronto-striatal circuits in mediating choice impulsivity. Administration of methylphenidate (MPH), an indirect dopaminergic agonist, was shown to reduce choice impulsivity in animals and pathological populations, although significant inter-individual variability in these effects was reported. Whether MPH impacts choice impulsivity among healthy individuals, and whether variability in the impact of MPH is related to fronto-striatal activation and connectivity patterns, has yet to be assessed. Here, fifty-seven healthy young adults completed the DD task twice during fMRI scans, after acute administration of either MPH (20 mg) or placebo, in a randomized double-blind placebo-controlled design. Acute MPH administration was found to reduce choice impulsivity at the group level, yet substantial variability in this behavioral response was observed. MPH was also found to increase activation in the bilateral putamen and the right caudate, and to enhance functional connectivity between the left putamen and medial prefrontal cortex (mPFC), particularly during non-impulsive choices. Notably, the more putamen-mPFC functional connectivity increased during non-impulsive choices following MPH administration, the less an individual was likely to make impulsive choices. These findings reveal, for the first time in healthy adults, that acute MPH administration is associated with reduced choice impulsivity and increased striatal activation and fronto-striatal connectivity; and furthermore, that the magnitude of MPH-induced change in fronto-striatal connectivity may account for individual differences in the impact of MPH on impulsive behavior.

The Placebo Response in Adult ADHD as Objectively Assessed by the TOVA Continuous Performance Test.

Objective: We compared the placebo response (PR) as measured by the Test of Variables of Attention (TOVA) and the Conners' Adult ADHD Rating Scale (CAARS) scores. Method: A retrospective data analysis from a double-blind placebo-controlled study of metadoxine-ER in adults with ADHD. An additional database was used for comparison to TOVA response after methylphenidate challenge (TOVA-MPH-R). Results: PR was highest when calculated from the TOVA-Attention Composite Score (ACS). The PR showed significantly fewer variables improving concomitantly compared with MPH-R. The most prominent correlation between the CAARS-PR and the TOVA-PR was in the Omissions score (p = .032), which was age-dependent (b = .0007, p <.001). Discussion: TOVA-PR has an index-specific profile compared with CAARS-PR and TOVA-MPH-R. The partial correlation of TOVA-PR with CAARS-PR suggests that a composite score of TOVA specific indices and CAARS could have a synergic impact to improve the reliability of the response assessment in adult ADHD.

The First Word Recalled Measure - A Potential Addition to Clinical Exams.

Characterizing episodic memory abilities is highly important in the diagnosis of Alzheimer's disease (AD) and mild cognitive impairment (MCI), and usually includes wordlist learning and recall tasks. Clinical evaluations typically focus on the number of words recalled, ignoring additional information, like serial position. Here, we tested the potential value of two serial positioning measures for clinical diagnosis - how retrieval is initiated, as measured by the first word recalled, and how it proceeds - using data from patients with AD and MCI that completed a wordlist learning and recall task. Our results show that during the early stages of learning, patients with AD are less prone to retrieve the first word from the wordlist, manifested as lower primacy effect in the first word recalled, compared with MCI patients. The first word recalled measure adds to the differentiation between the groups over and above the total number of words learned. Thus, the first word recalled during word list learning and recall tasks may be used as a simple complementary measure to distinguish between MCI and AD during standard neuropsychological evaluations.

Ethnic Differences in Attending a Tertiary Dementia Clinic in Israel.

Introduction: Variations in lifestyle, socioeconomic status and general health likely account for differences in dementia disparities across racial groups. Our aim was to evaluate the characteristics of Arab (AS) and Jewish (JS) subjects attending a tertiary dementia clinic in Israel. Methods: Retrospective data regarding subjects attending the Cognitive Neurology Institute at Rambam Health Care Campus between April 1, 2010, and April 31, 2016, for complaints of cognitive decline were collected from the institutional registry. AS and consecutive JS, aged ≥50 years without a previous history of structural brain disease, were included. Results: The records of 6,175 visits were found; 3,246 subjects were ≥50 years at the initial visit. One hundred and ninety-nine AS and consecutive JS cases were reviewed. Mean age at first visit was 68.4 ± 8.8 for AS and 74.3 for JS (p < 0.0001). Mean education was 7.7 ± 4.8 years for AS and 11.3 years for JS (p < 0.0001). Mean duration of cognitive complaints prior to first visit did not differ between the groups. Initial complaints of both ethnicities were failing memory (97%) and behavioral changes (59%). Functional impairment was reported by 59% of AS and 45% of JS (p = 0.005). MMSE on first evaluation was 19.2 ± 7 for AS and 23.1 ± 5.9 for JS; p = 0.001. Alzheimer's disease was diagnosed in 32% AS and 23% JS, mild cognitive impairment in 12% AS and 21% JS. Normal cognition was diagnosed in 2% AS and 9% JS; p = 0.0001. Conclusions: Compared to JS, AS attend a tertiary clinic when their cognitive impairment already affects their functional abilities providing a comprehensive benchmark for social health care interventions to reduce disparities.

Apparent lack of practice effects in the Test of Variables of Attention (TOVA) in adult ADHD.

The test of variables of attention (TOVA) is a continuous performance test commonly used as an aid for diagnosis of ADHD and assessment of treatment response. It has been studied and standardized in both children and adults. As a repetitive measurement of treatment efficacy, used both in research and in the clinic, it's important to disprove a practice effect. A retrospective cohort analysis was done, using only the placebo-arm participants from two different randomized, multicenter, double-blind clinical trials on the efficacy of a non-stimulant (metadoxine-XR). In order to reveal the practice effects, only the participants that showed no placebo effect (< 25% improvement), in the Conners' Adult ADHD Rating Scale-investigator rated (CAARS-Inv), the gold standard, were included. Demographic data, CAARS-Inv baseline and TOVA results during each visit were recorded and analyzed. Ninety-one participants from two studies were pooled (2014 n = 24, 2016 n = 67). They did not differ significantly in any demographic parameter, most side effect frequencies, and CAARS-Inv baseline scores. The baseline TOVA performances demonstrated similarity in the degree of inattention, variability, impulsivity, and response time. The TOVA scores were not altered significantly between visits, as assessed by repeated-measures analysis of variance. No significant differences were detected between the TOVA baseline-to-endpoint scores as assessed by paired t test. No practice effects were detected, in both clinical trials, suggesting that the results of the TOVA are likely to represent genuine changes in attentional performance. Further studies are needed to replicate these findings.

A randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy, safety, and tolerability of extended-release metadoxine in adults with attention-deficit/hyperactivity disorder.

OBJECTIVE: To evaluate the efficacy, safety, and tolerability of an oral extended-release (ER) formulation of the nonstimulant metadoxine in the treatment of adult attention-deficit/hyperactivity disorder (ADHD). METHOD: This was a 1:1 randomized, double-blind, placebo-controlled, parallel-design, phase 2 study of metadoxine ER 1,400 mg/d treatment for 6 weeks, following a 2-week baseline/screening period, involving 120 adults with DSM-IV-defined ADHD. A follow-up assessment occurred 2 weeks after the trial was completed. Efficacy measures included changes in Conners' Adult ADHD Rating Scale-Investigator Rated (CAARS-INV) total ADHD symptoms score with adult ADHD prompts (primary measure), response rates (≥ 25% or 40% improvement in CAARS-INV total ADHD symptom score), Test of Variables of Attention (TOVA) performance, and Adult ADHD Quality of Life (AAQoL) total score. The study was conducted from March 15, 2011, to August 21, 2011. RESULTS: Intent-to-treat analysis revealed that subjects receiving metadoxine ER showed statistically significant improvement in CAARS-INV total ADHD symptoms score (P = .02), higher rate of response (≥ 25% [P = .03] or ≥ 40% [P = .04] improvement) on the CAARS-INV total ADHD symptoms score, and improvement in TOVA score (P = .02) and AAQoL score (P = .01) compared with the placebo group. Improvements in ADHD symptoms (scored by CAARS-INV) were significantly different in subjects treated with metadoxine ER versus placebo as early as 2 weeks following treatment initiation. Metadoxine ER was generally well tolerated, with nausea (17% [10/58] vs 0% [0/59]), fatigue (31% [18/58] vs 27% [16/59]), and headaches (29% [17/58] vs 39% [23/59]) being the most frequently reported adverse effects for the metadoxine ER and placebo groups, respectively. CONCLUSIONS: Findings suggest that metadoxine ER is a well-tolerated and effective treatment for adults with ADHD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01243242.