Background: Treatment with transcranial direct current stimulation (tDCS) has resulted in language improvements in a variety of populations. Objective: To determine the feasibility of tDCS in adolescents with autism spectrum disorder (ASD) and to examine fMRI activation changes associated with tDCS. To provide preliminary information on whether the left or right inferior frontal gyrus (IFG) is a better target for language improvement. Methods: We applied anodal tDCS to the left or right IFG in eight adolescents (11–17 years) with ASD and examined changes in fluency and fMRI activation during a semantic task. Results: tDCS was well tolerated and all participants were able to complete the session. Of the participants who received right tDCS, 67% (2/3) showed improvements in letter and category fluency. None of the participants who received left tDCS showed improvement in both letter and category fluency. We were unable to collect two usable fMRI scans forhalf of the participants. Individual fMRI activation data did not produce reliable results regarding tDCS-induced changes. Conclusion: Our preliminary results add to findings suggesting tDCS is feasible in adolescents with ASD, including those with severely impaired language abilities. Right IFG stimulation should be investigated in a larger population, as our pilot findings suggest slightly greater improvement in language fluency relative to left IFG stimulation. It may not be practical or reliable to use fMRI to evaluate the effectiveness of tDCS in individuals with ASD.
Computational models have not found a place in either mainstream preclinical science or in the clinical science of cognitive function. In an effort to address this problem, I review the major computational models as they apply to brain function. These include parallel distributed processing (PDP) models, integrate and fire networks, brain in silico models, convolutional networks, statistical models, and others. I discuss PDP models in the greatest detail because they have most successfully accounted for a wide variety of behaviors in individuals who are healthy and those with brain damage. After discussing the strengths and weaknesses of all major models, I make proposals for further research. Due to the breadth of this review, a glossary of specialized terms is included in the Appendix, Supplemental Digital Content 1, http://links.lww.com/CBN/A155. The learning algorithms used in these models are problematic, including backpropagation in PDP models and unsupervised learning in others. Therefore, I review the extensive evidence that acetylcholine, delivered by the basal forebrain nuclei, both provides the crucial signal that Hebbian learning is to occur and enables that learning. Afferent input to these nuclei largely comes from the networks that represent subjective value, such as those in the orbitofrontal cortex. Of particular relevance to PDP models, a mechanism has recently been proposed by which backpropagation might occur in situ-triggered by acetylcholine-resulting in learning by virtue of the differential processing that occurs in dendrites and axons.
BACKGROUND:Mild cognitive impairment (MCI) sits between normal aging and Alzheimer disease (AD). Identification of accessible serum biomarkers linked with Alzheimer pathology may facilitate early detection and intervention, potentially delaying disease progression. OBJECTIVE:To explore the associations between serum sirtuin-3 (SIRT3) levels in individuals with MCI with AD pathological markers related to cognitive function. METHODS:This prospective observational study included 106 participants with MCI and 100 age- and sex-matched cognitively healthy controls (HC). We quantified SIRT3, inflammatory cytokines (IL-6 and IL-17), and AD biomarkers (Aβ40, Aβ42, and p-Tau) by enzyme-linked immunosorbent assay. We used standardized neuropsychological tests to assess cognitive function. Logistic regression and receiver operating characteristic curve analyses were conducted to evaluate the diagnostic potential of serum SIRT3. RESULTS:SIRT3 levels were significantly lower in individuals with MCI compared to HC (p < 0.05). Individuals with MCI exhibited decreased serum Aβ42, reduced Aβ42/Aβ40 ratio, and increased p-Tau levels (p < 0.05). SIRT3 levels were positively correlated with cognitive performance scores, positively associated with Aβ42 and Aβ42/Aβ40 ratio, and negatively correlated with p-Tau levels. Receiver operating characteristic curve analysis demonstrated that SIRT3 had promising diagnostic value in differentiating individuals with MCI from HC. Logistic regression analysis identified lower SIRT3 levels, reduced Aβ42, and a decreased Aβ42/Aβ40 ratio as significant independent risk factors for MCI. CONCLUSION:Reduced SIRT3 levels were associated with cognitive impairment and AD biomarkers in individuals with MCI, suggesting that SIRT3 might serve as a novel, minimally invasive adjunctive biomarker for early identification of MCI.
BACKGROUND:Emotion perception is the capacity that enables humans to correctly identify the cues that guide interpersonal interactions, forming the basis for social behavior. The parahippocampal cortex may contribute to emotion perception by mediating the associations between context and emotion. Individuals with behavioral variant frontotemporal dementia (bvFTD) and Alzheimer disease (AD) appear to show deficits in this process. Investigating emotion perception impairment in these individuals could offer valuable insights into the underlying neurobiological mechanisms. METHODS:Participants included a convenience sample of 29 individuals with bvFTD, 25 with AD, and a comparison group of 15 individuals without bvFTD or AD. We performed an extensive neuropsychological assessment and administered the Comprehensive Affect Testing System (CATS) to evaluate the emotion perception process. We then used multiple regression analysis to assess the relationship between CATS main quotient scores and parahippocampal thickness (P ≤ 0.001) obtained from MRI analysis. RESULTS:Participants with bvFTD scored higher on cognitive tests than participants with AD but showed greater deficits in social behavior. On the CATS, participants with bvFTD had lower scores in all 3 emotional quotients (ie, face, prosody, and global), with a statistically significant correlation to parahippocampal thickness. Participants with AD showed milder deficits in all 3 emotion quotients, with no statistically significant correlation to parahippocampal thickness. DISCUSSION:Our data suggest a significant emotion perception deficit in individuals with bvFTD and support the importance of the parahippocampal gyrus in context-emotion associations. Targeted rehabilitation with the objective of improving emotion perception deficits may be beneficial for individuals with bvFTD.
BACKGROUND:Although cognitive decline in Parkinson disease (PD) is common, there are currently no easily accessible clinical tools to predict the risk of cognitive decline in PD. OBJECTIVE:To refine a tool to predict cognitive decline in PD and identify potentially modifiable factors. METHODS:We used neuropsychological scores from the Parkinson's Progression Markers Initiative de novo PD cohort to calculate a composite cognitive score (CCS) for each participant. Participants with a decrease of ≥0.5 SD in CCS between baseline and Year 4 were considered to have cognitive decline (PD-Decline), as predicted by conditional linear mixed modeling to account for nonignorable dropouts. We identified risk factors for PD-Decline using logistic regression and developed the PD Risk Estimator for Decline In Cognition Tool (PREDICT) scoring system using the regression β coefficients. The selected risk factors and the discriminative ability of the PREDICT scoring system were evaluated using bootstrapped samples. RESULTS:Participants with excessive daytime sleepiness (odds ratio [OR]=2.8; 95% CI [1.3, 6.0]), moderate-severe motor symptoms (OR=2.6; 95% CI [1.2, 5.4]), and fewer years of formal education (OR=2.2; 95% CI [1.1, 4.1]) had significantly increased odds of being categorized as PD-decline. Possible PREDICT scores ranged from 0 to 3.5. The average bootstrap sensitivity and specificity were 59.9% and 43.5%, respectively. CONCLUSION:We identified excessive daytime sleepiness and moderate-severe motor symptoms as potentially modifiable factors. In the future, PREDICT may offer wider opportunities for personalized risk assessment and potential risk reduction.
BACKGROUND:Cognitive impairment is a common and disabling symptom in multiple sclerosis (MS). OBJECTIVE:To examine the reliability and validity of the Japanese version of the Brief Repeatable Battery of Neuropsychological Tests (BRB‑N) and develop individualized classification thresholds for detecting cognitive impairment in MS. METHOD:Twenty‑two individuals with MS and 43 healthy controls completed the BRB‑N. We assessed internal consistency using Cronbach's α. Discriminative ability was evaluated with receiver operating characteristic analyses and Bayesian logistic regression adjusted for age, sex, and education. We derived classification thresholds using the Youden Index. Frequentist logistic regression served as a sensitivity analysis. Finally, we assessed parallel-form reliability by comparing versions A and B of the BRB-N in healthy controls using the Wilcoxon signed-rank test. RESULTS:The Japanese BRB‑N demonstrated acceptable internal consistency (Cronbach's α = 0.78) and stable model convergence (R‑hat ≤ 1.01, ESS ≥ 400). All measures achieved an area under the curve of ≥0.70, with scores on the Paced Auditory Serial Addition Test 2 and 3 and the Symbol Digit Modalities Test showing the highest values (0.92, 0.92, and 0.87, respectively). Eight of 13 measures showed strong effects, with 95% highest posterior density intervals excluding 1 and posterior probabilities exceeding 95%. Frequentist analyses yielded consistent patterns. Parallel‑form comparisons between versions A and B showed no significant differences. A computational tool for individualized threshold estimation was developed. CONCLUSION:These preliminary findings support the reliability and potential clinical utility of the Japanese BRB‑N for MS.
Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disorder that causes rapidly progressive dementia. While it typically presents with cognitive decline, ataxia, and myoclonus, atypical presentations are increasingly recognized. Here we present the case of a 57-year-old male with the MM1 subtype of sCJD. He had an atypical presentation of progressive language difficulties and subtle visual disturbances, initially diagnosed as primary progressive aphasia. Brain MRI showed an indistinct left parietal-occipital T2 hyperintensity. Subsequent MRI scans of the brain taken over a period of several months showed left caudate diffusion restriction. EEG demonstrated left hemispheric slowing and bifrontal triphasic discharges. The patient also began exhibiting prominent visual disturbances and hallucinations, which are typically associated with the Heidenhain variant of Creutzfeldt-Jakob disease (CJD). However, his aphasia differed from the classic Heidenhain presentation. This case highlights that sCJD can be easily misdiagnosed as other neurological conditions due to its variable presentation, in this case, initially resembling primary progressive aphasia. Awareness of atypical presentations is crucial for early identification and diagnosis of sCJD.
Transient global amnesia (TGA) is a well-characterized neurological syndrome primarily affecting adults over the age of 50. It is marked by the sudden onset of anterograde amnesia with repetitive questioning while other cognitive functions remain intact. To date, only a few pediatric cases of TGA have been documented. Here we present the case of a previously healthy 9-year-old girl who developed sudden-onset anterograde amnesia, manifesting with repetitive stereotyped questions and temporal disorientation consistent with the "broken record" phenomenon. The patient's neurological examination and routine laboratory investigations were unremarkable. Brain MRI obtained within 4 hours of symptom onset was reported as normal, although the slice thickness exceeded the optimal parameters for detecting TGA-related lesions. EEG, urine toxicology screening, and cardiologic evaluation were all normal. The amnestic episode resolved spontaneously within 11 hours, and no recurrence was observed over 21 months of follow-up. The patient met all established diagnostic criteria for TGA, with no identifiable underlying etiology. TGA should be considered as a diagnostic option in children presenting with isolated acute amnesia and the characteristic "broken record" phenomenon, particularly when no alternative explanation can be identified after thorough differential diagnostic evaluation.
Background:Facial emotion recognition (FER) deficits in Alzheimer disease (AD) are associated with atypical eye-gaze strategies and exacerbated behavioral and psychological symptoms of dementia (BPSD). This results in increased caregiver burden and impacts social interactions and quality of life.Objective:To evaluate the effects of Training of Affect Recognition (TAR), a targeted cognitive remediation program, on FER, eye-gaze patterns, and BPSD in individuals with AD, as well as caregiver burden. We hypothesized improvements in emotional processing and associated clinical outcomes.Methods:Twenty-four patient-caregiver dyads participated in this single-blind randomized controlled pilot study. Each patient was assigned to participate in the TAR program (ie, the AD-TAR group; n = 12) or to receive cognitive stimulation intervention twice weekly for 6 weeks (ie, the AD-CS group; n = 12). We assessed FER using static (n = 24) and dynamic (n = 16) stimuli with eye-tracking. We used the Neuropsychiatric Inventory to assess BPSD and the Zarit Burden Interview to assess caregiver burden. Each assessment was completed at baseline, post-intervention, and 1-month follow-up.Results:The AD-TAR group showed improvements in static FER accuracy and recognition speed, as well as increased dynamic FER speed. There were concomitant beneficial changes in eye-gaze strategies in static FER and reinforced observation strategies for dynamic FER. Reductions in BPSD and caregiver burden persisted at the 1-month follow-up.Conclusion:Targeted FER remediation is a promising intervention for improving emotional processing in AD, with potential clinical implications for managing BPSD and enhancing quality of life for individuals with AD and their caregivers.
Background: Evaluation of cognitive health is an important aspect of clinical care for individuals with neurologic and/or psychiatric conditions. To our knowledge, prior studies have not established normative data for cognitive health among adults residing in the Philippines. Objective: This study aimed to adapt a multidomain cognitive testing protocol optimized for cultural relevance and establish empirically derived normative data adjusted for demographic factors using regression-based methods. Methods: We recruited healthy Filipino adults ages 18-65 years. Study participants underwent a multidomain cognitive testing protocol examining seven neurocognitive domains. We generated normative scoring systems using regression-based methods using age, sex assigned at birth, level of education, and body mass index as predictors. We defined statistical significance as p<0.05. Results: Two hundred ninety-six sex-matched participants with a mean age of 40.7 years (SD 12.7) and 10.81 years of education (SD 4.3) completed the multidomain cognitive testing protocol. In all domains, lower age, higher level of education, and female sex were associated with better test performance. For grip strength, male sex and higher body mass index were significantly associated with better performance. Conclusion: This study provides support for a multidomain cognitive test protocol designed for diverse populations. Furthermore, we established normative data for the clinical interpretation of neurocognitive performance in the Filipino population.
BACKGROUND:Apathy is a common neuropsychiatric syndrome in neurodegenerative dementias, though its underlying mechanisms are not well understood. It is characterized, in part, by a reduction in self-initiated action (ie, voluntary actions instigated by internal or external stimuli). The sense of agency (SoA) refers to the feeling of control over one's actions and the outcomes of those actions. Experimentally, SoA can be measured using the intentional binding effect, where the perceptual attraction of a voluntary action to an immediate effect of that action is indicative of increased SoA. OBJECTIVE:The current study aimed to investigate aberrant SoA as a potential mechanism contributing to apathy. METHOD:Thirty-eight participants with mild cognitive impairment or Alzheimer disease, frontotemporal dementia, Lewy body disease or Parkinson disease (LBD/PD), and healthy controls were recruited for this study. We used the total score on the Apathy Evaluation Scale to index apathy severity across participants. RESULTS:Our results did not show an association between apathy and intentional binding. However, there were significant group-based differences. Compared to healthy controls, participants in the LBD/PD group demonstrated significantly more intentional binding driven by a pronounced perceptual attraction of their actions to the subsequent outcomes. CONCLUSION:These findings suggest altered sensorimotor and cognitive control processes that may be associated with the self-initiation deficits seen in individuals with neurodegenerative dementias and apathy.
BACKGROUND:Perseveration, an inappropriate continuation of a response, is a well-established clinical sign of neurological dysfunction. The shoulder-tapping sign (STS) is a newly described and easily identified motor perseveration. OBJECTIVE:Investigate the diagnostic utility of the STS for identifying neurocognitive disorders in patients referred for neuropsychological evaluation. METHOD:We administered a five-step verbal command from the Commands subtest of the Boston Diagnostic Aphasia Examination ("Tap each shoulder twice with two fingers keeping your eyes shut") to 400 consecutive patients ( MAGE = 67.3, SD = 10.9) with suspected cognitive decline. The STS sign was considered positive if the patient tapped either shoulder more than twice. The STS was analyzed as a measure of neurocognitive disorder and compared with the final diagnosis. Analysis included calculations of sensitivity, specificity, and positive and negative likelihood ratios with 95% confidence intervals. RESULTS:The STS was positive in 23% of our sample, 96% of whom met criteria for a neurocognitive disorder. The STS was seen in 38% with dementia, 21% with mild neurocognitive disorder, and 4% with no neurocognitive diagnosis. As a diagnostic marker of neurocognitive disorders, the STS had a specificity of 0.96 and sensitivity of 0.28. Positive and negative likelihood ratios were 6.15 and 0.76, respectively. CONCLUSIONS:The STS is a highly specific indicator of neurocognitive disorders. Despite low sensitivity, the brevity and potential diagnostic yield make it a valuable addition to the cognitive assessment toolkit. When positive, the STS can be a defining feature of neurocognitive disorders in brief mental status examinations.
Genetic variants in MSL3 lead to Basilicata-Akhtar syndrome, typically characterized by developmental delay and other multisystem symptoms. Here we report on the neurodevelopmental profile of a 12-year-old female who was diagnosed and followed over a period of years by a multidisciplinary team of clinicians in medical genetics, neurology, neuropsychology, and other specialties. The patient underwent a battery of standardized tests to comprehensively assess her functioning at various ages. She had global developmental delay, pervasive motor weaknesses, and specific concomitant medical issues, but her overall clinical presentation was less severe than that of other individuals with MSL3 syndrome. Since she did not exhibit substantial global impairment, we will discuss the nuances of her neurocognitive profile, including uneven strengths (eg, expressive language, comprehension, problem-solving) and limitations (eg, motor, attention, social, processing speed, learning). We will differentiate between the medical, psychiatric, and neurocognitive functions of a child with this rare condition over time by evaluating her development across several domains. We will also draw comparisons to other individuals with MSL3 syndrome, as well as those with more common conditions. This case report adds to the existing knowledge of MSL3 syndrome, illustrates the importance of serial and detailed assessments, and may assist in treatment planning and management for other individuals with this condition.
