Characterizing Longitudinal Patterns in Cognition, Mood, And Activity in Depression With 6-Week High-Frequency Wearable Assessment: Observational Study.

BACKGROUND: Cognitive symptoms are an underrecognized aspect of depression that are often untreated. High-frequency cognitive assessment holds promise for improving disease and treatment monitoring. Although we have previously found it feasible to remotely assess cognition and mood in this capacity, further work is needed to ascertain the optimal methodology to implement and synthesize these techniques. OBJECTIVE: The objective of this study was to examine (1) longitudinal changes in mood, cognition, activity levels, and heart rate over 6 weeks; (2) diurnal and weekday-related changes; and (3) co-occurrence of fluctuations between mood, cognitive function, and activity. METHODS: A total of 30 adults with current mild-moderate depression stabilized on antidepressant monotherapy responded to testing delivered through an Apple Watch (Apple Inc) for 6 weeks. Outcome measures included cognitive function, assessed with 3 brief n-back tasks daily; self-reported depressed mood, assessed once daily; daily total step count; and average heart rate. Change over a 6-week duration, diurnal and day-of-week variations, and covariation between outcome measures were examined using nonlinear and multilevel models. RESULTS: Participants showed initial improvement in the Cognition Kit N-Back performance, followed by a learning plateau. Performance reached 90% of individual learning levels on average 10 days after study onset. N-back performance was typically better earlier and later in the day, and step counts were lower at the beginning and end of each week. Higher step counts overall were associated with faster n-back learning, and an increased daily step count was associated with better mood on the same (P<.001) and following day (P=.02). Daily n-back performance covaried with self-reported mood after participants reached their learning plateau (P=.01). CONCLUSIONS: The current results support the feasibility and sensitivity of high-frequency cognitive assessments for disease and treatment monitoring in patients with depression. Methods to model the individual plateau in task learning can be used as a sensitive approach to better characterize changes in behavior and improve the clinical relevance of cognitive data. Wearable technology allows assessment of activity levels, which may influence both cognition and mood.

Test-retest reliability on the Cambridge Neuropsychological Test Automated Battery: Comment on Karlsen et al. (2020).

Test-retest reliability is essential to the development and validation of psychometric tools. Here we respond to the article by Karlsen et al. (Applied Neuropsychology: Adult, 2020), reporting test-retest reliability on the Cambridge Neuropsychological Test Automated Battery (CANTAB), with results that are in keeping with prior research on CANTAB and the broader cognitive assessment literature. However, after adopting a high threshold for adequate test-retest reliability, the authors report inadequate reliability for many measures. In this commentary we provide examples of stable, trait-like constructs which we would expect to remain highly consistent across longer time periods, and contrast these with measures which show acute within-subject change in response to contextual or psychological factors. Measures characterized by greater true within-subject variability typically have lower test-retest reliability, requiring adequate powering in research examining group differences and longitudinal change. However, these measures remain sensitive to important clinical and functional outcomes. Setting arbitrarily elevated test-retest reliability thresholds for test adoption in cognitive research limits the pool of available tools and precludes the adoption of many well-established tests showing consistent contextual, diagnostic, and treatment sensitivity. Overall, test-retest reliability must be balanced with other theoretical and practical considerations in study design, including test relevance and sensitivity.

Developing Digital Tools for Remote Clinical Research: How to Evaluate the Validity and Practicality of Active Assessments in Field Settings.

The ability of remote research tools to collect granular, high-frequency data on symptoms and digital biomarkers is an important strength because it circumvents many limitations of traditional clinical trials and improves the ability to capture clinically relevant data. This approach allows researchers to capture more robust baselines and derive novel phenotypes for improved precision in diagnosis and accuracy in outcomes. The process for developing these tools however is complex because data need to be collected at a frequency that is meaningful but not burdensome for the participant or patient. Furthermore, traditional techniques, which rely on fixed conditions to validate assessments, may be inappropriate for validating tools that are designed to capture data under flexible conditions. This paper discusses the process for determining whether a digital assessment is suitable for remote research and offers suggestions on how to validate these novel tools.

The relationship of domain-general serial order memory and reading ability in school children with and without dyslexia.

Recent evidence suggests that reading development when learning alphabetic languages is related to the underlying cognitive ability to maintain the serial order of information in short-term memory (STM). However, it remains unclear at which time point in reading development serial order STM is most important. Here, we established a crucial link between the reading development of primary school children and their serial order STM performance for both verbal and nonverbal materials. In a large cohort study of 113 Italian-speaking elementary school children in Grades 1-4, we investigated this relationship by implementing a novel double-probe design. In Experiment 1, we found that serial order STM performance was related to children's reading abilities, especially in Grades 2 and 3, corresponding to the training phase of grapheme-phoneme decoding skills. In Experiment 2, we assessed children with developmental dyslexia (DD) and found that their serial order STM performance was significantly lower than that of chronological age-matched controls (CA). It also differed from that of reading age-matched controls when accounting for individual reading performance. Furthermore, the CA group displayed an implicit serial order facilitation for item memory, whereas this implicit recruitment of serial order abilities was completely absent in children with DD. Our results suggest that the domain-general cognitive ability to maintain the serial order of information interacts with the development of reading competency, especially during a middle training phase of word reading, and this particular relationship is markedly impaired in children with DD.

The effects of aging on the working memory processes of multimodal information.

Normal aging is associated with deficits in working memory processes. However, the majority of research has focused on storage or inhibitory processes using unimodal paradigms, without addressing their relationships using different sensory modalities. Hence, we pursued two objectives. First, was to examine the effects of aging on storage and inhibitory processes. Second, was to evaluate aging effects on multisensory integration of visual and auditory stimuli. To this end, young and older participants performed a multimodal task for visual and auditory pairs of stimuli with increasing memory load at encoding and interference during retention. Our results showed an age-related increased vulnerability to interrupting and distracting interference reflecting inhibitory deficits related to the off-line reactivation and on-line suppression of relevant and irrelevant information, respectively. Storage capacity was impaired with increasing task demands in both age groups. Additionally, older adults showed a deficit in multisensory integration, with poorer performance for new visual compared to new auditory information.

The Role of Working Memory in the Probabilistic Inference of Future Sensory Events.

The ability to represent the emerging regularity of sensory information from the external environment has been thought to allow one to probabilistically infer future sensory occurrences and thus optimize behavior. However, the underlying neural implementation of this process is still not comprehensively understood. Through a convergence of behavioral and neurophysiological evidence, we establish that the probabilistic inference of future events is critically linked to people's ability to maintain the recent past in working memory. Magnetoencephalography recordings demonstrated that when visual stimuli occurring over an extended time series had a greater statistical regularity, individuals with higher working-memory capacity (WMC) displayed enhanced slow-wave neural oscillations in the θ frequency band (4-8 Hz.) prior to, but not during stimulus appearance. This prestimulus neural activity was specifically linked to contexts where information could be anticipated and influenced the preferential sensory processing for this visual information after its appearance. A separate behavioral study demonstrated that this process intrinsically emerges during continuous perception and underpins a realistic advantage for efficient behavioral responses. In this way, WMC optimizes the anticipation of higher level semantic concepts expected to occur in the near future.

Differential lateralization of hippocampal connectivity reflects features of recent context and ongoing demands: an examination of immediate post-task activity.

Neuroimaging studies have shown that task demands affect connectivity patterns in the human brain not only during task performance but also during subsequent rest periods. Our goal was to determine whether ongoing connectivity patterns during rest contain information about both the current rest state, as well as the recently terminated task. Our experimental design consisted of two types of active tasks that were followed by two types of low-demand rest states. Using this design, we examined whether hippocampal functional connectivity during wakeful rest reflects both features of a recently terminated task and those of the current resting-state condition. We identified four types of networks: (i) one whose connectivity with the hippocampus was determined only by features of a recently terminated task, (ii) one whose connectivity was determined only by features of the current resting-state, (iii) one whose connectivity reflected aspects of both the recently terminated task and ongoing resting-state features, and (iv) one whose connectivity with the hippocampus was strong, but not affected by any external factor. The left and right hippocampi played distinct roles in these networks. These findings suggest that ongoing hippocampal connectivity networks mediate information integration across multiple temporal scales, with hippocampal laterality moderating these connectivity patterns.

Alleviating memory impairment through distraction.

Distraction typically has a negative impact on memory for recent events and patients with existing memory impairment are particularly vulnerable to distractor interference. In contrast, here we establish a beneficial effect for distractor presentation in humans for both patients with memory impairment due to bilateral hippocampal lesions and healthy adults with low memory performance. Recognition memory for images of place scenes, which had to be memorized for short delay periods was significantly improved with the presentation of a distractor face during the delay. Magnetoencephalography recordings of neural oscillations in the theta frequency range obtained in healthy adults suggest that this memory improvement results from the interruption of rehearsal by the distractor. Our results highlight circumstances where active memory rehearsal may paradoxically increase memory impairments and distraction alleviates these memory deficits in patients with hippocampal injury and healthy adults.

Prolonged disengagement from attentional capture in normal aging.

Older adults are more vulnerable to a negative impact of irrelevant information on cognitive performance. We used a psychophysical approach to evaluate which aspects of distraction are altered in aging: susceptibility for attention to be captured by a distractor, or the timing of disengagement from processing a distractor. We found that younger and older adults were equally susceptible to a detrimental influence of attentional capture on target detection in the initial moments after distractor presentation, but older adults exhibited a longer time window for the negative effects of capture to resolve. As was recently shown in younger adults, the timing of disengagement from capture correlated with individual differences in visual working memory capacity in the older cohort. These results suggest that the larger impact by distraction on perceptual abilities in normal aging is not the result of a greater susceptibility to attentional capture by distraction, but rather the prolonged processing of distractors.

A new selective developmental deficit: Impaired object recognition with normal face recognition.

INTRODUCTION: Studies of developmental deficits in face recognition, or developmental prosopagnosia, have shown that individuals who have not suffered brain damage can show face recognition impairments coupled with normal object recognition (Duchaine and Nakayama, 2005; Duchaine et al., 2006; Nunn et al., 2001). However, no developmental cases with the opposite dissociation - normal face recognition with impaired object recognition - have been reported. The existence of a case of non-face developmental visual agnosia would indicate that the development of normal face recognition mechanisms does not rely on the development of normal object recognition mechanisms. METHODS: To see whether a developmental variant of non-face visual object agnosia exists, we conducted a series of web-based object and face recognition tests to screen for individuals showing object recognition memory impairments but not face recognition impairments. Through this screening process, we identified AW, an otherwise normal 19-year-old female, who was then tested in the lab on face and object recognition tests. RESULTS: AW's performance was impaired in within-class visual recognition memory across six different visual categories (guns, horses, scenes, tools, doors, and cars). In contrast, she scored normally on seven tests of face recognition, tests of memory for two other object categories (houses and glasses), and tests of recall memory for visual shapes. Testing confirmed that her impairment was not related to a general deficit in lower-level perception, object perception, basic-level recognition, or memory. DISCUSSION: AW's results provide the first neuropsychological evidence that recognition memory for non-face visual object categories can be selectively impaired in individuals without brain damage or other memory impairment. These results indicate that the development of recognition memory for faces does not depend on intact object recognition memory and provide further evidence for category-specific dissociations in visual recognition.

Theta-coupled periodic replay in working memory.

Working memory allows information from transient events to persist as active neural representations that can be used for goal-directed behaviors such as decision making and learning. Computational modeling based on neuronal firing patterns in animals suggests that one putative mechanism enabling working memory is periodic reactivation (henceforth termed "replay") of the maintained information coordinated by neural oscillations at theta (4-8 Hz) and gamma (30-80 Hz) frequency. To investigate this possibility, we trained multivariate pattern classifier decoding algorithms on oscillatory brain responses to images depicting natural scenes, recorded with high temporal resolution via magnetoencephalography. These classifiers were applied to brain activity recorded during the subsequent five second maintenance of the scenes. This decoding revealed replay during the entire maintenance interval. Replay was specific to whether an indoor or an outdoor scene was maintained and whether maintenance centered on configural associations of scene elements or just single scene elements. Replay was coordinated by the phase of theta and the amount of theta coordination was correlated with working memory performance. By confirming the predictions of a mechanistic model and linking these to behavioral performance in humans, these findings identify theta-coupled replay as a mechanism of working memory maintenance.

Hippocampus-dependent and -independent theta-networks of active maintenance.

Recent studies in humans and animals raise the possibility that actively maintaining a detailed memory of a scene within working memory may require the hippocampus, a brain structure better known for its role in long-term memory. We show that the hippocampus is behaviorally and functionally critical for configural-relational (CR) maintenance by orchestrating the synchrony of occipital and temporal brain regions in the theta-frequency range. Using magnetoencephalography in healthy adults and patients with bilateral hippocampal sclerosis, we distinguish this hippocampus-dependent theta-network from one that is independent of the hippocampus and used for non-CR scene maintenance. This non-CR theta-network involved frontal and parietal brain regions. We also show that the functional and topographical dissociation between these two networks cannot be accounted for by perceptual difficulty or the amount of information to be maintained ("load"). Also, we confirm in healthy adults that active maintenance of the CR arrangement of objects within a scene is impaired by task-interference during the delay in a manner akin to working-memory maintenance processes. Together, these findings demand reconsideration of the classical functional-anatomical distinctions between long- and short-term memory.

Voxel-based optimized morphometry (VBM) of gray and white matter in temporal lobe epilepsy (TLE) with and without mesial temporal sclerosis.

PURPOSE: In temporal lobe epilepsy (TLE) with evidence of hippocampal sclerosis (TLE-MTS) volumetric gray (GM) and white (WM) matter abnormalities are not restricted to the hippocampus but also are found in extrahippocampal structures. Less is known about extrahippocampal volumetric abnormalities in TLE without hippocampal sclerosis (TLE-no). In this study, we used optimized voxel-based morphometry (VBM) with and without modulation with the following aims: (a) to identify WM and GM abnormalities beyond the hippocampus in TLE-MTS and TLE-no; and (b) to determine whether extratemporal WM and GM abnormalities differ between TLE-MTS and TLE-no. METHODS: Optimized VBM of GM and WM with and without modulation was performed in 26 TLE-MTS (mean age, 35.6 +/- 9.7 years), 17 TLE-no (mean age, 35.6 +/- 11.1 years), and 30 healthy controls (mean age, 30.3 +/- 11.1 years). RESULTS: In TLE-MTS, GM/WM volume and concentration reductions were found in the ipsilateral limbic system, ipsi- and contralateral neocortical regions, thalamus, cerebellum, internal capsule, and brainstem when compared with controls. In contrast, no differences of GM/WM volumes/concentrations were found between TLE-no and controls or between TLE-no and TLE-MTS. CONCLUSIONS: In TLE-MTS, optimized VBM showed extensive GM and WM volume reductions in the ipsilateral hippocampus and in ipsi- and contralateral extrahippocampal regions. In contrast, no GM/WM volume or concentration reductions were found in TLE-no. This further supports the hypothesis that TLE-no is a distinct clinicopathologic entity from TLE-MTS and probably heterogeneous in itself.

Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4 T.

Proton magnetic resonance spectroscopy was performed at 4 T to determine effects of age, region and gender on glutamate and glutamine in the normal human brain. Furthermore, glutamate and glutamine alterations with age were tested for correlations with other cerebral metabolites. Two 8 cm3 volumes were selected in corona radiata and mesial motor cortex in normal subjects (N = 24) between 24 and 68 years old. Older subjects had lower glutamate concentration in the motor cortex compared to younger subjects (p < 0.001). In corona radiata, older subjects demonstrated a trend in higher glutamine compared to younger subjects (p = 0.05). Glutamate in the motor cortex was positively correlated with glutamine, N-acetyl aspartate and creatine. Reduced glutamate and N-acetyl aspartate in the motor cortex is consistent with neuronal loss/shrinkage with age. In conclusion, different patterns in association with normal aging in these brain regions were detected in this study.

Scyllo-inositol in normal aging human brain: 1H magnetic resonance spectroscopy study at 4 Tesla.

The scyllo-inositol and myo-inositol concentrations of 24 normal human subjects were measured in vivo using 1H magnetic resonance spectroscopy at 4 T. Single-voxel short-echo (TE = 15 ms) metabolite spectra were collected from the white matter region of the corona radiata. Test-retest studies performed on 10 normal subjects demonstrated coefficient of variation for scyllo-inositol measurement of 37%, compared with 6% for N-acetyl aspartate. Comparisons between old and young subjects showed higher concentration of scyllo-inositol and myo-inositol in older subjects and a trend for a correlation between scyllo-inositol and myo-inositol levels across subjects.

Identification of the epileptogenic lobe in neocortical epilepsy with proton MR spectroscopic imaging.

PURPOSE: The aim of this study was to evaluate the usefulness of multislice magnetic resonance spectroscopic imaging (MRSI) in combination with tissue segmentation for the identification of the epileptogenic focus in neocortical epilepsy (NE). METHODS: Twenty patients with NE (10 with MRI-visible malformations, 10 with normal MRI) and 19 controls were studied. In controls, N-acetylaspartate NAA/Cr and NAA/Cho of all voxels of a given lobe were expressed as a function of white matter, and thresholds were determined by calculating the 95% prediction intervals (PIs) for NAA/Cr and NAA/Cho. Voxels with NAA/Cr or NAA/Cho values less than the 95% PI were defined as "pathological." Z-scores were calculated. Depending on the magnitude of those z-scores, we used two different methods (score-localization or forced-localization) to identify in a given subject the lobe with the highest percentage of pathological voxels, which was supposed to represent the epileptogenic lobe. RESULTS: MRSI correctly identified the lobe containing the epileptogenic focus as defined by EEG in 65% of the NE patients. MRSI localization of the focus was correct in 70% of the patients with an MRI-visible malformation and in 60% of the patients with normal MRI. Of the patients, 15% had metabolically abnormal brain regions outside the epileptogenic lobe, and 35% of the patients had evidence for secondary hippocampal damage. CONCLUSIONS: MRSI may be helpful for the identification of the epileptogenic focus in NE patients, even in NE with normal MRI.

Identification of abnormal neuronal metabolism outside the seizure focus in temporal lobe epilepsy.

PURPOSE: The aim of this study was to identify metabolically abnormal extrahippocampal brain regions in patients with temporal lobe epilepsy with (TLE-MTS) and without (TLE-no) magnetic resonance imaging (MRI) evidence for mesial-temporal sclerosis (MTS) and to assess their value for focus lateralization by using multislice 1H magnetic resonance spectroscopic imaging (MRSI). METHODS: MRSI in combination with tissue segmentation was performed on 14 TLE-MTS and seven TLE-no and 12 age-matched controls. In controls, N-acetylaspartate/(creatine + choline) [NAA/(Cr+Cho)] of all voxels of a given lobe was expressed as a function of white matter content to determine the 95% prediction interval for any additional voxel of a given tissue composition. Voxels with NAA/(Cr+Cho) below the lower limit of the 95% prediction interval were defined as "pathological" in patients and controls. Z-scores were used to identify regions with a higher percentage of pathological voxels than those in controls. RESULTS: Reduced NAA/(Cr+Cho) was found in ipsilateral temporal and parietal lobes and bilaterally in insula and frontal lobes. Temporal abnormalities identified the epileptogenic focus in 70% in TLE-MTS and 83% of TLE-no. Extratemporal abnormalities identified the epileptogenic focus in 78% of TLE-MTS but in only 17% of TLE-no. CONCLUSIONS: TLE is associated with extrahippocampal reductions of NAA/(Cr+Cho) in several lobes consistent with those brain areas involved in seizure spread. Temporal and extratemporal NAA/(Cr+Cho) reductions might be helpful for focus lateralization.