Association Between Accelerometer-Derived Physical Activity Measurements and Brain Structure: A Population-Based Cohort Study.

BACKGROUND AND OBJECTIVES: While there is growing evidence that physical activity promotes neuronal health, studies examining the relation between physical activity and brain morphology remain inconclusive. We therefore examined whether objectively quantified physical activity is related to brain volume, cortical thickness, and gray matter density in a large cohort study. In addition, we assessed molecular pathways that may underlie the effects of physical activity on brain morphology. METHODS: We used cross-sectional baseline data from 2,550 eligible participants (57.6% women; mean age: 54.7 years, range: 30-94 years) of a prospective cohort study. Physical activity dose (metabolic equivalent hours and step counts) and intensity (sedentary and light-intensity and moderate-to-vigorous intensity activities) were recorded with accelerometers. Brain volumetric, gray matter density, and cortical thickness measures were obtained from 3T MRI scans using FreeSurfer and Statistical Parametric Mapping. The relation of physical activity (independent variable) and brain structure (outcome) was examined with polynomial multivariable regression, while adjusting for age, sex, intracranial volume, education, and smoking. Using gene expression profiles from the Allen Brain Atlas, we extracted molecular signatures associated with the effects of physical activity on brain morphology. RESULTS: Physical activity dose and intensity were independently associated with larger brain volumes, gray matter density, and cortical thickness of several brain regions. The effects of physical activity on brain volume were most pronounced at low physical activity quantities and differed between men and women and across age. For example, more time spent in moderate-to-vigorous intensity activities was associated with greater total gray matter volume, but the relation leveled off with more activity (standardized ß [95% CIs]: 1.37 [0.35-2.39] and -0.70 [-1.25 to -0.15] for the linear and quadratic terms, respectively). The strongest effects of physical activity were observed in motor regions and cortical regions enriched for genes involved in mitochondrial respiration. DISCUSSION: Our findings suggest that physical activity benefits brain health, with the strongest effects in motor regions and regions with a high oxidative demand. While young adults may particularly profit from additional high-intensity activities, older adults may already benefit from light-intensity activities. Physical activity and reduced sedentary time may be critical in the prevention of age-associated brain atrophy and neurodegenerative diseases.

Genetic Alzheimer's Disease Risk Affects the Neural Mechanisms of Pattern Separation in Hippocampal Subfields.

The hippocampal subfields perform distinct operations during acquisition, differentiation, and recollection of episodic memories, and deficits in pattern separation are among the first symptoms of Alzheimer's disease (AD). We investigated how hippocampal subfields contribute to pattern separation and how this is affected by Apolipoprotein-E (APOE), the strongest AD genetic risk factor. Using ultra-high-field (7T) functional magnetic resonance imaging (fMRI), APOE-ε3-ε3 carriers predominantly recruited cornu ammonis 3 (CA3) during a spatial mnemonic discrimination task, whereas APOE-ε3-ε4 and APOE-ε3-ε2 carriers engaged CA3 and dentate gyrus (DG) to the same degree. Specifically, APOE-ε3-ε4 carriers showed reduced pattern separation in CA3, whereas APOE-ε3-ε2 carriers exhibited increased effects in DG and pattern separation-related functional connectivity between DG and CA3. Collectively, these results demonstrate that AD genetic risk alters hemodynamic responses in young pre-symptomatic individuals, paving the way for development of biomarkers for preclinical AD.

Transcranial magnetic stimulation of right inferior parietal cortex causally influences prefrontal activation for visual detection.

For effective interactions with the environment, the brain needs to form perceptual decisions based on noisy sensory evidence. Accumulating evidence suggests that perceptual decisions are formed by widespread interactions amongst sensory areas representing the noisy sensory evidence and fronto-parietal areas integrating the evidence into a decision variable that is compared to a decisional threshold. This concurrent transcranial magnetic stimulation (TMS)-fMRI study applied 10 Hz bursts of four TMS (or Sham) pulses to the intraparietal sulcus (IPS) to investigate the causal influence of IPS on the neural systems involved in perceptual decision-making. Participants had to detect visual signals at threshold intensity that were presented in their left lower visual field on 50% of the trials. Critically, we adjusted the signal strength such that participants failed to detect the visual stimulus on approximately 30% of the trials allowing us to categorise trials into hits, misses and correct rejections (CR). Our results show that IPS-relative to Sham-TMS attenuated activation increases for misses relative to CR in the left middle and superior frontal gyri. Critically, while IPS-TMS did not significantly affect participants' performance accuracy, it affected how observers adjusted their response times after making an error. We therefore suggest that activation increases in superior frontal gyri for misses relative to correct responses may not be critical for signal detection performance, but rather reflect post-decisional processing such as metacognitive monitoring of choice accuracy or decisional confidence.

Audiovisual integration supports face-name associative memory formation.

Prior multisensory experience influences how we perceive our environment, and hence how memories are encoded for subsequent retrieval. This study investigated if audiovisual (AV) integration and associative memory formation rely on overlapping or distinct processes. Our functional magnetic resonance imaging results demonstrate that the neural mechanisms underlying AV integration and associative memory overlap substantially. In particular, activity in anterior superior temporal sulcus (STS) is increased during AV integration and also determines the success of novel AV face-name association formation. Dynamic causal modeling results further demonstrate how the anterior STS interacts with the associative memory system to facilitate successful memory formation for AV face-name associations. Specifically, the connection of fusiform gyrus to anterior STS is enhanced while the reverse connection is reduced when participants subsequently remembered both face and name. Collectively, our results demonstrate how multisensory associative memories can be formed for subsequent retrieval.

Reduced grid-cell-like representations in adults at genetic risk for Alzheimer's disease.

Alzheimer's disease (AD) manifests with memory loss and spatial disorientation. AD pathology starts in the entorhinal cortex, making it likely that local neural correlates of spatial navigation, particularly grid cells, are impaired. Grid-cell-like representations in humans can be measured using functional magnetic resonance imaging. We found that young adults at genetic risk for AD (APOE-ε4 carriers) exhibit reduced grid-cell-like representations and altered navigational behavior in a virtual arena. Both changes were associated with impaired spatial memory performance. Reduced grid-cell-like representations were also related to increased hippocampal activity, potentially reflecting compensatory mechanisms that prevent overt spatial memory impairment in APOE-ε4 carriers. Our results provide evidence of behaviorally relevant entorhinal dysfunction in humans at genetic risk for AD, decades before potential disease onset.

Human Hippocampal Dynamics during Response Conflict.

Besides its relevance for declarative memory functions, hippocampal activation has been observed during disambiguation of uncertainty and conflict. Uncertainty and conflict may arise on various levels. On the perceptual level, the hippocampus has been associated with signaling of contextual deviance and disambiguation of similar items (i.e., pattern separation). Furthermore, conflicts can occur on the response level. Animal experiments showed a role of the hippocampus for inhibition of prevailing response tendencies and suppression of automatic stimulus-response mappings, potentially related to increased theta oscillations (3-8 Hz). In humans, a recent fMRI study demonstrated hippocampal involvement in approach-avoidance conflicts. However, the more general significance of hippocampal activity for dealing with response conflicts also on a cognitive level is still unknown. Here, we investigated the role of the hippocampus for response conflict in the Stroop task by combining intracranial electroencephalography (iEEG) recordings from the hippocampus of epilepsy patients with region of interest-based fMRI in healthy participants. Both methods revealed converging evidence that the hippocampus is recruited in a regionally specific manner during response conflict. Moreover, our iEEG data show that this activation depends on theta oscillations and is relevant for successful response conflict resolution.

Selective processing of buildings and faces during working memory: the role of the ventral striatum.

The ventral striatum seems to play an important role during working memory (WM) tasks when irrelevant information needs to be filtered out. However, the concrete neural mechanisms underlying this process are still unknown. In this study, we investigated these mechanisms in detail. Eighteen healthy human participants were presented with multiple items consisting of faces or buildings. They either had to maintain two or four items from one category (low- and high-memory-load condition), or two from one category and suppress (filter out) two items from the other category (distraction condition). Striatal activity was increased in the distraction as compared with the high-load condition. Activity in category-specific regions in the inferior temporal cortex [fusiform face area (FFA) and parahippocampal place area (PPA)] was reduced when items from the other category needed to be selectively maintained. Furthermore, functional connectivity analysis showed significant reduction of striatal-PPA correlations during selective maintenance of faces. However, striatal-FFA connectivity was not reduced during maintenance of buildings vs. faces, possibly because face stimuli are more salient. Taken together, our results suggest that the ventral striatum supports selective WM maintenance by reduced gating of task-irrelevant activity via attenuating functional connectivity without increasing task-relevant activity correspondingly.

Music expertise shapes audiovisual temporal integration windows for speech, sinewave speech, and music.

This psychophysics study used musicians as a model to investigate whether musical expertise shapes the temporal integration window for audiovisual speech, sinewave speech, or music. Musicians and non-musicians judged the audiovisual synchrony of speech, sinewave analogs of speech, and music stimuli at 13 audiovisual stimulus onset asynchronies (±360, ±300 ±240, ±180, ±120, ±60, and 0 ms). Further, we manipulated the duration of the stimuli by presenting sentences/melodies or syllables/tones. Critically, musicians relative to non-musicians exhibited significantly narrower temporal integration windows for both music and sinewave speech. Further, the temporal integration window for music decreased with the amount of music practice, but not with age of acquisition. In other words, the more musicians practiced piano in the past 3 years, the more sensitive they became to the temporal misalignment of visual and auditory signals. Collectively, our findings demonstrate that music practicing fine-tunes the audiovisual temporal integration window to various extents depending on the stimulus class. While the effect of piano practicing was most pronounced for music, it also generalized to other stimulus classes such as sinewave speech and to a marginally significant degree to natural speech.

Temporal prediction errors in visual and auditory cortices.

To form a coherent percept of the environment, the brain needs to bind sensory signals emanating from a common source, but to segregate those from different sources [1]. Temporal correlations and synchrony act as prominent cues for multisensory integration [2-4], but the neural mechanisms by which such cues are identified remain unclear. Predictive coding suggests that the brain iteratively optimizes an internal model of its environment by minimizing the errors between its predictions and the sensory inputs [5,6]. This model enables the brain to predict the temporal evolution of natural audiovisual inputs and their statistical (for example, temporal) relationship. A prediction of this theory is that asynchronous audiovisual signals violating the model's predictions induce an error signal that depends on the directionality of the audiovisual asynchrony. As the visual system generates the dominant temporal predictions for visual leading asynchrony, the delayed auditory inputs are expected to generate a prediction error signal in the auditory system (and vice versa for auditory leading asynchrony). Using functional magnetic resonance imaging (fMRI), we measured participants' brain responses to synchronous, visual leading and auditory leading movies of speech, sinewave speech or music. In line with predictive coding, auditory leading asynchrony elicited a prediction error in visual cortices and visual leading asynchrony in auditory cortices. Our results reveal predictive coding as a generic mechanism to temporally bind signals from multiple senses into a coherent percept.

Electrical engram: how deep brain stimulation affects memory.

Deep brain stimulation (DBS) is a surgical procedure involving implantation of a pacemaker that sends electric impulses to specific brain regions. DBS has been applied in patients with Parkinson's disease, depression, and obsessive-compulsive disorder (among others), and more recently in patients with Alzheimer's disease to improve memory functions. Current DBS approaches are based on the concept that high-frequency stimulation inhibits or excites specific brain regions. However, because DBS entails the application of repetitive electrical stimuli, it primarily exerts an effect on extracellular field-potential oscillations similar to those recorded with electroencephalography. Here, we suggest a new perspective on how DBS may ameliorate memory dysfunction: it may enhance normal electrophysiological patterns underlying long-term memory processes within the medial temporal lobe.

Long-term music training tunes how the brain temporally binds signals from multiple senses.

Practicing a musical instrument is a rich multisensory experience involving the integration of visual, auditory, and tactile inputs with motor responses. This combined psychophysics-fMRI study used the musician's brain to investigate how sensory-motor experience molds temporal binding of auditory and visual signals. Behaviorally, musicians exhibited a narrower temporal integration window than nonmusicians for music but not for speech. At the neural level, musicians showed increased audiovisual asynchrony responses and effective connectivity selectively for music in a superior temporal sulcus-premotor-cerebellar circuitry. Critically, the premotor asynchrony effects predicted musicians' perceptual sensitivity to audiovisual asynchrony. Our results suggest that piano practicing fine tunes an internal forward model mapping from action plans of piano playing onto visible finger movements and sounds. This internal forward model furnishes more precise estimates of the relative audiovisual timings and hence, stronger prediction error signals specifically for asynchronous music in a premotor-cerebellar circuitry. Our findings show intimate links between action production and audiovisual temporal binding in perception.

Physical and perceptual factors shape the neural mechanisms that integrate audiovisual signals in speech comprehension.

Face-to-face communication challenges the human brain to integrate information from auditory and visual senses with linguistic representations. Yet the role of bottom-up physical (spectrotemporal structure) input and top-down linguistic constraints in shaping the neural mechanisms specialized for integrating audiovisual speech signals are currently unknown. Participants were presented with speech and sinewave speech analogs in visual, auditory, and audiovisual modalities. Before the fMRI study, they were trained to perceive physically identical sinewave speech analogs as speech (SWS-S) or nonspeech (SWS-N). Comparing audiovisual integration (interactions) of speech, SWS-S, and SWS-N revealed a posterior-anterior processing gradient within the left superior temporal sulcus/gyrus (STS/STG): Bilateral posterior STS/STG integrated audiovisual inputs regardless of spectrotemporal structure or speech percept; in left mid-STS, the integration profile was primarily determined by the spectrotemporal structure of the signals; more anterior STS regions discarded spectrotemporal structure and integrated audiovisual signals constrained by stimulus intelligibility and the availability of linguistic representations. In addition to this "ventral" processing stream, a "dorsal" circuitry encompassing posterior STS/STG and left inferior frontal gyrus differentially integrated audiovisual speech and SWS signals. Indeed, dynamic causal modeling and Bayesian model comparison provided strong evidence for a parallel processing structure encompassing a ventral and a dorsal stream with speech intelligibility training enhancing the connectivity between posterior and anterior STS/STG. In conclusion, audiovisual speech comprehension emerges in an interactive process with the integration of auditory and visual signals being progressively constrained by stimulus intelligibility along the STS and spectrotemporal structure in a dorsal fronto-temporal circuitry.

Anatomical traces of vocabulary acquisition in the adolescent brain.

A surprising discovery in recent years is that the structure of the adult human brain changes when a new cognitive or motor skill is learned. This effect is seen as a change in local gray or white matter density that correlates with behavioral measures. Critically, however, the cognitive and anatomical mechanisms underlying these learning-related structural brain changes remain unknown. Here, we combined brain imaging, detailed behavioral analyses, and white matter tractography in English-speaking monolingual adolescents to show that a critical linguistic prerequisite (namely, knowledge of vocabulary) is proportionately related to relative gray matter density in bilateral posterior supramarginal gyri. The effect was specific to the number of words learned, regardless of verbal fluency or other cognitive abilities. The identified region was found to have direct connections to other inferior parietal areas that separately process either the sounds of words or their meanings, suggesting that the posterior supramarginal gyrus plays a role in linking the basic components of vocabulary knowledge. Together, these analyses highlight the cognitive and anatomical mechanisms that mediate an essential language skill.