Human performance on visual texture discrimination tasks improves slowly (over days) in the absence of additional training. This 'slow learning' requires nocturnal sleep after training and is limited to the region of visual space in which training occurred. Here, we tested human subjects four times in one day and found that with repeated, within-day testing, perceptual thresholds actually increased progressively across the four test sessions. This performance deterioration was prevented either by shifting the target stimuli to an untrained region of visual space or by having the subjects take a mid-day nap between the second and third sessions.

Hippocampal theta waves recorded during rapid eye movement (REM) sleep are thought to play a critical role in memory consolidation in lower mammals, but previous attempts to detect similar theta oscillations in the human hippocampus have been unsuccessful. Using subdural and depth recordings from epileptic patients, we now report the first evidence of state-dependent hippocampal theta waves (4-7 Hz) in humans. Unlike the continuous theta in rodents, however, these oscillations were consistently observed during REM sleep in short (approximately 1 sec) bursts and during transitions to wake in longer epochs. Theta waves were also observed in the basal temporal lobe and frontal cortex during transitions from sleep to wake and in quiet wakefulness but not in REM, and they were not coherent with hippocampal theta oscillations. The absence of functional coupling between neocortex and hippocampus during theta periods indicates that multiple theta generators exist in the human brain, and that they are dynamically regulated by brain state. Gamma oscillations were also present during REM theta bursts, but the fluctuations in gamma power were not associated with theta phase, pointing out another significant difference between rodent and human theta properties. Together, these findings suggest that the generation mechanisms of theta oscillations in humans might have evolved from tonic to phasic in hippocampus during REM sleep and extended from hippocampus to cortex, where they appear in certain wakefulness-related states.

Improvement in perception takes place within the training session and from one session to the next. The present study aims at determining the time course of perceptual learning as revealed by changes in auditory event-related potentials (ERPs) reflecting preattentive processes. Subjects were trained to discriminate two complex auditory patterns in a single session. ERPs were recorded just before and after training, while subjects read a book and ignored stimulation. ERPs showed a negative wave called mismatch negativity (MMN)-which indexes automatic detection of a change in a homogeneous auditory sequence-just after subjects learned to consciously discriminate the two patterns. ERPs were recorded again 12, 24, 36, and 48 h later, just before testing performance on the discrimination task. Additional behavioral and neurophysiological changes were found several hours after the training session: an enhanced P2 at 24 h followed by shorter reaction times, and an enhanced MMN at 36 h. These results indicate that gains in performance on the discrimination of two complex auditory patterns are accompanied by different learning-dependent neurophysiological events evolving within different time frames, supporting the hypothesis that fast and slow neural changes underlie the acquisition of improved perception.

Neuropathological studies suggest that the basal forebrain cholinergic system (BFCS) is affected in Alzheimer's disease (AD), but there is no in vivo evidence of early damage to this system in subjects at high risk of developing AD. Here, we found that mild cognitive impairment (MCI) patients exhibited significant volume reduction of the nucleus basalis of Meynert (NbM) using recently developed probabilistic maps of the BFCS space. In addition, volumes of different magnocellular compartments varied significantly with regional gray matter atrophy in regions known to be affected by AD and were found to correlate with cognitive decline in MCI patients. Bilateral reductions of the horizontal nucleus of the diagonal band of Broca (Ch3) and frontal lobe (medial frontal, orbital, subcallosal gyrus, anterior cingulate, and middle frontal gyrus) were significantly associated with a global decline in cognitive status, whereas volume reduction of the posterior compartment of Ch4 (NbM) and temporal lobe (including hippocampus, entorhinal cortex, and amygdala) were associated with impaired delayed recall in MCI patients. These findings establish, for the first time, a link between degeneration of specific cholinergic compartments of the BFCS and cognitive-related deficits in subjects at high risk of developing AD.

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IntroductionThe Alzheimer's disease (AD) process is likely initiated many years before clinical onset. Biomarkers of preclinical disease are critical for the development of disease-modifying or even preventative therapies. Current biomarkers for early disease, including cerebrospinal fluid tau and amyloid β (Aβ) levels, structural and functional magnetic resonance imaging, and the use of brain amyloid imaging, are limited because they are very invasive or expensive. Noninvasive biomarkers may be a more accessible alternative, but none can currently detect preclinical AD with the required sensitivity and specificity.MethodsHere, we show a novel, straight-forward, and noninvasive approach for assessment of early stages of cognitive decline. Salivary samples from cases of amnestic mild cognitive impairment (aMCI) and AD, and neurology controls were analyzed.ResultsWe have discovered and validated a new single saliva biomarker, lactoferrin, which in our cross-sectional investigation perfectly discriminates clinically diagnosed aMCI and AD patients from a cognitively healthy control group. The accuracy for AD diagnosis shown by salivary lactoferrin was greater than that obtained from core cerebrospinal fluid (CSF) biomarkers, including total tau and CSF Aβ42. Furthermore, salivary lactoferrin can be used for population screening and for identifying those underdiagnosed subjects with very early stages of mild cognitive impairment and AD.ConclusionThis biomarker may offer new insights in the early diagnostics for AD.

Few studies have investigated in vivo changes of the cholinergic basal forebrain in Alzheimer’s disease (AD) and amnestic mild cognitive impairment (MCI), an at risk stage of AD. Even less is known about alterations of cortical projecting fiber tracts associated with basal forebrain atrophy. In this study, we determined regional atrophy within the basal forebrain in 21 patients with AD and 16 subjects with MCI compared to 20 healthy elderly subjects using deformation-based morphometry of MRI scans. We assessed effects of basal forebrain atrophy on fiber tracts derived from high-resolution diffusion tensor imaging (DTI) using tract-based spatial statistics. We localized significant effects relative to a map of cholinergic nuclei in MRI standard space as determined from a postmortem brain. Patients with AD and MCI subjects showed reduced volumes in basal forebrain areas corresponding to anterior medial and lateral, intermediate and posterior nuclei of the Nucleus basalis of Meynert (NbM) as well as in the diagonal band of Broca nuclei (P < 0.01). Effects in MCI subjects were spatially more restricted than in AD, but occurred at similar locations. The volume of the right antero-lateral NbM nucleus was correlated with intracortical projecting fiber tract integrity such as the corpus callosum, cingulate, and the superior longitudinal, inferior longitudinal, inferior fronto-occipital, and uncinate fasciculus (P < 0.05, corrected for multiple comparisons). Our findings suggest that a multimodal MRI-DTI approach is supportive to determine atrophy of cholinergic nuclei and its effect on intracortical projecting fiber tracts in AD.

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