Basal Forebrain Nuclei Research Articles

Relationship between consciousness and injury of ascending reticular activating system in patients with hypoxic ischaemic brain injury

Impaired consciousness is one of the main sequelae of hypoxic ischemic brain injury(HI-BI).1 The ascending reticular activating system (ARAS) comprised arousal pathways and awareness networks, which mainly originates in the...

Segregation of the human basal forebrain using resting state functional MRI

The basal forebrain (BF) is poised to play an important neuromodulatory role in brain regions important to cognition due to its broad projections and complex neurochemistry. While significant in vivo work has been done to elaborate BF function in nonhuman rodents and primates, comparatively limited work has examined the in vivo function of the human BF. In the current study we used multi-echo resting state functional magnetic resonance imaging (rs-fMRI) from 100 young adults (18–34 years) to assess the potential segregation of human BF nuclei as well as their associated projections. Multi-echo processing provided significant gains in SNR throughout the brain as compared to traditional single-echo processing, with some of the largest increases observed in the BF. Bottom-up clustering of voxel-wise BF functional connectivity maps yielded adjacent functional clusters within the BF that closely aligned with the distinct, hypothesized nuclei important to cognition: the nucleus basalis of Meynert (NBM) and the medial septum/diagonal band of Broca (MS/DB). Examining their separate functional connections, the NBM and MS/DB revealed distinct projection patterns, suggesting a conservation of nuclei-specific functional connectivity with homologous regions known to be anatomically innervated by the BF. Specifically, the NBM demonstrated coupling with a widespread cortical network as well as the amygdala, whereas the MS/DB revealed coupling with a more circumscribed network, including the orbitofrontal cortex and hippocampal complex. Collectively, these in vivo rs-fMRI data demonstrate that the human BF nuclei support distinct aspects of resting-state functional networks, suggesting that the human BF may be a neuromodulatory hub important for orchestrating network dynamics.

Basal forebrain contributes to default mode network regulation

The default mode network (DMN) is a collection of cortical brain regions that is active during states of rest or quiet wakefulness in humans and other mammalian species. A pertinent characteristic of the DMN is a suppression of local field potential gamma activity during cognitive task performance as well as during engagement with external sensory stimuli. Conversely, gamma activity is elevated in the DMN during rest. Here, we document that the rat basal forebrain (BF) exhibits the same pattern of responses, namely pronounced gamma oscillations during quiet wakefulness in the home cage and suppression of this activity during active exploration of an unfamiliar environment. We show that gamma oscillations are localized to the BF and that gamma-band activity in the BF has a directional influence on a hub of the rat DMN, the anterior cingulate cortex, during DMN-dominated brain states. The BF is well known as an ascending, activating, neuromodulatory system involved in wake-sleep regulation, memory formation, and regulation of sensory information processing. Our findings suggest a hitherto undocumented role of the BF as a subcortical node of the DMN, which we speculate may be important for switching between internally and externally directed brain states. We discuss potential BF projection circuits that could underlie its role in DMN regulation and highlight that certain BF nuclei may provide potential target regions for up- or down-regulation of DMN activity that might prove useful for treatment of DMN dysfunction in conditions such as epilepsy or major depressive disorder.

Differential cholinergic and serotonergic neuromodulation of network activity in the mouse medial prefrontal cortex

Differential cholinergic and serotonergic neuromodulation of network activity in the mouse medial prefrontal cortex

Changes in cytoarchitectonics, neuronal metabolic activity and estrogen receptor expression in the human hypothalamic and anterior basal forebrain nuclei in aging, Alzheimer's disease, and vascular dementia

Changes in cytoarchitectonics, neuronal metabolic activity and estrogen receptor expression in the human hypothalamic and anterior basal forebrain nuclei in aging, Alzheimer's disease, and vascular dementia

In vivo cholinergic basal forebrain atrophy predicts cognitive decline in de novo Parkinson's disease.

See Gratwicke and Foltynie (doi:10.1093/brain/awx333) for a scientific commentary on this article.Cognitive impairments are a prevalent and disabling non-motor complication of Parkinson's disease, but with variable expression and progression. The onset of serious cognitive decline occurs alongside substantial cholinergic denervation, but imprecision of previously available techniques for in vivo measurement of cholinergic degeneration limit their use as predictive cognitive biomarkers. However, recent developments in stereotactic mapping of the cholinergic basal forebrain have been found useful for predicting cognitive decline in prodromal stages of Alzheimer's disease. These methods have not yet been applied to longitudinal Parkinson's disease data. In a large sample of people with de novo Parkinson's disease (n = 168), retrieved from the Parkinson's Progressive Markers Initiative database, we measured cholinergic basal forebrain volumes, using morphometric analysis of T1-weighted images in combination with a detailed stereotactic atlas of the cholinergic basal forebrain nuclei. Using a binary classification procedure, we defined patients with reduced basal forebrain volumes (relative to age) at baseline, based on volumes measured in a normative sample (n = 76). Additionally, relationships between the basal forebrain volumes at baseline, risk of later cognitive decline, and scores on up to 5 years of annual cognitive assessments were assessed with regression, survival analysis and linear mixed modelling. In patients, smaller volumes in a region corresponding to the nucleus basalis of Meynert were associated with greater change in global cognitive, but not motor scores after 2 years. Using the binary classification procedure, patients classified as having smaller than expected volumes of the nucleus basalis of Meynert had ∼3.5-fold greater risk of being categorized as mildly cognitively impaired over a period of up to 5 years of follow-up (hazard ratio = 3.51). Finally, linear mixed modelling analysis of domain-specific cognitive scores revealed that patients classified as having smaller than expected nucleus basalis volumes showed more severe and rapid decline over up to 5 years on tests of memory and semantic fluency, but not on tests of executive function. Thus, we provide the first evidence that volumetric measurement of the nucleus basalis of Meynert can predict early cognitive decline. Our methods therefore provide the opportunity for multiple-modality biomarker models to include a cholinergic biomarker, which is currently lacking for the prediction of cognitive deterioration in Parkinson's disease. Additionally, finding dissociated relationships between nucleus basalis status and domain-specific cognitive decline has implications for understanding the neural basis of heterogeneity of Parkinson's disease-related cognitive decline.

Beyond Acetylcholinesterase Inhibitors: Novel Cholinergic Treatments for Alzheimer's Disease.

The major components of the cholinergic receptor system of the human brain include projections from the basal forebrain nuclei, and utilize the two types of receptors that they synapse on, nicotinic and muscarinic acetylcholine receptors. With the widespread cortical and subcortical projections of the basal forebrain, activity of these two receptor systems provide modulation of neurotransmitter activity underlying normal cognitive processes, such as attention, episodic memory, and working memory. Alzheimer's disease (AD) targets and damages cholinergic neurons in the basal forebrain, and as these projections are lost, cognitive performance progressively declines. Currently, the most widely prescribed treatment for AD is acetylcholinesterase inhibitor medications, which work by partially blocking the degradation of acetylcholine in the synapse and enabling more of the neurotransmitter to reach and activate cholinergic receptors. However since these medications have limited effectiveness, alternate treatments that focus on augmenting the activity of the receptors themselves, independent of acetylcholinesterase inhibition, are being explored. This review will discuss: 1) the role of the cholinergic system in modulating cognition, 2) novel cholinergic treatment strategies for AD-related cognitive decline, in particular treatments intended to increase cholinergic system activity by selectively targeting muscarinic and nicotinic acetylcholinergic receptors to improve cognitive performance, 3) risks, and additional considerations for cholinergic cognitive treatments for AD.

Hippocampal phospho-tau/MAPT neuropathology in the fornix in Alzheimer disease: an immunohistochemical autopsy study.

Whereas early Alzheimer disease (AD) neuropathology and mild cognitive impairment are relatively common in aging, accurate prediction of patients that will progress to dementia requires new biomarkers. Recently, substantial work has focused on phospho-tau/MAPT (p-MAPT) neuropathology since its regional propagation correlates with the degree of cognitive impairment in AD. Recent diffusion tensor imaging studies in AD suggest that increased diffusion in the fornix secondary to p-MAPT-related axonal injury could serve as a predictive biomarker of the risk of disease progression. However, our knowledge of p-MAPT neuropathology in the fornix is limited. To address this gap in knowledge, we examined p-MAPT neuropathology in the fornix and basal forebrain nuclei via AT8 immunohistochemistry in 39 brain autopsies spanning the spectrum of AD neuropathologic changes. We found that the fornix and its precommissural efferent target nuclei (septum and nucleus accumbens) demonstrated neuronal and thread-like p-MAPT neuropathology only in National Institute on Aging/Alzheimer Association (NIA/AA) stages B2 and B3 of neurofibrillary degeneration, consistent with involvement after (and propagation from) the hippocampal formation. Interestingly, although tau astrogliopathy was frequently observed in the mammillary bodies in stage B2, neuronal tauopathy was not observed in the postcommissural targets (mammillary bodies and anterior thalamic nucleus) until stage B3. Tauopathy in the nucleus basalis of Meynert was strongly correlated with p-MAPT-positive axons in the fornix, suggesting that projections to the hippocampus also likely contribute to fornix tauopathy. Our cross-sectional autopsy findings indicate that the fornix is involved by p-MAPT neuropathology secondary to hippocampal involvement by AD neuropathology. Furthermore, our findings are compatible with the goal of in vivo detection of p-MAPT-related axonal pathology in the fornix in AD as a possible biomarker of p-MAPT progression from the hippocampal formation and underscore a need for additional clinical-radiologic-pathologic correlation studies.

Atrophy and structural covariance of the cholinergic basal forebrain in primary progressive aphasia

Primary progressive aphasia (PPA) is characterized by profound destruction of cortical language areas. Anatomical studies suggest an involvement of cholinergic basal forebrain (BF) in PPA syndromes, particularly in the area of the nucleus subputaminalis (NSP). Here we aimed to determine the pattern of atrophy and structural covariance as a proxy of structural connectivity of BF nuclei in PPA variants. We studied 62 prospectively recruited cases with the clinical diagnosis of PPA and 31 healthy older control participants from the cohort study of the German consortium for frontotemporal lobar degeneration (FTLD). We determined cortical and BF atrophy based on high-resolution magnetic resonance imaging (MRI) scans. Patterns of structural covariance of BF with cortical regions were determined using voxel-based partial least square analysis. We found significant atrophy of total BF and BF subregions in PPA patients compared with controls [F(1, 82) = 20.2, p < .001]. Atrophy was most pronounced in the NSP and the posterior BF, and most severe in the semantic variant and the nonfluent variant of PPA. Structural covariance analysis in healthy controls revealed associations of the BF nuclei, particularly the NSP, with left hemispheric predominant prefrontal, lateral temporal, and parietal cortical areas, including Broca's speech area (p < .001, permutation test). In contrast, the PPA patients showed preserved structural covariance of the BF nuclei mostly with right but not with left hemispheric cortical areas (p < .001, permutation test). Our findings agree with the neuroanatomically proposed involvement of the cholinergic BF, particularly the NSP, in PPA syndromes. We found a shift from a structural covariance of the BF with left hemispheric cortical areas in healthy aging towards right hemispheric cortical areas in PPA, possibly reflecting a consequence of the profound and early destruction of cortical language areas in PPA.

Association Between Smoking and Cholinergic Basal Forebrain Volume in Healthy Aging and Prodromal and Dementia Stages of Alzheimer's Disease.

Smoking has been found associated with decreased cerebral volumes in healthy adults and in various neuropsychiatric disorders. We aimed to determine whether chronic nicotine exposure through smoking is associated with reduced volume of cortically projecting cholinergic basal forebrain nuclei in healthy aging, mild cognitive impairment (MCI), and dementia stages of Alzheimer's disease (AD). We retrieved cross-sectional data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database including 179 cognitively normal elderly subjects, 270 subjects with early stage MCI, 136 subjects in later, more advanced, stage of MCI, and 86 subjects in dementia stages of AD. We determined the association between past or current smoking versus lifetime non-smoker status on the volumes of the basal forebrain determined from volumetric MRI scans. Hippocampus volume was used as a control region. Significant effects were controlled for mediating or moderating effects of respiratory and cardiovascular morbidity. In cognitively healthy individuals and early MCI, past or current smoking was significantly associated with smaller basal forebrain volume. This effect was independent from age, sex, or cardiovascular or respiratory morbidity. Hippocampus volume was not associated with smoking. In late MCI and AD dementia, smoking was not associated with basal forebrain or hippocampus volumes. Our findings suggest that chronic nicotine exposure through smoking may lead to atrophy of cholinergic input areas of the basal forebrain. This effect may account for an increased risk of AD dementia onset with smoking by exhausting the cholinergic system reserve capacity.

Hippocampal Sclerosis but Not Normal Aging or Alzheimer Disease Is Associated With TDP-43 Pathology in the Basal Forebrain of Aged Persons.

Transactivating responsive sequence (TAR) DNA-binding protein 43-kDa (TDP-43) pathology has been described in various brain diseases, but the full anatomical distribution and clinical and biological implications of that pathology are incompletely characterized. Here, we describe TDP-43 neuropathology in the basal forebrain, hypothalamus, and adjacent nuclei in 98 individuals (mean age, 86 years; median final mini-mental state examination score, 27). On examination blinded to clinical and pathologic diagnoses, we identified TDP-43 pathology that most frequently involved the ventromedial basal forebrain in 19 individuals (19.4%). As expected, many of these brains had comorbid pathologies including those of Alzheimer disease (AD), Lewy body disease (LBD), and/or hippocampal sclerosis of aging (HS-Aging). The basal forebrain TDP-43 pathology was strongly associated with comorbid HS-Aging (odds ratio = 6.8, p = 0.001), whereas there was no significant association between basal forebrain TDP-43 pathology and either AD or LBD neuropathology. In this sample, there were some cases with apparent preclinical TDP-43 pathology in the basal forebrain that may indicate that this is an early affected area in HS-Aging. We conclude that TDP-43 pathology in the basal forebrain is strongly associated with HS-Aging. These results raise questions about a specific pathogenetic relationship between basal forebrain TDP-43 and non-HS-Aging comorbid diseases (AD and LBD).

Atrophy of the cholinergic basal forebrain in dementia with Lewy bodies and Alzheimer's disease dementia.

Similar to Alzheimer's disease (AD), dementia with Lewy bodies (DLB) is characterized by a profound degeneration of cortically-projecting cholinergic neurons of the basal forebrain (BF) and associated depletion of cortical cholinergic activity. We aimed to investigate subregional atrophy of the BF in DLB in vivo and compare it to the pattern of BF atrophy in AD. Structural MRI scans of 11 patients with DLB, 11 patients with Alzheimer's disease, and 22 healthy controls were analysed using a recently developed technique for automated BF morphometry based on high-dimensional image warping and cytoarchitectonic maps of BF cholinergic nuclei. For comparison, hippocampus volume was assessed within the same morphometric framework using recently published consensus criteria for the definition of hippocampus outlines on MRI. The DLB group demonstrated pronounced and subregion-specific atrophy of the BF which was comparable to BF atrophy in AD: volume of the nucleus basalis Meynert was significantly reduced by 20-25%, whereas rostral BF nuclei were only marginally affected. By contrast, hippocampus volume was markedly less affected in DLB compared to AD. Global cognition as determined by MMSE score was associated with BF volume in AD, but not in DLB, whereas visuoperceptual function as determined by the trail making test was associated with BF volume in DLB, but not in AD. DLB may be characterized by a more selective degeneration of the cholinergic BF compared to AD, which may be related to the differential cognitive profiles in both conditions.

Non-noxious skin stimulation activates the nucleus basalis of Meynert and promotes NGF secretion in the parietal cortex via nicotinic ACh receptors.

The effects of non-noxious skin stimulation on nerve growth factor (NGF) secretion in the parietal cortex were examined in anesthetized rats. Innocuous skin stimulation was delivered to the left hindlimb with a soft-hair brush. Extracellular NGF in the right parietal cortex was collected by microdialysis methods using a protein-permeable probe and was measured using an enzyme-linked immune-sorbent assay. Brushing produced a significant increase in extracellular NGF levels. This NGF response was not observed in rats pretreated with a nicotinic ACh receptor (nAChR) antagonist mecamylamine. We further examined whether brushing could activate the basal forebrain nucleus (nucleus basalis of Meynert, NBM), which is the main source of cholinergic fibers in the cerebral cortex, by means of functional MRI. The blood oxygen level-dependent signal in the right NBM was significantly higher during brushing compared to baseline. The results suggest that non-noxious skin stimulation activates NBM and promotes NGF secretion in the parietal cortex via nAChRs.

Cholinergic Contributions to Supramodal Attentional Processes in Rats

Cholinergic neurotransmission has been shown to play an important role in modulating attentional processing of visual stimuli. However, it is not yet clear whether the neurochemical acetylcholine (ACh) is necessary exclusively for visual attention, or if it also contributes to attentional functions through some modality-independent (supramodal) mechanism. To answer this question, we examined the effects of reduced cortical cholinergic afferentation on both a traditional visual and a novel olfactory five-choice serial reaction time task (5-CSRTT), the benchmark rodent test of sustained attention in rats. Following the successful acquisition of both modalities of the task, the rats underwent either a cholinergic immunotoxic- or sham-lesion surgery of the nucleus basalis magnocellularis (NBM), the basal forebrain nuclei that provide the majority of neocortical ACh. Reduced cholinergic afferentation to the neocortex was induced by bilaterally infusing the cholinergic immunotoxin 192 IgG-saporin into the NBM. After surgery, ACh-NBM-lesioned rats performed comparably to sham-lesioned rats under the conditions of low attentional demand, but displayed behavioral decrements relative to the sham-lesioned rats when the attentional demands of the task were increased. Moreover, this decrement in attentional functioning correlated significantly with the number of choline acetyltransferase-immunoreactive cells in the NBM. Importantly, the nature of this behavioral decrement was identical in the visual and olfactory 5-CSRTTs. Together, these data suggest the presence of a supramodal attentional modulatory cortical network whose activity is dependent on cholinergic innervation from the NBM.

Basal forebrain atrophy and cortical amyloid deposition in nondemented elderly subjects

BackgroundBoth neurodegeneration of the cholinergic basal forebrain (BF) and deposition of β-amyloid are early events in the course of Alzheimer's disease (AD). Associations between increased amyloid pathology and cholinergic atrophy have been described in autopsy studies. MethodsWe used structural MRI and AV45-PET amyloid imaging data of 225 cognitively normal or mildly impaired elderly subjects from the Alzheimer's Disease Neuroimaging Initiative to assess in vivo associations between BF atrophy and cortical amyloid deposition. Associations were examined using region-of-interest (ROI) and voxel-based approaches with reference to cytoarchitectonic mappings of the cholinergic BF nuclei. ResultsROI- and voxel-based approaches yielded complementary evidence for an association between BF volume and cortical amyloid deposition in presymptomatic and predementia stages of AD, irrespective of age, gender, and APOE genotype. ConclusionsThe observed correlations between BF atrophy and cortical amyloid load likely reflect associations between cholinergic degeneration and amyloid pathology as reported in neuropathologic examination studies.

Principles, Anatomical Origin and Applications of Brainwaves: A Review, Our Experience and Hypothesis Related to Microgravity and the Question on Soul

Brainwave is a kind of traceable neurophysiological energy in a living brain. Invisible to human eyes, it is only detectable using electroencephalography (EEG), electrocorticography (ECoG) and magnetoencephalography (MEG). The waves or oscillations or rhythms are produced mainly by the oscillatory networks of the brain. Three main oscillatory networks are thalamocortical, extrathalamic-cortical and cortical-cortical networks. Greater limbic system (reticular system, hypothalamus, thalamus, basal forebrain nuclei, limbic system) has a great influence on these oscillatory networks. This system which is in microgravity position lies deep inside and surrounded by the ventricles of the brain. It receives all information from inside and outside of our body and then projects to all areas of the brain (from all to one and from one to all—nearly similar concept to “from God back to God”). Therefore, the greater limbic system could be regarded as “a core of the neuroaxis” which lies in microgravity compartment and in microgravity position (“T”-shape or curving shape; whilst gravity position is “I”-shape or vertical shape). By knowing the origin of the brainwaves and methods to detect them, one may study seizure networks, normal and abnormal brain networks and arguably, even to explore the relationship between the “invisibles”: “invisible” brainwaves and “invisible” soul.

Modern pharmacological models of Alzheimer’s disease

In vivo experimental models of Alzheimer’s disease are powerful tools for studying the mechanisms of pathogenesis and the search for new therapeutic agents. Pharmacological models, based on the injection of neurotoxins (beta-amyloid fragments, cholinotoxins, ibotenic acid) into the brain allow simulation the cognitive impairment typical for Alzheimer’s disease, and yield evaluation the impact of drugs on various indicators (biochemical, genetic, electrophysiological). The most validity was showed for the in vivo model of neurotoxic beta-amyloid fragments injection into basal forebrain nuclei.

Unusual neural connection between injured cingulum and brainstem in a patient with subarachnoid hemorrhage.

Unusual neural connection between injured cingulum and brainstem in a patient with subarachnoid hemorrhage.

The role of serotonin 5-HT7 receptor in regulating sleep and wakefulness

Different approaches have been followed to characterize the role of 5-hydroxytryptamine (serotonin) receptor 7 (5-HT7) in the regulation of sleep-wake behavior: (1) 5-HT7 receptor knockout mice spend less time in rapid eye movement sleep than their wild-type counterparts, mainly during the light period. In contrast, there is no difference between the genotypes in time spent in wakefulness or slow-wave sleep. (2) Systemic administration of the selective 5-HT7 receptor agonist LP-211 significantly increased wakefulness (time spent awake) and reduced rapid eye movement sleep in the rat. Direct infusion of LP-211 into the dorsal raphe nucleus, locus coeruleus nucleus, basal forebrain (horizontal limb of the diagonal band of Broca), or laterodorsal tegmental nucleus also produced a decrease in rapid eye movement sleep. Additionally, microinjection of the 5-HT7 receptor agonist into the basal forebrain augmented the time animals remained awake. Local injection of the 5-HT7 receptor agonist LP-44 into the dorsal raphe nucleus also suppressed rapid eye movement sleep in the rat. (3) A similar reduction of rapid eye movement sleep has been described following intraperitoneal injection of the selective 5-HT7 receptor antagonists SB-269970 and SB-656104 in the rat and oral administration of the 5-HT7 receptor antagonist NJ-18038683 to rat and man. Local microinjection of SB-269970 into the dorsal raphe nucleus and basal forebrain also induced a decrease in rapid eye movement sleep in the rat. This tends to suggest that the on-off (activation/blockade), two-state ligand-receptor interaction model is not tenable for the 5-HT7 receptor.

Brain atrophy in primary progressive aphasia involves the cholinergic basal forebrain and Ayala's nucleus

Primary progressive aphasia (PPA) is characterized by left hemispheric frontotemporal cortical atrophy. Evidence from anatomical studies suggests that the nucleus subputaminalis (NSP), a subnucleus of the cholinergic basal forebrain, may be involved in the pathological process of PPA. Therefore, we studied the pattern of cortical and basal forebrain atrophy in 10 patients with a clinical diagnosis of PPA and 18 healthy age-matched controls using high-resolution magnetic resonance imaging (MRI). We determined the cholinergic basal forebrain nuclei according to Mesulam's nomenclature and the NSP in MRI reference space based on histological sections and the MRI scan of a post-mortem brain in cranio. Using voxel-based analysis, we found left hemispheric cortical atrophy in PPA patients compared with controls, including prefrontal, lateral temporal and medial temporal lobe areas. We detected cholinergic basal forebrain atrophy in left predominant localizations of Ch4p, Ch4am, Ch4al, Ch3 and NSP. For the first time, we have described the pattern of basal forebrain atrophy in PPA and confirmed the involvement of NSP that had been predicted based on theoretical considerations. Our findings may enhance understanding of the role of cholinergic degeneration for the regional specificity of the cortical destruction leading to the syndrome of PPA.