Ngfr+ cholinergic projection from SI/nBM to mPFC selectively regulates temporal order recognition memory.

Acetylcholine regulates various cognitive functions through broad cholinergic innervation. However, specific cholinergic subpopulations, circuits and molecular mechanisms underlying recognition memory remain largely unknown. Here we show that Ngfr+ cholinergic neurons in the substantia innominate (SI)/nucleus basalis of Meynert (nBM)-medial prefrontal cortex (mPFC) circuit selectively underlies recency judgements. Loss of nerve growth factor receptor (Ngfr-/- mice) reduced the excitability of cholinergic neurons in the SI/nBM-mPFC circuit but not in the medial septum (MS)-hippocampus pathway, and impaired temporal order memory but not novel object and object location recognition. Expression of Ngfr in Ngfr-/- SI/nBM restored defected temporal order memory. Fiber photometry revealed that acetylcholine release in mPFC not only predicted object encounters but also mediated recency judgments of objects, and such acetylcholine release was absent in Ngfr-/- mPFC. Chemogenetic and optogenetic inhibition of SI/nBM projection to mPFC in ChAT-Cre mice diminished mPFC acetylcholine release and deteriorated temporal order recognition. Impaired cholinergic activity led to a depolarizing shift of GABAergic inputs to mPFC pyramidal neurons, due to disturbed KCC2-mediated chloride gradients. Finally, potentiation of acetylcholine signaling upregulated KCC2 levels, restored GABAergic driving force and rescued temporal order recognition deficits in Ngfr-/- mice. Thus, NGFR-dependent SI/nBM-mPFC cholinergic circuit underlies temporal order recognition memory.

Frontoparietal-Striatal Network and Nucleus Basalis Modulation in Patients With Parkinson Disease and Gait Disturbance.

BACKGROUND AND OBJECTIVES: Neural computations underlying gait disorders in Parkinson disease (PD) are multifactorial and involve impaired expression of stereotactic locomotor patterns and compensatory recruitment of cognitive functions. This study aimed to clarify the network mechanisms of cognitive contribution to gait control and its breakdown in patients with PD. METHODS: Patients with PD were instructed to walk at a comfortable pace on a mat with pressure sensors. The characterization of cognitive-motor interplay was enhanced by using a gait with a secondary cognitive task (dual-task condition) and a gait without additional tasks (single-task condition). Participants were scanned using 3-T MRI and 123I-ioflupane SPECT. RESULTS: According to gait characteristics, cluster analysis assisted by a nonlinear dimensionality reduction technique, t-distributed stochastic neighbor embedding, categorized 56 patients with PD into 3 subpopulations. The preserved gait (PG) subgroup (n = 23) showed preserved speed and variability during gait, both with and without additional cognitive load. Compared with the PG subgroup, the mildly impaired gait (MIG) subgroup (n = 16) demonstrated deteriorated gait variability with additional cognitive load and impaired speed and gait variability without additional cognitive load. The severely impaired gait (SIG) subgroup (n = 17) revealed the slowest speed and highest gait variability. In addition, group differences were found in attention/working memory and executive function domains, with the lowest performance in the SIG subgroup than in the PG and MIG subgroups. Using resting-state functional MRI, the SIG subgroup demonstrated lower functional connectivity of the left and right frontoparietal network (FPN) with the caudate than the PG subgroup did (left FPN, d = 1.21, p < 0.001; right FPN, d = 1.05, p = 0.004). Cortical thickness in the FPN and 123I-ioflupane uptake in the striatum did not differ among the 3 subgroups. By contrast, the severity of Ch4 density loss was significantly correlated with the level of functional connectivity degradation of the FPN and caudate (left FPN-caudate, r = 0.27, p = 0.04). DISCUSSION: These findings suggest that the functional connectivity of the FPN with the caudate, as mediated by the cholinergic Ch4 projection system, underlies the compensatory recruitment of attention and executive function for damaged automaticity in gait in patients with PD.

Cholinergic nucleus degeneration and its association with gait impairment in Parkinson's disease.

BACKGROUND: The contribution of cholinergic degeneration to gait disturbance in Parkinson's disease (PD) is increasingly recognized, yet its relationship with dopaminergic-resistant gait parameters has been poorly investigated. We investigated the association between comprehensive gait parameters and cholinergic nucleus degeneration in PD. METHODS: This cross-sectional study enrolled 84 PD patients and 69 controls. All subjects underwent brain structural magnetic resonance imaging to assess the gray matter density (GMD) and volume (GMV) of the cholinergic nuclei (Ch123/Ch4). Gait parameters under single-task (ST) and dual-task (DT) walking tests were acquired using sensor wearables in PD group. We compared cholinergic nucleus morphology and gait performance between groups and examined their association. RESULTS: PD patients exhibited significantly decreased GMD and GMV of the left Ch4 compared to controls after reaching HY stage > 2. Significant correlations were observed between multiple gait parameters and bilateral Ch123/Ch4. After multiple testing correction, the Ch123/Ch4 degeneration was significantly associated with shorter stride length, lower gait velocity, longer stance phase, smaller ankle toe-off and heel-strike angles under both ST and DT condition. For PD patients with HY stage 1-2, there were no significant degeneration of Ch123/4, and only right side Ch123/Ch4 were corrected with the gait parameters. However, as the disease progressed to HY stage > 2, bilateral Ch123/Ch4 nuclei showed correlations with gait performance, with more extensive significant correlations were observed in the right side. CONCLUSIONS: Our study demonstrated the progressive association between cholinergic nuclei degeneration and gait impairment across different stages of PD, and highlighting the potential lateralization of the cholinergic nuclei's impact on gait impairment. These findings offer insights for the design and implementation of future clinical trials investigating cholinergic treatments as a promising approach to address gait impairments in PD.

Dysregulation of neurotrophin expression in prefrontal cortex and nucleus basalis magnocellularis during and after adolescent intermittent ethanol exposure.

A preclinical model of human adolescent binge drinking, adolescent intermittent ethanol exposure (AIE) recreates the heavy binge withdrawal consummatory patterns of adolescents and has identified the loss of basal forebrain cholinergic neurons as a pathological hallmark of this model. Cholinergic neurons of the nucleus basalis magnocellularis (NbM) that innervate the prefrontal cortex (PFC) are particularly vulnerable to alcohol related neurodegeneration. Target derived neurotrophins (nerve growth factor [NGF] and brain-derived neurotrophic factor [BDNF]) regulate cholinergic phenotype expression and survival. Evidence from other disease models implicates the role of immature neurotrophin, or proneurotrophins, activity at neurotrophic receptors in promoting cholinergic degeneration; however, it has yet to be explored in adolescent binge drinking. We sought to characterize the pro- and mature neurotrophin expression, alongside their cognate receptors and cholinergic markers in an AIE model. Male and female Sprague Dawley rats underwent 5 g/kg 20% EtOH or water gavage on two-day-on, two-day-off cycles from post-natal day 25-57. Rats were sacrificed 2 h, 24 h, or 3 weeks following the last gavage, and tissue were collected for protein measurement. Western blot analyses revealed that ethanol intoxication reduced the expression of BDNF and vesicular acetylcholine transporter (vAChT) in the PFC, while NGF was lower in the NbM of AIE treated animals. During acute alcohol withdrawal, proNGF in the PFC was increased while proBDNF decreased, and in the NbM proBDNF increased while NGF decreased. During AIE abstinence, the expression of neurotrophins, their receptors, and vAChT did not differ from controls in the PFC. In contrast, in the NbM the expression of both NGF and choline acetyltransferase (ChAT) were reduced long-term following AIE. Taken together these findings suggest that AIE alters the expression of proneurotrophins and neurotrophins during intoxication and withdrawal that favor prodegenerative mechanisms by increasing the expression of proNGF and proBDNF, while also reducing NGF and BDNF.

Causal evidence for cholinergic stabilization of attractor landscape dynamics.

There is substantial evidence that neuromodulatory systems critically influence brain state dynamics; however, most work has been purely descriptive. Here, we quantify, using data combining local inactivation of the basal forebrain with simultaneous measurement of resting-state fMRI activity in the macaque, the causal role of long-range cholinergic input to the stabilization of brain states in the cerebral cortex. Local inactivation of the nucleus basalis of Meynert (nbM) leads to a decrease in the energy barriers required for an fMRI state transition in cortical ongoing activity. Moreover, the inactivation of particular nbM sub-regions predominantly affects information transfer in cortical regions known to receive direct anatomical projections. We demonstrate these results in a simple neurodynamical model of cholinergic impact on neuronal firing rates and slow hyperpolarizing adaptation currents. We conclude that the cholinergic system plays a critical role in stabilizing macroscale brain state dynamics.

Neural processing in the primary auditory cortex following cholinergic lesions of the basal forebrain in ferrets.

Cortical acetylcholine (ACh) release has been linked to various cognitive functions, including perceptual learning. We have previously shown that cortical cholinergic innervation is necessary for accurate sound localization in ferrets, as well as for their ability to adapt with training to altered spatial cues. To explore whether these behavioral deficits are associated with changes in the response properties of cortical neurons, we recorded neural activity in the primary auditory cortex (A1) of anesthetized ferrets in which cholinergic inputs had been reduced by making bilateral injections of the immunotoxin ME20.4-SAP in the nucleus basalis (NB) prior to training the animals. The pattern of spontaneous activity of A1 units recorded in the ferrets with cholinergic lesions (NB ACh-) was similar to that in controls, although the proportion of burst-type units was significantly lower. Depletion of ACh also resulted in more synchronous activity in A1. No changes in thresholds, frequency tuning or in the distribution of characteristic frequencies were found in these animals. When tested with normal acoustic inputs, the spatial sensitivity of A1 neurons in the NB ACh- ferrets and the distribution of their preferred interaural level differences also closely resembled those found in control animals, indicating that these properties had not been altered by sound localization training with one ear occluded. Simulating the animals' previous experience with a virtual earplug in one ear reduced the contralateral preference of A1 units in both groups, but caused azimuth sensitivity to change in slightly different ways, which may reflect the modest adaptation observed in the NB ACh- group. These results show that while ACh is required for behavioral adaptation to altered spatial cues, it is not required for maintenance of the spectral and spatial response properties of A1 neurons.

Basal Forebrain Cholinergic Neurons Have Specific Characteristics during the Perinatal Period.

Cholinergic neurons of the basal forebrain represent the main source of cholinergic innervation of large parts of the neocortex and are involved in adults in the modulation of attention, memory, and arousal. During the first postnatal days, they play a crucial role in the development of cortical neurons and cortical cytoarchitecture. However, their characteristics, during this period have not been studied. To understand how they can fulfill this role, we investigated the morphological and electrophysiological maturation of cholinergic neurons of the substantia innominata-nucleus basalis of Meynert (SI/NBM) complex in the perinatal period in mice. We show that cholinergic neurons, whether or not they express gamma-aminobutyric acid (GABA) as a cotransmitter, are already functional at Embryonic Day 18. Until the end of the first postnatal week, they constitute a single population of neurons with a well developed dendritic tree, a spontaneous activity including bursting periods, and a short-latency response to depolarizations (early-firing). They are excited by both their GABAergic and glutamatergic afferents. During the second postnatal week, a second, less excitable, neuronal population emerges, with a longer delay response to depolarizations (late-firing), together with the hyperpolarizing action of GABAA receptor-mediated currents. This classification into early-firing (40%) and late-firing (60%) neurons is again independent of the coexpression of GABAergic markers. These results strongly suggest that during the first postnatal week, the specific properties of developing SI/NBM cholinergic neurons allow them to spontaneously release acetylcholine (ACh), or ACh and GABA, into the developing cortex.

Combined in vivo MRI assessment of locus coeruleus and nucleus basalis of Meynert integrity in amnestic Alzheimer's disease, suspected-LATE and frontotemporal dementia.

BACKGROUND: The locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer's disease (AD). Little is known about LC and NBM alteration in limbic-predominant age-related TDP-43 encephalopathy (LATE) and frontotemporal dementia (FTD). The aim of the present study is to investigate in vivo LC and NBM integrity in patients with suspected-LATE, early-amnestic AD and FTD in comparison with controls. METHODS: Seventy-two participants (23 early amnestic-AD patients, 17 suspected-LATE, 17 FTD patients, defined by a clinical-biological diagnosis reinforced by amyloid and tau PET imaging, and 15 controls) underwent neuropsychological assessment and 3T brain MRI. We analyzed the locus coeruleus signal intensity (LC-I) and the NBM volume as well as their relation with cognition and with medial temporal/cortical atrophy. RESULTS: We found significantly lower LC-I and NBM volume in amnestic-AD and suspected-LATE in comparison with controls. In FTD, we also observed lower NBM volume but a slightly less marked alteration of the LC-I, independently of the temporal or frontal phenotype. NBM volume was correlated with the global cognitive efficiency in AD patients. Strong correlations were found between NBM volume and that of medial temporal structures, particularly the amygdala in both AD and FTD patients. CONCLUSIONS: The alteration of LC and NBM in amnestic-AD, presumed-LATE and FTD suggests a common vulnerability of these structures to different proteinopathies. Targeting the noradrenergic and cholinergic systems could be effective therapeutic strategies in LATE and FTD.

Cholinergic Neuromodulation of Prefrontal Attractor Dynamics Controls Performance in Spatial Working Memory.

The behavioral and neural effects of the endogenous release of acetylcholine following stimulation of the nucleus basalis (NB) of Meynert have been recently examined in two male monkeys (Qi et al., 2021). Counterintuitively, NB stimulation enhanced behavioral performance while broadening neural tuning in the prefrontal cortex (PFC). The mechanism by which a weaker mnemonic neural code could lead to better performance remains unclear. Here, we show that increased neural excitability in a simple continuous bump attractor model can induce broader neural tuning and decrease bump diffusion, provided neural rates are saturated. Increased memory precision in the model overrides memory accuracy, improving overall task performance. Moreover, we show that bump attractor dynamics can account for the nonuniform impact of neuromodulation on distractibility, depending on distractor distance from the target. Finally, we delve into the conditions under which bump attractor tuning and diffusion balance in biologically plausible heterogeneous network models. In these discrete bump attractor networks, we show that reducing spatial correlations or enhancing excitatory transmission can improve memory precision. Altogether, we provide a mechanistic understanding of how cholinergic neuromodulation controls spatial working memory through perturbed attractor dynamics in the PFC.

The following article for this Special Issue was previously published and can be found in its respective issue online: "Whole-brain neural connectivity to cholinergic neurons in the nucleus basalis of Meynert".

Whole-brain neural connectivity to cholinergic neurons in the nucleus basalis of Meynert (Published in JNC 166.2 issue) https://onlinelibrary.wiley.com/doi/10.1111/jnc.15873.

Degeneration in Nucleus basalis of Meynert signals earliest stage of Alzheimer's disease progression.

Nucleus Basalis of Meynert (NbM), a crucial source of cholinergic projection to the entorhinal cortex (EC) and hippocampus (HC), has shown sensitivity to neurofibrillary degeneration in the early stages of Alzheimer's Disease. Using deformation-based morphometry (DBM) on up-sampled MRI scans from 1447 Alzheimer's Disease Neuroimaging Initiative participants, we aimed to quantify NbM degeneration along the disease trajectory. Results from cross-sectional analysis revealed significant differences of NbM volume between cognitively normal and early mild cognitive impairment cohorts, confirming recent studies suggesting that NbM degeneration happens before degeneration in the EC or HC. Longitudinal linear mixed-effect models were then used to compare trajectories of volume change after realigning all participants into a common timeline based on their cognitive decline. Results indicated the earliest deviations in NbM volumes from the cognitively healthy trajectory, challenging the prevailing idea that Alzheimer's originates in the EC. Converging evidence from cross-sectional and longitudinal models suggest that the NbM may be a focal target of early AD progression, which is often obscured by normal age-related decline.

The following article for this Special Issue was previously published and can be found in its respective issue online: "Long-term nucleus basalis cholinergic depletion induces attentional deficits and impacts cortical neurons and BDNF levels without affecting the NGF synthesis".

Long-term nucleus basalis cholinergic depletion induces attentional deficits and impacts cortical neurons and BDNF levels without affecting the NGF synthesis (Published in JNC 163.2 issue) https://onlinelibrary.wiley.com/doi/10.1111/jnc.15683.

Abnormally decreased functional connectivity of the right nucleus basalis of Meynert in Alzheimer's disease patients with depression symptoms.

Dysfunction of the basal forebrain is the main pathological feature in patients with Alzheimer's disease (AD). The aim of this study was to explore whether depressive symptoms cause changes in the functional network of the basal forebrain in AD patients. We collected MRI data from depressed AD patients (n = 24), nondepressed AD patients (n = 14) and healthy controls (n = 20). Resting-state functional magnetic resonance imaging data and functional connectivity analysis were used to study the characteristics of the basal forebrain functional network of the three groups of participants. The functional connectivity differences among the three groups were compared using ANCOVA and post hoc analyses. Compared to healthy controls, depressed AD patients showed reduced functional connectivity between the right nucleus basalis of Meynert and the left supramarginal gyrus and the supplementary motor area. These results increase our understanding of the neural mechanism of depressive symptoms in AD patients.

Free-Water Imaging of the Nucleus Basalis of Meynert in Patients With Idiopathic REM Sleep Behavior Disorder and Parkinson Disease.

BACKGROUND AND OBJECTIVES: Cognitive impairments are common in idiopathic REM sleep behavior disorder (iRBD), in which the cholinergic degeneration of nucleus basalis of Meynert (NBM) may play an important role. However, the progressive changes of NBM, the relationship between progressive NBM degeneration and progression of cognitive impairments, and whether degeneration of the NBM can predict cognitive decline in patients with iRBD remain unclear. This study aimed to investigate the cross-sectional and longitudinal microstructural alterations in the NBM of patients with iRBD using free-water imaging and whether free water in the NBM is related to cognitive, mood, and autonomic function. METHODS: We compared the baseline free-water values in the NBM between 59 healthy controls (HCs), 57 patients with iRBD, 57 patients with Parkinson disease (PD) with normal cognition (PD-NC), and 64 patients with PD with cognitive impairment (PD-CI). Thirty patients with iRBD and 40 HCs had one longitudinal data. In patients with iRBD, we explored the associations between baseline and longitudinal changes of free-water values in the NBM and clinical characteristics and whether baseline free-water values in the NBM could predict cognitive decline. RESULTS: IRBD, PD-NC, and PD-CI groups had significantly increased free-water values in the NBM compared with HCs, whereas PD-CI had higher free-water values compared with iRBD and PD-NC. In patients with iRBD, free-water values in the NBM were progressively elevated over follow-up and correlated with the progression of cognitive impairment and depression. Free-water values in the NBM could predict cognitive decline in the iRBD group. Furthermore, we found that patients with iRBD with cognitive impairment had higher relative change of free-water value in the NBM compared with patients with iRBD with normal cognition over follow-up. DISCUSSION: This study proves that free-water values in the NBM are elevated cross-sectionally and longitudinally and are associated with the progression of cognitive impairment and depression in patients with iRBD. Moreover, the free-water value in the NBM can predict cognitive decline in patients with iRBD. Whether free-water imaging of the NBM has the potential to be a marker for monitoring progressive cognitive impairment and predicting the conversion to dementia in synucleinopathies needs further investigation.

Perioperative Levels of IL8 and IL18, but not IL6, are Associated with Nucleus Basalis Magnocellularis Atrophy Three Months after Surgery.

Past studies have observed that brain atrophy may accelerate after surgical procedures. Furthermore, an association of systemic inflammation with neurodegeneration has been described. We hypothesize that postoperative interleukin (IL) levels in circulation as well as the perioperative change in interleukin levels are associated with increased postoperative atrophy in the Nucleus basalis magnocellularis (of Meynert, NBM) which is the major source of cortical acetylcholine. We analyzed data from the BioCog cohort which included patients ≥ 65 years presenting for elective major surgery (≥ 60min). Blood samples were taken before surgery and on the first postoperative day. Magnetic resonance imaging of the brain and neuropsychological assessments were conducted before surgery and after three months follow-up. We used linear regression analysis to determine the association of three interleukins (IL6, IL8 and IL18) with NBM atrophy (in % volume change from baseline before surgery to follow-up), as well as to examine the associations of NBM atrophy and volume with postoperative cognitive ability and perioperative cognitive change. Receiver-operating curves were used to determine the prognostic value of preoperative interleukin levels. For IL8 (N = 97) and IL18 (N = 217), but not IL6 (N = 240), we observed significant associations of higher postoperative IL levels at the first postoperative day with higher NBM atrophy at three months after surgery. Subsequent analyses suggested that in both IL8 and IL18, this association was driven by a more general association of chronically elevated IL levels and NBM atrophy, reflected by preoperative IL concentrations, rather than IL response to surgery, measured as the difference between pre- and postoperative IL concentrations. At follow-up, NBM volume was positively associated with the level of cognitive performance, but NBM atrophy was not significantly related to perioperative cognitive change. Prognostic value of preoperative IL concentrations for NBM atrophy was low. Our results suggest that an association of postoperative interleukin levels with NBM atrophy is driven by preoperatively elevated interleukins due to pre-existing inflammation, rather than perioperative change in interleukin levels in response to surgery and anesthesia. The BioCog study has been registered at clinicaltrials.gov on Oct 15, 2014 (NCT02265263).

Nucleus Basalis of Meynert Degeneration Predicts Cognitive Decline in Corticobasal Syndrome.

BACKGROUND: Cognitive changes are common in corticobasal syndrome (CBS) and significantly impact quality of life and caregiver burden. However, relatively few studies have investigated the neural substrates of cognitive changes in CBS, and reliable predictors of cognitive impairment are currently lacking. The nucleus basalis of Meynert (NbM), which serves as the primary source of cortical cholinergic innervation, has been functionally associated with cognition. This study aimed to explore whether patients with CBS exhibit reduced NbM volumes compared with healthy control participants and whether NbM degeneration can serve as a predictor of cognitive impairment in patients with CBS. METHODS: In this study, we investigated in vivo volumetric changes of the NbM in 38 patients with CBS and 84 healthy control participants. Next, we assessed whether gray matter degeneration of the NbM evaluated at baseline could predict cognitive impairment during a 12-month follow-up period in patients with CBS. All volumetric analyses were performed using 3T T1-weighted images obtained from the 4-Repeat Tauopathy Neuroimaging Initiative. RESULTS: Patients with CBS displayed significantly lower NbM volumes than control participants (p < .001). Structural damage of the NbM also predicted the development of cognitive impairment in patients with CBS as assessed by longitudinal measurements of the Clinical Dementia Rating Sum of Boxes (p < .001) and Mini-Mental State Examination (p = .035). CONCLUSIONS: Our findings suggest that NbM atrophy may represent a promising noninvasive in vivo marker of cognitive decline in CBS and provide new insights into the neural mechanisms that underlie cognitive impairment in CBS.

Effect of cerebral small vessel disease on the integrity of cholinergic system in mild cognitive impairment patients: a longitudinal study.

We aimed to investigate the effect of cerebral small vessel disease (SVD) on cholinergic system integrity in mild cognitive impairment (MCI) patients. Nucleus basalis of Meynert (NBM) volume and cholinergic pathways integrity was evaluated at baseline, 1-, 2-, and 4-year follow-ups in 40 cognitively unimpaired (CU) participants, 29 MCI patients without SVD, and 23 MCI patients with SVD. We compared cholinergic markers among three groups and examined their associations with SVD burden in MCI patients. We used linear mixed models to assess longitudinal changes in cholinergic markers over time among groups. Mediation analysis was employed to investigate the mediating role of cholinergic system degeneration between SVD and cognitive impairment. Increased mean diffusivity (MD) in medial and lateral pathways was observed in MCI patients with SVD compared to those without SVD and CU participants. Both MCI groups showed decreased NBM volume compared to CU participants, while there was no significant difference between the two MCI groups. Longitudinally, compared to CU participants, MCI patients with SVD displayed a more rapid change in MD in both pathways, but not in NBM volume. Furthermore, SVD burden was associated with cholinergic pathway disruption and its faster rate of change in MCI patients. However, mediation analyses showed that cholinergic pathways did not mediate significant indirect effects of SVD burden on cognitive impairment. Our findings suggest that SVD could accelerate the degeneration of cholinergic pathways in MCI patients. However, they do not provide evidence to support that SVD could contribute to cognitive impairment through cholinergic system injury.

Integrity of the nucleus basalis of meynert and self-reported cognitive dysfunction during wearing-off periods in parkinson's disease.

BACKGROUND: Cognition in Parkinson's Disease can be impacted by the wearing-off phenomenon which results from changes in dopaminergic tone throughout the day. Given the well-established role of the cholinergic basal forebrain in cognition, we hypothesized that the Nucleus Basalis of Meynert may support cognitive processes during wearing-off periods. Specifically, we evaluated whether worsening of cognitive symptoms during wearing-off is more likely to occur with structural degeneration of the Nucleus Basalis of Meynert. METHODS: Cognitive wearing-off was evaluated via the Movement Disorders Society Non-Motor Fluctuation Assessment Questionnaire in 33 Parkinson's Disease participants undergoing evaluation for deep brain stimulation. Pre-operative diffusion MRIs were used to measure brain diffusion metrics of the Nucleus Basalis of Meynert and control regions (caudate and putamen). RESULTS: The number of cognitive symptoms which worsened during OFF periods positively correlated with mean diffusivity (ρ = 0.561, p = 0.0007) and generalized fractional anisotropy (ρ=-0.447, p = 0.009) within the Nucleus Basalis of Meynert but not in the caudate or putamen. Meanwhile, stable cognitive symptoms, and ON-state cognitive performance as measured by the DRS-2 did not correlate with Nucleus Basalis of Meynert metrics. Correlations were corrected for age, sex, scanner type, disease duration, education and LEDD. CONCLUSIONS: Our study suggests that reduced structural integrity of the Nucleus Basalis of Meynert is associated with worsening of participant-reported cognitive deficits during OFF periods, but not overall cognitive functioning in the ON-state. These findings support the hypothesis that structural integrity of the cholinergic Nucleus Basalis of Meynert may provide resilience to cognitive worsening during dopamine-related wearing-off.

The anterior perforated substance (APS) revisited: Commented anatomical and imagenological views.

INTRODUCTION: Since 2002, when we published our article about the anterior perforated substance (APS), the knowledge about the region has grown enormously. OBJECTIVE: To make a better description of the anatomy of the zone with new dissection material added to the previous, to sustain the anatomical analysis of the MRI employing the SPACE sequence, interacting with our imagenology colleagues. Especially, we aim to identify and topographically localize by MRI the principal structures in APS-substantia innominata (SI). METHOD: The presentation follows various steps: (1) location and boundaries of the zone and its neighboring areas; (2) schematic description of the region with simple outlines; (3) cursory revision of the SI and its three systems; (4) serial images of the dissections of the zone and its vessels, illustrated and completed when possible, by MRI images of a voluntary experimental subject (ES). RESULTS: With this method, we could expose most of the structures of the region anatomically and imagenologically. DISCUSSION: The zone can be approached for dissection with magnification and the habitual microsurgical instruments with satisfactory results. We think that fibers in this region should be followed by other anatomical methods in addition to tractography. The principal structures of ventral striopallidum and extended amygdala (EA) can be identified with the SPACE sequence. The amygdala and the basal ganglion of Meynert (BGM) are easily confused because of their similar signal. Anatomical clues can orient the clinician about the different clusters of the BGM in MRI. CONCLUSIONS: The dissection requires a previous knowledge of the zone and a good amount of patience. The APS is a little space where concentrate essential vessels for the telencephalon, "en passage" or perforating, and neural structures of relevant functional import. From anatomical and MRI points of view, both neural and vascular structures follow a harmonious and topographically describable plan. The SPACE MRI sequence has proved to be a useful tool for identifying different structures in this area as the striatopallidal and EA. Anatomical knowledge of the fibers helps in the search of clusters of the basal ganglion.