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Deep brain stimulation of the nucleus basalis of Meynert in Alzheimer’s dementia
Abstract and Figures
Cholinergic neurons of the medial forebrain are considered important contributors to brain plasticity and neuromodulation. A reduction of cholinergic innervation can lead to pathophysiological changes of neurotransmission and is observed in Alzheimer's disease. Here we report on six patients with mild to moderate Alzheimer's disease (AD) treated with bilateral low-frequency deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM). During a four-week double-blind sham-controlled phase and a subsequent 11-month follow-up open label period, clinical outcome was assessed by neuropsychological examination using the Alzheimer's Disease Assessment Scale-cognitive subscale as the primary outcome measure. Electroencephalography and [(18)F]-fluoro-desoxyglucose positron emission tomography were, besides others, secondary endpoints. On the basis of stable or improved primary outcome parameters twelve months after surgery, four of the six patients were considered responders. No severe or non-transitional side effects related to the stimulation were observed. Taking into account all limitations of a pilot study, we conclude that DBS of the NBM is both technically feasible and well tolerated.Molecular Psychiatry advance online publication, 6 May 2014; doi:10.1038/mp.2014.32.
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... The promising experimental results in animals have led several investigators to explore the use of deep brain stimulation (DBS) of NBM for the treatment of dementia in clinical trials (Barnikol et al., 2010;Freund et al., 2009Freund et al., , 2009Gratwicke et al., 2018;Kuhn et al., 2015a;Lee et al., 2019;Nombela et al., 2019). Similar to the anti-amyloid antibody trials, these studies showed a slowing of the rate of progression compared with controls, but not a dramatic effect. ...
... Similar to the anti-amyloid antibody trials, these studies showed a slowing of the rate of progression compared with controls, but not a dramatic effect. In the Kuhn trial of NBM DBS in 6 AD patients, the group mean worsened by 3 points in the AD assessment score (ADAS-Cog) over the course of the year (Kuhn et al., 2015a) with tonic stimulation. This represents a preliminary improvement over the decrease of 4.5 seen in a large long-term study of progression of AD in patients treated with anti-dementia drugs (Scarmeas et al., 2007), the 4.2 point worsening seen in the Phase 1 fornix DBS trial, and the complete lack of benefit reported in the Phase 2b Fornix trial. ...
... There are important differences in the stimulation parameters used in all the prior animal work as compared to the human trials. The pilot trials of NBM stimulation in AD, PDD, and Lewy body dementia all employed a tonic stimulation (Freund et al., 2009;Gratwicke et al., 2018;Hardenacke et al., 2016;Kuhn et al., 2015aKuhn et al., , 2015aMaltête et al., 2020;Nombela et al., 2019). ...
Background
Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has been preliminarily investigated as a potential treatment for dementia. The degeneration of NBM cholinergic neurons is a pathological feature of many forms of dementia. Although stimulation of the NBM has been demonstrated to improve learning, the ideal parameters for NBM stimulation have not been elucidated. This study assesses the differential effects of varying stimulation patterns and duration on learning in a dementia rat model.
Methods
192-IgG-saporin (or vehicle) was injected into the NBM to produce dementia in rats. Next, all rats underwent unilateral implantation of a DBS electrode in the NBM. The experimental groups consisted of i-normal, ii-untreated demented, and iii-demented rats receiving NBM DBS. The stimulation paradigms included testing different modes (tonic and burst) and durations (1-hr, 5-hrs, and 24-hrs/day) over 10 daily sessions. Memory was assessed pre- and post-stimulation using two established learning paradigms: novel object recognition (NOR) and auditory operant chamber learning.
Results
Both normal and stimulated rats demonstrated improved performance in NOR and auditory learning as compared to the unstimulated demented group. The burst stimulation groups performed better than the tonic stimulated group. Increasing the daily stimulation duration to 24-hr did not further improve cognitive performance in an auditory recognition task and degraded the results on a NOR task as compared with 5-hr.
Conclusion
The present findings suggest that naturalistic NBM burst DBS may offer a potential effective therapy for treating dementia and suggests potential strategies for the reevaluation of current human NBM stimulation paradigms.
... A six-patient pilot trial of NBM-DBS at 20 Hz demonstrated safety and suggested a possible slowing of cognitive deterioration [64]. Anecdotally, it appeared that younger patients with milder disease were more likely to fare well with NBM-DBS, and therefore an additional two patients were treated, one of whom improved and the other remained stable at 2 years [65]. ...
... Anecdotally, it appeared that younger patients with milder disease were more likely to fare well with NBM-DBS, and therefore an additional two patients were treated, one of whom improved and the other remained stable at 2 years [65]. Brain metabolism increased with a similar pattern to what was seen with DBS-f, widespread with marked changes in the temporal lobe, suggesting an overall network-level effect [64]. ...
... In order to complete preoperative assessments, scans, and follow-up programming, it is necessary to treat patients with mild ADoften measured using the clinical dementia rating (CDR) of 0.5-1.0. Increasingly, there is a push toward incorporating AD biomarkers into inclusion criteria, such as requiring elevated CSF amyloid beta and CSF tau levels [64]. ...
Introduction:
Alzheimer's disease (AD) requires novel therapeutic approaches due to limited efficacy of current treatments.
Areas covered:
This article explores AD as a manifestation of neurocircuit dysfunction and evaluates deep brain stimulation (DBS) as a potential intervention. Focusing on fornix-targeted stimulation (DBS-f), the article summarizes safety, feasibility, and outcomes observed in phase 1/2 trials, highlighting findings such as cognitive improvement, increased metabolism, and hippocampal growth. Topics for further study include optimization of electrode placement, and the role of stimulation-induced autobiographical-recall. Nucleus basalis of Meynert (DBS-NBM) DBS is also discussed and compared with DBS-f. Challenges with both DBS-f and DBS-NBM are identified, emphasizing the need for further research on optimal stimulation parameters. The article also reviews alternative DBS targets, including medial temporal lobe structures and the ventral capsule/ventral striatum.
Expert opinion:
Looking ahead, a phase-3 DBS-f trial, and the prospect of closed-loop stimulation using EEG-derived biomarkers or hippocampal theta activity are highlighted. Recent FDA-approved therapies and other neuromodulation techniques like temporal interference and low-intensity ultrasound are considered. The article concludes by underscoring the importance of imaging-based diagnosis and staging to allow for circuit-targeted therapies, given the heterogeneity of AD and varied stages of neurocircuit dysfunction.
... If this region receives intermittent pulse train stimulation (e.g. for 20 s every minute) in young primates, humans, or mice, both acute and enduring executive function behavioral improvements can be measured [9][10][11] . However, continuous stimulation of the same region in animal models and humans with Alzheimer's, Lewy Body, or Parkinson's dementias is without enduring executive function improvement [12][13][14] . ...
Aging and some dementias feature parallel declines in the basal forebrain and cognitive capacity. Here, we tested the potential of one-hour daily intermittent basal forebrain stimulation to restore cognitive performance in aged male and female monkeys. Stimulation improved working memory in weeks, with performance remaining above study entry through the 15 month duration of the intervention. Effects persisted for at least 12 weeks after stimulation ceased. Parallel studies with a cholinesterase inhibitor did not produce lasting improvements in behavior. Brain stimulation led to immediate increases in tissue plasminogen activator levels in cerebrospinal fluid, and long-term increases in PET measures of glucose utilization. Intermittent basal forebrain stimulation thus triggers key components of neurotrophic signaling and leads to improved brain metabolism and better performance in working memory in senescent monkeys.
As a crucial component of the cerebral cholinergic system and the Papez circuit in the basal forebrain, dysfunction of the nucleus basalis of Meynert (NBM) is associated with various neurodegenerative disorders. However, no drugs, including existing cholinesterase inhibitors, have been shown to reverse this dysfunction. Due to advancements in neuromodulation technology, researchers are exploring the use of deep brain stimulation (DBS) therapy targeting the NBM (NBM-DBS) to treat mental and neurological disorders as well as the related mechanisms. Herein, we provided an update on the research progress on cognition-related neural network oscillations and complex anatomical and projective relationships between the NBM and other cognitive structures and circuits. Furthermore, we reviewed previous animal studies of NBM lesions, NBM-DBS models, and clinical case studies to summarize the important functions of the NBM in neuromodulation. In addition to elucidating the mechanism of the NBM neural network, future research should focus on to other types of neurons in the NBM, despite the fact that cholinergic neurons are still the key target for cell type-specific activation by DBS.
Neuromodulation (or neurostimulation) therapies are of particular importance in geriatric psychiatry, as older adults are often unable to tolerate adequate pharmacotherapy of depressive disorders. Among neurostimulation treatments, electroconvulsive therapy (ECT) remains the principal and usually most definitive alternative to medications. However, newer treatments such as repetitive transcranial magnetic stimulation (rTMS) and deep brain stimulation (DBS) are emerging. rTMS involves stimulation of the brain using a magnetic coil applied to the scalp surface and is administered without anesthetic or loss of consciousness. It is very well-tolerated by most patients and has a high degree of acceptability. Its efficacy for treating depressive disorders is more modest than that of ECT, and early evidence suggested that it was less effective in older patients. However, more recent rTMS treatment protocols involving longer treatment courses and higher intensity of treatment parameters are showing promise in treating depressive disorders in older adults, with response rates of 30–60% and remission rates of 10–30%. rTMS is a useful addition to the armamentarium of treatments in geriatric psychiatry; its place in treatment algorithms will evolve with emerging research and increased availability for routine clinical use. Its uses for other indications (e.g., for anxiety disorders), or to improve cognition in major neurocognitive disorder, are also being explored in current research. DBS via direct bilateral stimulation of Brodmann area Cg25 with implanted electrodes showed some promise in open trials, but subsequent randomized controlled trials failed to demonstrate its efficacy; it remains an investigational treatment.
Alzheimer`s disease (AD) is a progressive neurodegenerative disease which accounts for most of the cases of dementia. The progression of the disease cannot be fully controlled by current medications, nor do they produce adequate therapeutic results. Understanding the molecular and cellular alterations linked to AD pathogenesis has advanced significantly in recent decades. Amyloid-peptide-containing cerebral plaques and thread-like neuronal structures made of the microtubule-associated protein TAU are two pathogenic features of the condition. Therefore, inhibiting amyloid formation, aggregation, or subsequent neurotoxic events is the primary goal of therapeutic drug development. Here, some newer therapeutic modalities are described, including anti-amyloid therapy, anti-tau therapy, antineuroinflammatory therapy, neuroprotective agents including N -methyl- d -aspartate (NMDA) receptor modulators, and brain stimulation. Drug repositioning may speed up the development of pharmaceuticals, but non-pharmacological therapies, particularly repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), also have the potential to be used in therapeutic settings. Here we discussed current symptomatic therapy for AD as well as novel prospective disease-modifying medicines that are presently being investigated in phase I–III trials in this review. The study emphasizes how taking into account the intricate nature of AD pathogenesis and investigating drug repurposing strategies which can open the door to the creation of innovative AD therapies.
Huge investments continue to be made in treatment for Alzheimer’s disease (AD), with more than one hundred drugs currently in development. Pharmacological approaches and drug development, particularly those targeting amyloid-β, have dominated the therapeutic landscape. At the same time, there is also a growing interest in devices for treating AD. This review aimed to identify and describe devices under development for AD treatment. In this review, we queried the devices that are in development for the treatment of AD. PubMed was searched through the end of 2021 using the terms “device,” “therapeutics,” and “Alzheimer’s” for articles that report on devices to treat AD. Ten devices with 31 references were identified as actively being developed for the treatment of AD. Many of these devices are far along in development. Device-based therapies are often overlooked when evaluating treatment approaches to AD. However, many devices for treating AD are in development and some show promising results.
Deep brain stimulation has been in clinical use for 30 years and during that time it has changed markedly from a small-scale treatment employed by only a few highly specialized centers into a widespread keystone approach to the management of disorders such as Parkinson's disease. In the intervening decades, many of the broad principles of deep brain stimulation have remained unchanged, that of electrode insertion into stereotactically targeted brain nuclei, however the underlying technology and understanding around the approach have progressed markedly. Some of the most significant advances have taken place over the last decade with the advent of artificial intelligence, directional electrodes, stimulation/recording implantable pulse generators and the potential for remote programming among many other innovations. New therapeutic targets are being assessed for their potential benefits and a surge in the number of deep brain stimulation implantations has given birth to a flourishing scientific literature surrounding the pathophysiology of brain disorders such as Parkinson's disease. Here we outline the developments of the last decade and look to the future of deep brain stimulation to attempt to discern some of the most promising lines of inquiry in this fast-paced and rapidly evolving field.
EEG and single-unit techniques have been used to study the EEG correlates of cellular firing in the neocortex, n. reticularis (RT) and "specific" thalamic nuclei, and the cholinergic forebrain area (nucleus basalis, NB). Neuronal firing was related to the ongoing behavior of the rat. In addition, using a 16-channel neocortical recording/mapping system, we studied the effects of ibotenic acid lesion of NB, RT, and other thalamic nuclei on the patterns and spatial distribution of neocortical electrical activity. The majority of neurons in neocortex, NB, and RT increased their firing rates during walking, as compared to during immobility, with concurrent decrease of delta power in the neocortical EEG. During immobility, high-voltage spindles (HVS; greater than 1 mV) were occasionally recorded from the neocortex. Depth profiles of HVS and slow delta waves were different in the neocortex. Neocortical cells decreased their discharge frequency during the positive portion of delta waves recorded in layers V and VI. All cells in the neocortex and specific thalamic nuclei fired rhythmically and phase-locked to the spike component of HVS. RT neurons showed an opposite phase relationship and fired mainly during the wave component of HVS. Half of the NB neurons also showed phasic modulation with HVS. Circumscribed lesion of RT and extensive damage of other thalamic regions, including the intralaminar nuclei, suppressed HVS but had no effect on the neocortical EEG correlates of behavior. In sharp contrast, damage to the NB resulted in a dramatic increase of slow delta waves on the side of the lesion, mimicking the effect of scopolamine administration. We suggest that the NB plays a key role in neocortical arousal by directly activating the neocortex and by suppressing the rhythm generation in the RT-thalamocortical circuitry. We further suggest that the NB system may serve as a structural basis for the concept of the generalized ascending activation of Moruzzi and Magoun (1949).
Subthalamic stimulation reduces motor disability and improves quality of life in patients with advanced Parkinson's disease who have severe levodopa-induced motor complications. We hypothesized that neurostimulation would be beneficial at an earlier stage of Parkinson's disease.
In this 2-year trial, we randomly assigned 251 patients with Parkinson's disease and early motor complications (mean age, 52 years; mean duration of disease, 7.5 years) to undergo neurostimulation plus medical therapy or medical therapy alone. The primary end point was quality of life, as assessed with the use of the Parkinson's Disease Questionnaire (PDQ-39) summary index (with scores ranging from 0 to 100 and higher scores indicating worse function). Major secondary outcomes included parkinsonian motor disability, activities of daily living, levodopa-induced motor complications (as assessed with the use of the Unified Parkinson's Disease Rating Scale, parts III, II, and IV, respectively), and time with good mobility and no dyskinesia.
For the primary outcome of quality of life, the mean score for the neurostimulation group improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points (between-group difference in mean change from baseline to 2 years, 8.0 points; P=0.002). Neurostimulation was superior to medical therapy with respect to motor disability (P<0.001), activities of daily living (P<0.001), levodopa-induced motor complications (P<0.001), and time with good mobility and no dyskinesia (P=0.01). Serious adverse events occurred in 54.8% of the patients in the neurostimulation group and in 44.1% of those in the medical-therapy group. Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients. An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of the patients in the neurostimulation group and for 94.5% of those in the medical-therapy group.
Subthalamic stimulation was superior to medical therapy in patients with Parkinson's disease and early motor complications. (Funded by the German Ministry of Research and others; EARLYSTIM ClinicalTrials.gov number, NCT00354133.).
Objective:
Deep brain stimulation (DBS) is a therapeutically effective neurosurgical method originally applied in movement disorders. Over time, the application of DBS has increasingly been considered as a therapeutic option for several neuropsychiatric disorders, including Gilles de la Tourette syndrome, obsessive compulsive disorder, major depression and addiction. Latest research suggests beneficial effects of DBS in Alzheimer dementia (AD). Because of the high prevalence and the considerable burden of the disease, we endeavored to discuss and reveal the challenges of DBS in AD.
Methods:
Recent literature on the pathophysiology of AD, including translational data and human studies, has been studied to generate a fundamental hypothesis regarding the effects of electrical stimulation on cognition and to facilitate our ongoing pilot study regarding DBS of the nucleus basalis Meynert (NBM) in patients with AD.
Results:
It is hypothesized that DBS in the nucleus basalis Meynert could probably improve or at least stabilize memory and cognitive functioning in patients with AD by facilitating neural oscillations and by enhancing the synthesis of nerve growth factors.
Conclusions:
Considering the large number of patients suffering from AD, there is a great need for novel and effective treatment methods. Our research provides insights into the theoretical background of DBS in AD. Providing that our hypothesis will be validated by our ongoing pilot study, DBS could be an opportunity in the treatment of AD.
The medial temporal structures, including the hippocampus and the entorhinal cortex, are critical for the ability to transform daily experience into lasting memories. We tested the hypothesis that deep-brain stimulation of the hippocampus or entorhinal cortex alters memory performance.
We implanted intracranial depth electrodes in seven subjects to identify seizure-onset zones for subsequent epilepsy surgery. The subjects completed a spatial learning task during which they learned destinations within virtual environments. During half the learning trials, focal electrical stimulation was given below the threshold that elicits an afterdischarge (i.e., a neuronal discharge that occurs after termination of the stimulus).
Entorhinal stimulation applied while the subjects learned locations of landmarks enhanced their subsequent memory of these locations: the subjects reached these landmarks more quickly and by shorter routes, as compared with locations learned without stimulation. Entorhinal stimulation also resulted in a resetting of the phase of the theta rhythm, as shown on the hippocampal electroencephalogram. Direct hippocampal stimulation was not effective. In this small series, no adverse events associated with the procedure were observed.
Stimulation of the entorhinal region enhanced memory of spatial information when applied during learning. (Funded by the National Institutes of Health and the Dana Foundation.).
The fourth edition of Atlas of the Human Brain presents the anatomy of the brain at macroscopic and microscopic levels, featuring different aspects of brain morphology and topography. This greatly enlarged new edition provides the most detailed and accurate delineations of brain structure available. It includes features which assist in the new fields of neuroscience – functional imaging, resting state imaging and tractography. Atlas of the Human Brain is an essential guide to those working with human brain imaging or attempting to relate their observations on experimental animals to humans. Totally new in this edition is the inclusion of Nissl plates with delineation of cortical areas (Brodmann’s areas), the first time that these areas have been presented in serial histological sections.
Objective:
To study patients' expectations of subthalamic deep brain stimulation (STN-DBS) and their subjective perceived outcome, by using qualitative and quantitative methods in Parkinson's disease (PD).
Methods:
PD patients were prospectively examined before and 3 months after surgery. Semistructured interviews regarding preoperative expectations and postsurgical subjective perceived outcome were conducted. These were analysed using content analysis. For statistical analyses, patients were classified according to their subjective perceived outcome, resulting in three different subjective outcome groups (negative, mixed, positive outcome). The groups were used for multiple comparisons between and within each group regarding motor impairment, quality of life (QoL), neuropsychiatric status and cognitive functioning, using standard instruments. A logistic regression analysis was conducted to find predictors of subjective negative outcome. Receiver operating characteristic curves were used to analyse cut-off scores for predictive tests.
Results:
Of the 30 PD patients participating, 8 had a subjective negative outcome, 8 a mixed and 14 a positive outcome. All groups significantly improved in motor functioning. Patients with subjective negative outcome were characterised by preoperative unrealistic expectations, no postsurgical improvement in QoL, and significantly higher presurgical and postsurgical apathy and depression scores. Higher preoperative apathy and depression scores were significant predictors of negative subjective outcome. Cut-off scores for apathy and depression were identified.
Conclusions:
The mixed-method approach proved useful in examining a patient's subjective perception of STN-DBS outcome. Our results show that significant motor improvement does not necessarily lead to a positive subjective outcome. Moreover, PD patients should be screened carefully before surgery regarding apathy and depression. (DRKS-ID: DRKS00003221).
The organization of projections from the cholinergic neurons of the basal forebrain to neocortex and associated structures was investigated in the rhesus monkey with the help of horseradish peroxidase transport, acetyl‐cholinesterase histochemistry, and choline acetyltransferase immunohis‐tochemistry. Four groups of neurons contained cholinergic perikarya and were designated as Chl‐Ch4. The Ch1 group corresponds to the medial septal nucleus; about 10% of its neurons are cholinergic, and it provides a substantial projection to the hippocampus. The Ch2 group corresponds to the vertical nucleus of the diagonal band; at least 70% of its neurons are cholinergic, and it is the major source of innervation that the hippocampus and hypothalamus receive from the Chl‐Ch4 complex. The Ch3 group most closely corresponds to the horizontal nucleus of the diagonal band; only 1% of its neurons can definitely be shown to be cholinergic, and it is the major source of Chl‐Ch4 projections to the olfactory bulb. The Ch4 group most closely corresponds to the nucleus basalis of Meynert; at least 90% of its neurons are cholinergic, and it has projections to widespread areas of cortex and to the amygdala. In fact, the Ch4 group provides the single major source of cholinergic innervation for the entire cortical surface. In this respect, it is analogous to the raphe nuclei and to the nucleus locus coeruleus, which constitute the major sources of widespread cortical serotonergic and nor‐adrenergic innervation, respectively.
The extensive Ch4 group can be divided into several subdivisions. Each subdivision has a preferential set of targets for its projections even though the connection patterns contain considerable overlap. The anteromedial subdivision of Ch4 is the major source of cholinergic projections to areas on the medial aspect of the cerebral hemispheres; the anterolateral Ch4 sub‐division is the major source of cholinergic projections to frontoparietal op‐ercular areas and to the amygdala; the intermediate Ch4 subdivision pro‐vides the major cholinergic input for a variety of dorsal prefrontal, insular, posterior parietal, inferotemporal, and peristriate areas; and the posterior subdivision of Ch4 provides the major cholinergic innervation of superior temporal and immediately adjacent areas.
The basal forebrain in the human contains a cytoarchitechture analogous to that of the monkey. The Ch4 group (nucleus basalis) of the human is very extensive and can be subdivided into the same components that were identfied in the monkey brain. Pathological changes in Ch4 neurons have been described in a variety of human disease. In Alzheimer's disease, the relatively selective depression of neocortical cholinergic innervation may be closely associated with the neuronal loss in Ch4, which has also been described inthis condition.
In the rhesus monkey, all types of cortical areas receive substantial projections from the hippocampus. Virtually all of this hypothalamic input into neocortex arises from acetylcholinesterase‐rich neurons which lack choline acetyltransferase. The hypothalamocortical pathway is therefore acetylcholinesterase‐rich but not cholinergic.
The mechanism of action of high frequency deep brain stimulation is still unknown. However, in all circumstances and in all target nuclei so far stimulated, the effects mimic those of lesions previously made during thalamotomies, pallidotomies or even subthalamotomies, suggesting an inhibition of at least the neuronal network containing the target, if not of the target itself. On the contrary, fiber bundles are consistently activated at low or high frequencies. The hypothetical mechanisms envisioned should therefore be compatible and even produce these observed effects, to be acceptable as hypotheses. The mechanism could be either one or a combination of several causes: jamming of a feedback loop, activation of inhibitory structures included in a more complex network, blockade of membrane ion channels, deplorisation blockade, synaptic exhaustion, induction of early genes, changes in local blood flow, neuroplasticity, etc. It is probable that some are more involved in the acute effects and others in the long term changes, close to neuroplasticity. It is clear that the understanding of this strange and powerful phenomenon will profit from both clinical observation and well designed animal experiments. © 2002 Movement Disorder Society
The present study examined the expression of the immediate-early gene c-fos in different brain regions following a single 20-min session of unilateral electrical stimulation of the nucleus basalis magnocellularis (NBM). Current findings confirm that NBM stimulation provides specific activation of several cortical and subcortical regions closely related to the NBM and involved in learning and memory processes, such as the cingulate, parietal, piriform and perirhinal cortices, dorsal subiculum, and the parafascicular, central lateral and central medial nuclei of the thalamus. In contrast, NBM stimulation did not increase c-Fos expression in some expected areas that receive direct NBM projections such as the entorhinal cortex or amygdala nuclei. Results are discussed in terms of the possibility that NBM electrical stimulation facilitates learning by inducing neural changes related to transcription factors such as c-Fos.