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.

Revisiting a Telencephalic Extent of the Ascending Reticular Activating System.

Is the cerebrum involved in its own activation to states of attention or arousal? "Telencephalon" is a term borrowed from embryology to identify not only the cerebral hemispheres of the forebrain, but also the basal forebrain. We review a generally undercited literature that describes nucleus basalis of Meynert, located within the substantia innominata of the ventrobasal forebrain, as a telencephalic extension of the ascending reticular activating formation. Although that formation's precise anatomical definition and localization have proven elusive over more than 70 years, a careful reading of sources reveals that there are histological features common to certain brainstem neurons and those of the nucleus basalis, and that a largely common dendritic architecture may be a morphological aspect that helps to define non-telencephalic structures of the ascending reticular activating formation (e.g., in brainstem) as well as those parts of the formation that are telencephalic and themselves responsible for cortical activation. We draw attention to a pattern of dendritic arborization described as "isodendritic," a uniform (isos-) branching in which distal dendrite branches are significantly longer than proximal ones. Isodendritic neurons also differ from other morphological types based on their heterogeneous, rather than specific afferentation. References reviewed here are consistent in their descriptions of histology, particularly in studies of locales rich in cholinergic neurons. We discuss the therapeutic implications of a basal forebrain site that may activate cortex. Interventions that specifically target nucleus basalis and, especially, the survival of its constituent neurons may benefit afflictions in which higher cortical function is compromised due to disturbed arousal or attentiveness, including not only coma and related syndromes, but also conditions colloquially described as states of cognitive "fog" or of "long-haul" mental compromise.

Anger management: pSI has a say in it.

In this issue of Neuron, Zhu et al. (2021) reveal that activities in posterior substantia innominate (pSI) neurons that project to the periaqueductal gray (PAG) are both necessary and sufficient to drive aggressive attacks in mice under various conditions.

A substantia innominata-midbrain circuit controls a general aggressive response.

Although aggressive behaviors are universal and essential for survival, "uncontrollable" and abnormal aggressive behaviors in animals or humans may have severe adverse consequences or social costs. Neural circuits regulating specific forms of aggression under defined conditions have been described, but how brain circuits govern a general aggressive response remains unknown. Here, we found that posterior substantia innominata (pSI) neurons responded to several aggression-provoking cues with the graded activity of differential dynamics, predicting the aggressive state and the topography of aggression in mice. Activation of pSI neurons projecting to the periaqueductal gray (PAG) increased aggressive arousal and robustly initiated/promoted all the types of aggressive behavior examined in an activity-level-dependent manner. Inactivation of the pSI circuit largely blocked diverse aggressive behaviors but not mating. By encoding a general aggressive response, the pSI-PAG circuit universally drives multiple aggressive behaviors and may provide a potential target for alleviating human pathological aggression.

Cortical cholinergic dysfunction correlates with microglial activation in the substantia innominata in REM sleep behavior disorder.

INTRODUCTION: In vivo PET studies in patients with isolated REM sleep behavior disorder (iRBD) have shown presence of neuroinflammation (microglial activation) in the substantia nigra, and reduced cortical acetylcholinesterase activity, suggestive of cholinergic dysfunction, that was more widespread in patients with poorer cognitive performances. This study aimed to explore whether reduced cortical acetylcholinesterase activity in iRBD is linked to microglial activation in the substantia innominata (SI), the major source of cholinergic input to the cortex. METHODS: We used 11C(R)-PK11195 and 11C-Donepezil PET to assess levels of activated microglia and cholinergic function, respectively, in 19 iRBD patients. 11C(R)-PK11195 binding potential (BPND) and 11C-Donepezil distribution volume ratio (DVR) values were correlated using the Pearson statistic. RESULTS: We found that a lower cortical 11C-Donepezil DVR correlated with a higher 11C(R)-PK11195 BPND in the SI (r = -0.48, p = 0.04). At a voxel level, the strongest negative correlations were found in the frontal and temporal lobes. CONCLUSION: Our results suggest that reduced cortical acetylcholinesterase activity observed in our iRBD patients could be linked to the occurrence of neuroinflammation in the SI. Early modulation of microglial activation might therefore preserve cortical cholinergic functions in these patients.

Reduced substantia innominata volume mediates contributions of microvascular and macrovascular disease to cognitive deficits in Alzheimer's disease.

The relationships between cholinergic system damage and cerebrovascular disease are not entirely understood. Here, we investigate associations between atrophy of the substantia innominata (SI; the origin of cortical cholinergic projections) and measures of large and small vessel disease; specifically, elongation of the juxtaposed internal carotid artery termination and Cholinergic Pathways Hyperintensity scores (CHIPS). The study (n = 105) consisted of patients with Alzheimer's disease (AD) and/or subcortical ischemic vasculopathy, and elderly controls. AD and subcortical ischemic vasculopathy groups showed greater impingement of the carotid termination on the SI and smaller SI volumes. Both carotid termination elongation and CHIPS were associated independently with smaller SI volumes in those with and without AD. Atrophy of the SI mediated effects of carotid termination elongation on language and memory functions and the effect of CHIPS on attention/working memory. In conclusion, SI atrophy was related to cerebrovascular disease of the large and small vessels and to cognitive deficits in people with and without AD.

A Central Amygdala-Substantia Innominata Neural Circuitry Encodes Aversive Reinforcement Signals.

Aversive stimuli can impact motivation and support associative learning as reinforcers. However, the neural circuitry underlying the processing of aversive reinforcers has not been elucidated. Here, we report that a subpopulation of central amygdala (CeA) GABAergic neurons expressing protein kinase C-delta (PKC-δ+) displays robust responses to aversive stimuli during negative reinforcement learning. Importantly, projections from PKC-δ+ neurons of the CeA to the substantia innominata (SI) could bi-directionally modulate negative reinforcement learning. Moreover, consistent with the idea that SI-projecting PKC-δ+ neurons of the CeA encode aversive information, optogenetic activation of this pathway produces conditioned place aversion, a behavior prevented by simultaneous ablating of SI glutamatergic neurons. Taken together, our data define a cell-type-specific neural circuitry modulating associative learning by encoding aversive reinforcement signals.

Early-onset mild cognitive impairment in Parkinson's disease: Altered corticopetal cholinergic network.

Degeneration of the substantia innominata (SI) is significantly correlated with cognitive performance in Parkinson's disease (PD). We examined functional and structural patterns of SI degeneration in drug-naïve PD patients according to the duration of parkinsonism before mild cognitive impairment (MCI) diagnosis. Twenty PD patients with a shorter duration (PD-MCI-SD, <1 year), 18 patients with a longer duration (PD-MCI-LD, ≥1 year), and 29 patients with intact cognition (PD-IC) were included. Seed-based resting-state functional connectivity (rsFC) analysis using bilateral SI seed and region-of-interest-based volumetric analysis were performed. Compared to PD-IC, the collapsed PD-MCI group showed altered rsFC in the right frontal and bilateral parietal areas. PD-MCI-SD showed rsFC alteration in broader frontal and parietal areas compared to the other groups. Decreased rsFC in the right frontal area was also significantly correlated with shorter disease duration. No significant SI volume change was found between the groups. Altered rsFC between the SI and the frontal and parietal areas might be relevant to cognitive dysfunction in PD. Decreased rsFC between the SI and frontal area might be associated with early-onset MCI, suggesting that cholinergic deficits in the frontal brain areas might play an important role in the acceleration of cognitive decline in PD.

Structural grey matter changes in the substantia innominata in Alzheimer's disease and dementia with Lewy bodies: a DARTEL-VBM study.

OBJECTIVES: Several cholinergic nuclei, and in particular the nucleus basalis of Meynert, are localised to the substantia innominata in the basal forebrain. These nuclei provide major cholinergic innervation to the cerebral cortex and hippocampus, and have an essential role in cognitive function. The aim of this study was to investigate volumetric grey matter (GM) changes in the substantia innominata from structural T1 images in Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and healthy older participants using voxel-based morphometry. METHODS: Participants (41 DLB, 47 AD and 39 controls) underwent 3 T T1 magnetic resonance imaging and cognitive assessments. Voxel-based morphometry analysis used SPM8 with a substantia innominata brain mask to define the subspace for voxel GM analyses. Group differences, and selected behavioural and clinical correlates, were assessed. RESULTS: Compared with that in controls, bilateral GM loss in the substantia innominata was apparent in both AD and DLB. Relative to controls, significant bilateral GM loss in the substantia innominata was observed in DLB and AD. In DLB, significant associations were also observed between substantia innominata GM volume loss, and the levels of cognitive impairment and severity of cognitive fluctuations. CONCLUSIONS: Relative to that controls, atrophy of the substantia innominata was apparent in DLB and AD, and is associated with specific clinical manifestations in DLB. © 2016 The Authors. International Journal of Geriatric Psychiatry Published by John Wiley & Sons Ltd.

Dynorphin inhibits basal forebrain cholinergic neurons by pre- and postsynaptic mechanisms.

KEY POINTS: The basal forebrain is an important component of the ascending arousal system and may be a key site through which the orexin neurons promote arousal. It has long been known that orexin-A and -B excite basal forebrain cholinergic neurons, but orexin-producing neurons also make the inhibitory peptide dynorphin. Using whole-cell recordings in brain slices, we found that dynorphin-A directly inhibits basal forebrain cholinergic neurons via κ-opioid receptors, and decreases afferent excitatory synaptic input to these neurons. While the effects of dynorphin-A and orexin-A desensitize over multiple applications, co-application of dynorphin-A and orexin-A produces a sustained response that reverses depending on the membrane potential of basal forebrain cholinergic neurons. At -40 mV the net effect of the co-application is inhibition by dynorphin-A, whereas at -70 mV the excitatory response to orexin-A prevails. ABSTRACT: The basal forebrain (BF) is an essential component of the ascending arousal systems and may be a key site through which the orexin (also known as hypocretin) neurons drive arousal and promote the maintenance of normal wakefulness. All orexin neurons also make dynorphin, and nearly all brain regions innervated by the orexin neurons express kappa opiate receptors, the main receptor for dynorphin. This is remarkable because orexin excites target neurons including BF neurons, but dynorphin has inhibitory effects. We identified the sources of dynorphin input to the magnocellular preoptic nucleus and substantia innominata (MCPO/SI) in mice and determined the effects of dynorphin-A on MCPO/SI cholinergic neurons using patch-clamp recordings in brain slices. We found that the orexin neurons are the main source of dynorphin input to the MCPO/SI region, and dynorphin-A inhibits MCPO/SI cholinergic neurons through κ-opioid receptors by (1) activation of a G protein-coupled inwardly rectifying potassium current, (2) inhibition of a voltage-gated Ca(2+) current and (3) presynaptic depression of the glutamatergic input to these neurons. The responses both to dynorphin-A and to orexin-A desensitize, but co-application of dynorphin-A and orexin-A produces a sustained response. In addition, the polarity of the response to the co-application depends on the membrane potential of BF neurons; at -40 mV the net effect of the co-application is inhibition by dynorphin-A, whereas at -70 mV the excitatory response to orexin-A prevails. This suggests that depending on their state of activation, BF cholinergic neurons can be excited or inhibited by signals from the orexin neurons.

Chronic sleep restriction induces long-lasting changes in adenosine and noradrenaline receptor density in the rat brain.

Although chronic sleep restriction frequently produces long-lasting behavioural and physiological impairments in humans, the underlying neural mechanisms are unknown. Here we used a rat model of chronic sleep restriction to investigate the role of brain adenosine and noradrenaline systems, known to regulate sleep and wakefulness, respectively. The density of adenosine A1 and A2a receptors and ß-adrenergic receptors before, during and following 5 days of sleep restriction was assessed with autoradiography. Rats (n = 48) were sleep-deprived for 18 h day(-1) for 5 consecutive days (SR1-SR5), followed by 3 unrestricted recovery sleep days (R1-R3). Brains were collected at the beginning of the light period, which was immediately after the end of sleep deprivation on sleep restriction days. Chronic sleep restriction increased adenosine A1 receptor density significantly in nine of the 13 brain areas analysed with elevations also observed on R3 (+18 to +32%). In contrast, chronic sleep restriction reduced adenosine A2a receptor density significantly in one of the three brain areas analysed (olfactory tubercle which declined 26-31% from SR1 to R1). A decrease in ß-adrenergic receptors density was seen in substantia innominata and ventral pallidum which remained reduced on R3, but no changes were found in the anterior cingulate cortex. These data suggest that chronic sleep restriction can induce long-term changes in the brain adenosine and noradrenaline receptors, which may underlie the long-lasting neurocognitive impairments observed in chronic sleep restriction.

Dexmedetomidine-induced sedation does not mimic the neurobehavioral phenotypes of sleep in Sprague Dawley rat.

STUDY OBJECTIVES: Dexmedetomidine is used clinically to induce states of sedation that have been described as homologous to nonrapid eye movement (NREM) sleep. A better understanding of the similarities and differences between NREM sleep and dexmedetomidine-induced sedation is essential for efforts to clarify the relationship between these two states. This study tested the hypothesis that dexmedetomidine-induced sedation is homologous to sleep. DESIGN: This study used between-groups and within-groups designs. SETTING: University of Michigan. PARTICIPANTS: Adult male Sprague Dawley rats (n = 40). INTERVENTIONS: Independent variables were administration of dexmedetomidine and saline or Ringer's solution (control). Dependent variables included time spent in states of wakefulness, sleep, and sedation, electroencephalographic (EEG) power, adenosine levels in the substantia innominata (SI), and activation of pCREB and c-Fos in sleep related forebrain regions. MEASUREMENTS AND RESULTS: Dexmedetomidine significantly decreased time spent in wakefulness (-49%), increased duration of sedation (1995%), increased EEG delta power (546%), and eliminated the rapid eye movement (REM) phase of sleep for 16 h. Sedation was followed by a rebound increase in NREM and REM sleep. Systemically administered dexmedetomidine significantly decreased (-39%) SI adenosine levels. Dialysis delivery of dexmedetomidine into SI did not decrease adenosine level. Systemic delivery of dexmedetomidine did not alter c-Fos or pCREB expression in the horizontal diagonal band, or ventrolateral, median, and medial preoptic areas of the hypothalamus. CONCLUSIONS: Dexmedetomidine significantly altered normal sleep phenotypes, and the dexmedetomidine-induced state did not compensate for sleep need. Thus, in the Sprague Dawley rat, dexmedetomidine-induced sedation is characterized by behavioral, electrographic, and immunohistochemical phenotypes that are distinctly different from similar measures obtained during sleep.

Basal forebrain cholinergic modulation of sleep transitions.

OBJECTIVES: The basal forebrain cholinergic system is involved in cognitive processes that require an attentive state, an increased level of arousal, and/ or cortical activation associated with low amplitude fast EEG activity. The activity of most neurons in the basal forebrain cholinergic space is tightly correlated with the cortical EEG and the activity state. While most cholinergic neurons fire maximally during waking and REM sleep, the activity of other types of basal forebrain neurons vastly differs across different arousal and sleep states. Numerous studies have suggested a role for the basal forebrain cholinergic neurons in eliciting cortical activation and arousal. However, the intricate local connectivity within the region requires the use of cell-specific manipulation methods to demonstrate such a causal relationship. DESIGN AND MEASUREMENTS: Here we have combined optogenetics with surface EEG recordings in freely moving mice in order to investigate the effects of acute cholinergic activation on the dynamics of sleep-to-wake transitions. We recorded from naturally sleeping animals and analyzed transitions from NREM sleep to REM sleep and/ or wakefulness in response to photo-stimulation of cholinergic neurons in substantia innominata. RESULTS AND CONCLUSIONS: Our results show that optogenetic activation of BF cholinergic neurons during NREM sleep is sufficient to elicit cortical activation and facilitate state transitions, particularly transitions to wakefulness and arousal, at a time scale similar to the activation induced by other subcortical systems. Our results provide in vivo cell-specific demonstration for the role of basal forebrain cholinergic system in induction of wakefulness and arousal.

Meynert and the basal nucleus / Meynert e o núcleo basal

Meynert described the "loop of the peduncular foot" (Schlinge des Hirnschenkelfusses), and its ganglion (Ganglion der Hirnschenkelschlinge) and related them to Reil's Substantia innominata and Gratiolet's Ansa peduncularis, from which he apparently built up his findings. Koelliker renamed the ganglion with the eponymous designation Meynert'sches Basalganglion (Meynert's basal ganglion), a name which endures to the present day, and described its topographical spread in relation to neighboring structures. Meynert and Koelliker also described aspects of cell composition of the ganglion (or nucleus) with a better account of the latter. Both, together with Reil and Gratiolet, were the outstanding personalities of the 19th century who performed the pioneering studies on basal formations of the forebrain. After these works, a considerable body of research appeared in the 20th century, with a focus on Meynert's basal nucleus and related structures. The development of further knowledge about these structures revealed their great importance in the activity of the brain, as evidenced in both normal and pathological states.

Meynert descreveu a "alça do pé do pedúnculo" (Schlingedes Hirnschenkelfusses) e seu gânglio (Ganglion der Hirnschenkelschlinge), relacionando-os à Substantia innominata de Reil e à Ansa peduncularis de Gratiolet, a partir dos quais aparentemente desenvolveu seus achados. Koelliker renomeou o gânglio com a designação epônima de Meynert'sches Basalganglion (gânglio basal de Meynert), que perdura até o presente, e descreveu sua extensão topográfica em relação às estruturas vizinhas. Meynert e Koelliker descreveram também aspectos da composição celular do gânglio (ou núcleo), com um relato melhor do segundo. Ambos, juntamente com Reil e Gratiolet, foram as personalidades de destaque do século 19 que realizaram os estudos pioneiros sobre formações basais do prosencéfalo. Após esses, um número considerável de estudos apareceu no século 20, com foco no núcleo basal de Meynert e estruturas relacionadas. O desenvolvimento ulterior do saber sobre as mesmas mostraram sua grande importância na atividade cerebral, como visto em condições normais e patológicas.

Is encroachment of the carotid termination into the substantia innominata associated with its atrophy and cognition in Alzheimer's disease?

The internal carotid artery termination (CAT) ends in a T-shaped bifurcation just below the substantia innominata (SI), which contains cognitively strategic cholinergic neurons and undergoes atrophy in Alzheimer's disease (AD). This study investigated whether an elongated CAT with possible resulting encroachment into the SI would correlate with SI atrophy and with cognitive dysfunction in AD. We rated the degree of CAT encroachment upon the SI and measured SI volume on magnetic resonance imaging in 30 AD patients, 30 AD patients with subcortical small vessel disease, and 30 age-matched controls. CAT encroachment significantly correlated with SI volume after adjusting for age within the overall group and the groups with dementia. AD patients with higher CAT encroachment scores had lower SI volumes and lower attention, memory, and executive test scores. These data suggest that CAT encroachment may mechanically injure the SI, exacerbating cholinergic damage and contributing to cognitive impairment. This process may represent a possible previously underappreciated mechanism for interaction between large-vessel cerebrovascular disease and AD.

[Food-procuring stereotype movements is accompanied by changes of c-Fos gene expression in the amygdala and modulation of heart rate in rats].

The distribution of Fos-immunoreactive (Fos-ir) and NADPH Diaphorase reactive (NADPH-dr-) neurons in the different subnuclei of amygdala and insular cortex (on the level -2,12 to -3,14 mm from bregma), and the associated changes of heart rate (HR) in intact, food-deprivated and executed food-procuring movements of rats were studied. In comparison with other groups of animals, the mean number of the Fos-ir neurons in the central nucleus of amygdala (Ce) and the insular cortex (GI/DI) at all studied levels was significantly greater in the executed food-procuring movements in rats. The main focus of localization of the Fos-ir neurons was found in lateral part of the Ce (58.5 +/- 1.9 units in 40-microm-thick section) at the level -2.56 mm. The mean number of Fos-ir neurons was significantly greater also in the lateral and capsular parts of the Ce. The mean number of Fos-ir neurons in the GI/DI was 165.5 +/- 3.2 cells in section. The number and density of NADPH-d reactive neurons was not significantly different in the brain structures of all animal groups studied. The double stained neurons (Fos-ir + NADPH-dr) were registered in medial, basolateral, anterior cortical amygdaloid nuclei and substantia innominata (SI) in rats after realization food-procuring movements. It was found that realization of food-procuring movements by the forelimb during repeated sessions was accompanied with the gradual decline of mean values of the HR (from 5% to 12% of control level) with subsequent renewal of them to the initial values (tonic component). The analysis of dynamics of the HR changes during realization of separate purposeful motion has shown the transient period of the HR suppression (500 ms), which coincided with the terminal phase of grasping of food pellet (phasic component). We suggest that the revealed focuses of localization of Fos-ir neurons in the lateral and medial subregions of amigdaloid Ce and also GI/DI, and SI testified that these structures of brain are involved in generation of the goal-directed motions. Direct projections of these subnuclei (and hypothalamus) to the cardiovascular centers of the medulla determine the associated regulation of the cardiovascular system function in the period of realization of the goal-directed motions in animals.

GABA-to-ACh ratio in basal forebrain and cerebral cortex varies significantly during sleep.

STUDY OBJECTIVES: GABAergic and cholinergic transmission within the basal forebrain and cerebral cortex contribute to the regulation of sleep and wakefulness. In contrast to levels of acetylcholine (ACh), levels of endogenous GABA in basal forebrain and cortex during sleep and wakefulness have not previously been quantified. This study (1) tested the hypothesis that there are differential, state-specific changes in GABA levels within the substantia innominata (SI) region of the basal forebrain and somatosensory cortex; and (2) quantified the ratio of GABAergic to cholinergic transmission in the SI, cortex, and pontine reticular formation during rapid eye movement sleep (REM), non-REM sleep (NREM), and wakefulness. DESIGN: Within/between subjects. SETTING: University of Michigan. PATIENTS OR PARTICIPANTS: Adult, male, purpose bred cats (n = 5). INTERVENTIONS: In vivo microdialysis, high performance liquid chromatography, electrophysiological recordings. MEASUREMENTS AND RESULTS: In the SI, GABA levels were significantly greater during NREM (17%) than during REM. In the cortex, GABA levels were significantly greater during NREM than during wakefulness (39%) and REM (63%). During prolonged wakefulness, there was a linear increase in cortical GABA levels, and the amount of time spent awake accounted for 87% of the variance in GABA. The GABA-to-ACh ratio was largest during NREM for all brain regions. REM was characterized by a 68% decrease in the GABA-to-ACh ratio across brain regions, always due to a decrease in GABA levels. CONCLUSION: Three of the brain regions that comprise the anatomically distributed, sleep-generating network have in common a GABA-mediated, sleep-dependent decrease in the GABA-to-ACh ratio.

Neuroanatomical substrates of visual hallucinations in patients with non-demented Parkinson's disease.

BACKGROUND: Visual hallucinations (VH), which are common in patients with Parkinson's disease (PD), lead to increased disability and are a significant predictor of the development of dementia. However, the neuroanatomical basis for VH in non-demented PD patients remains controversial. METHODS: A total of 110 patients with PD were classified into PD with VH (n=46) and PD without VH (n=64) groups, depending on the presence of VH assessed by the caregiver-based structured interview of the Neuropsychiatric Inventory. We performed voxel-based morphometry (VBM) for grey matter (GM) volume and a region-of-interest-based volumetric analysis of the substantia innominata (SI) between two groups. RESULTS: The comprehensive neuropsychological assessment showed that PD patients with VH showed more severe cognitive deficits in delayed visual memory and frontal executive functions compared with those without VH. A VBM analysis revealed that PD patients with VH had significantly lower GM volume in the right orbitofrontal, left temporal and left thalamic areas compared with those without VH. The normalised SI volume was significantly reduced in PD patients with VH compared with those without VH (1.28 ± 0.22 vs 1.41 ± 0.25, p=0.005). CONCLUSIONS: The present study demonstrates that non-demented PD patients with VH exhibited a smaller volume in the frontal, temporal and thalamic areas as well as the SI, suggesting that PD hallucinators may have distinctive neuroanatomical bases relative to PD non-hallucinators.

Volumetric analysis of the substantia innominata in patients with Parkinson's disease according to cognitive status.

The cholinergic system arising from the substantia innominata (SI) of the basal forebrain has an important role in the cognitive functions of Parkinson's disease (PD). We performed magnetic resonance imaging based volumetric analysis to evaluate the SI volume in patients with PD-intact cognition (PD-IC), PD-mild cognitive impairment (PD-MCI), and PD dementia (PDD). The mean normalized SI volume was significantly decreased in patients with PD-IC (1.54 ± 0.12, p < 0.001), PD-MCI (1.49 ± 0.12, p < 0.001), and PDD (1.39 ± 0.12, p < 0.001) compared with that of control subjects (1.68 ± 0.11). The normalized SI volume did not differ between patients with PD-IC and PD-MCI; however, the normalized SI volume was significantly decreased in patients with PDD compared with that in those with PD-IC (p < 0.001) or PD-MCI (p = 0.016). The normalized SI volume was significantly correlated with general cognitive status (r = 0.51, p < 0.001) as well as with performance in each cognitive subdomain, with a particularly significant independent association with attention (ß = 0.33, p = 0.003) and object naming (ß = 0.26, p = 0.017). The present study demonstrated that the SI volume in PD differs depending on cognitive status and is significantly correlated with cognitive performance.

Buprenorphine disrupts sleep and decreases adenosine concentrations in sleep-regulating brain regions of Sprague Dawley rat.

BACKGROUND: Buprenorphine, a partial µ-opioid receptor agonist and κ-opioid receptor antagonist, is an effective analgesic. The effects of buprenorphine on sleep have not been well characterized. This study tested the hypothesis that an antinociceptive dose of buprenorphine decreases sleep and decreases adenosine concentrations in regions of the basal forebrain and pontine brainstem that regulate sleep. METHODS: Male Sprague Dawley rats were implanted with intravenous catheters and electrodes for recording states of wakefulness and sleep. Buprenorphine (1 mg/kg) was administered systemically via an indwelling catheter and sleep-wake states were recorded for 24 h. In additional rats, buprenorphine was delivered by microdialysis to the pontine reticular formation and substantia innominata of the basal forebrain while adenosine was simultaneously measured. RESULTS: An antinociceptive dose of buprenorphine caused a significant increase in wakefulness (25.2%) and a decrease in nonrapid eye movement sleep (-22.1%) and rapid eye movement sleep (-3.1%). Buprenorphine also increased electroencephalographic delta power during nonrapid eye movement sleep. Coadministration of the sedative-hypnotic eszopiclone diminished the buprenorphine-induced decrease in sleep. Dialysis delivery of buprenorphine significantly decreased adenosine concentrations in the pontine reticular formation (-14.6%) and substantia innominata (-36.7%). Intravenous administration of buprenorphine significantly decreased (-20%) adenosine in the substantia innominata. CONCLUSIONS: Buprenorphine significantly increased time spent awake, decreased nonrapid eye movement sleep, and increased latency to sleep onset. These disruptions in sleep architecture were mitigated by coadministration of the nonbenzodiazepine sedative-hypnotic eszopiclone. The buprenorphine-induced decrease in adenosine concentrations in basal forebrain and pontine reticular formation is consistent with the interpretation that decreasing adenosine in sleep-regulating brain regions is one mechanism by which opioids disrupt sleep.