Morphological characteristics of cerebellum, pons and thalamus in Reccurent isolated sleep paralysis - A pilot study.

Introduction: Recurrent isolated sleep paralysis (RISP) is a rapid eye movement sleep (REM) parasomnia, characterized by the loss of voluntary movements upon sleep onset and/or awakening with preserved consciousness. Evidence suggests microstructural changes of sleep in RISP, although the mechanism of this difference has not been clarified yet. Our research aims to identify potential morphological changes in the brain that can reflect these regulations. Materials and methods: We recruited 10 participants with RISP (8 women; mean age 24.7 years; SD 2.4) and 10 healthy control subjects (w/o RISP; 3 women; mean age 26.3 years; SD 3.7). They underwent video-polysomnography (vPSG) and sleep macrostructure was analyzed. After that participants underwent magnetic resonance imaging (MRI) of the brain. We focused on 2-dimensional measurements of cerebellum, pons and thalamus. Statistical analysis was done in SPSS program. After analysis for normality we performed Mann-Whitney U test to compare our data. Results: We did not find any statistically significant difference in sleep macrostructure between patients with and w/o RISP. No evidence of other sleep disturbances was found. 2-dimensional MRI measurements revealed statistically significant increase in cerebellar vermis height (p = 0.044) and antero-posterior diameter of midbrain-pons junction (p = 0.018) in RISP compared to w/o RISP. Discussion: Our results suggest increase in size of cerebellum and midbrain-pons junction in RISP. This enlargement could be a sign of an over-compensatory mechanism to otherwise dysfunctional regulatory pathways. Further research should be done to measure these differences in time and with closer respect to the frequency of RISP episodes.

Drug Evaluation of Parkinson's Disease Patient-Derived Midbrain Organoids Using Mesoporous Au Nanodot-Patterned 3D Concave Electrode.

Brain organoids are being recognized as valuable tools for drug evaluation in neurodegenerative diseases due to their similarity to the human brain's structure and function. However, a critical challenge is the lack of selective and sensitive electrochemical sensing platforms to detect the response of brain organoids, particularly changes in the neurotransmitter concentration upon drug treatment. This study introduces a 3D concave electrode patterned with a mesoporous Au nanodot for the detection of electrochemical signals of dopamine in response to drugs in brain organoids for the first time. The mesoporous Au nanodot-patterned film was fabricated using laser interference lithography and electrochemical deposition. Then, the film was attached to a polymer-based 3D concave mold to obtain a 3D concave electrode. Midbrain organoids generated from Parkinson's disease (PD) patient-derived iPSCs with gene mutations (named as PD midbrain organoid) or normal midbrain organoids were positioned on the developed 3D concave electrode. The 3D concave electrode showed a 1.4 times higher electrochemical signal of dopamine compared to the bare gold electrode. And the dopamine secreted from normal midbrain organoids or PD midbrain organoids on the 3D concave electrode could be detected electrochemically. After the treatment of PD midbrain organoids with levodopa, the drug for PD, the increase in dopamine level was detected due to the activation of dopaminergic neurons by the drug. The results suggest the potential of the proposed 3D concave electrode combined with brain organoids as a useful tool for assessing drug efficacy. This sensing system can be applied to a variety of organoids for a comprehensive drug evaluation.

Vertical 'half-and-half' syndrome with ipsilateral pseudo-abducens palsy due to rostral midbrain lacunar infarction.

Vertical 'half-and-half' syndrome, characterized by contralateral upward and ipsilateral downward gaze palsy, is a rare variant of vertical eye movement disturbance. Similarly, pseudo-abducens palsy, manifesting as abductive palsy despite no lesion to the pons, constitutes another rare type of eye movement disturbance. Both conditions have been associated with lesions in the thalamo-mesencephalic junction. We present a rare case report detailing a patient exhibiting vertical 'half-and-half' syndrome with ipsilateral pseudo-abducens palsy following a left lacunar infarction of the thalamo-mesencephalic junction. Additionally, we discuss the potential underlying mechanisms contributing to this rare combination of eye movement disorders.

Molecular evidence of altered stress responsivity related to neuroinflammation in the schizophrenia midbrain.

Stress and inflammation are risk factors for schizophrenia. Chronic psychosocial stress is associated with subcortical hyperdopaminergia, a core feature of schizophrenia. Hyperdopaminergia arises from midbrain neurons, leading us to hypothesise that changes in stress response pathways may occur in this region. To identify whether transcriptional changes in glucocorticoid and mineralocorticoid receptors (NR3C1/GR, NR3C2/MR) or other stress signalling molecules (FKBP4, FKBP5) exist in schizophrenia midbrain, we measured gene expression in the human brain (N = 56) using qRT-PCR. We assessed whether alterations in these mRNAs were related to previously identified high/low inflammatory status. We investigated relationships between stress-related transcripts themselves, and between FKBP5 mRNA, dopaminergic, and glial cell transcripts in diagnostic and inflammatory subgroups. Though unchanged by diagnosis, GR mRNA levels were reduced in high inflammatory compared to low inflammatory schizophrenia cases (p = 0.026). We found no effect of diagnosis or inflammation on MR mRNA. FKBP4 mRNA was decreased and FKBP5 mRNA was increased in schizophrenia (p < 0.05). FKBP5 changes occurred in high inflammatory (p < 0.001), whereas FKBP4 changes occurred in low inflammatory schizophrenia cases (p < 0.05). The decrease in mRNA encoding the main stress receptor (GR), as well as increased transcript levels of the stress-responsive negative regulator (FKBP5), may combine to blunt the midbrain response to stress in schizophrenia when neuroinflammation is present. Negative correlations between FKBP5 mRNA and dopaminergic transcripts in the low inflammatory subgroup suggest higher levels of FKBP5 mRNA may also attenuate dopaminergic neurotransmission in schizophrenia even when inflammation is absent. We report alterations in GR-mediated stress signalling in the midbrain in schizophrenia.

Blunted midbrain reward activation during smoking withdrawal: a preliminary study.

Introduction: Tobacco smoking is the leading preventable cause of death, causing more than six million deaths annually worldwide, mainly due to cardiovascular disease and cancer. Many habitual smokers try to stop smoking but only about 7% are successful, despite widespread knowledge of the risks. Development of addiction to a range of substances is associated with progressive blunting of brain reward responses and sensitisation of stress responses, as described by the allostasis theory of addiction. There is pre-clinical evidence from rodents for a dramatic decrease in brain reward function during nicotine withdrawal. Methods: Here we tested the hypothesis that habitual smokers would also exhibit blunted reward function during nicotine withdrawal using a decision-making task and fMRI. Results: Our findings supported this hypothesis, with midbrain reward-related responses particularly blunted. We also tested the hypothesis that smokers with a longer duration of smoking would have more pronounced abnormalities. Contrary to expectations, we found that a shorter duration of smoking in younger smokers was associated with the most marked abnormalities, with blunted midbrain reward related activation including the dopaminergic ventral tegmental area. Discussion: Given the substantial mortality associated with smoking, and the small percent of people who manage to achieve sustained abstinence, further translational studies on nicotine addiction mechanisms are indicated.

Knockdown of Esr1 from DRD1-Rich Brain Regions Affects Adipose Tissue Metabolism: Potential Crosstalk between Nucleus Accumbens and Adipose Tissue.

Declining estrogen (E2) leads to physical inactivity and adipose tissue (AT) dysfunction. Mechanisms are not fully understood, but E2's effects on dopamine (DA) activity in the nucleus accumbens (NAc) brain region may mediate changes in mood and voluntary physical activity (PA). Our prior work revealed that loss of E2 robustly affected NAc DA-related gene expression, and the pattern correlated with sedentary behavior and visceral fat. The current study used a new transgenic mouse model (D1ERKO) to determine whether the abolishment of E2 receptor alpha (ERα) signaling within DA-rich brain regions affects PA and AT metabolism. Adult male and female wild-type (WT) and D1ERKO (KD) mice were assessed for body composition, energy intake (EE), spontaneous PA (SPA), and energy expenditure (EE); underwent glucose tolerance testing; and were assessed for blood biochemistry. Perigonadal white AT (PGAT), brown AT (BAT), and NAc brain regions were assessed for genes and proteins associated with DA, E2 signaling, and metabolism; AT sections were also assessed for uncoupling protein (UCP1). KD mice had greater lean mass and EE (genotype effects) and a visible change in BAT phenotype characterized by increased UCP1 staining and lipid depletion, an effect seen only among females. Female KD had higher NAc Oprm1 transcript levels and greater PGAT UCP1. This group tended to have improved glucose tolerance (p = 0.07). NAc suppression of Esr1 does not appear to affect PA, yet it may directly affect metabolism. This work may lead to novel targets to improve metabolic dysfunction following E2 loss, possibly by targeting the NAc.

The Mesocortical System Encodes the Strength of Subsequent Force Generation.

Our minds impact motor outputs. Such mind-motor interactions are critical for understanding motor control mechanisms and optimizing motor performance. In particular, incentive motivation strongly enhances motor performance. Dopaminergic neurons located in the ventral midbrain (VM) are believed to be the center of incentive motivation. Direct projections from the VM to the primary motor cortex constitute a mesocortical pathway. However, the functional role of this pathway in humans remains unclear. Recently, we demonstrated the functional role of the mesocortical pathway in human motor control in the context of incentive motivation by using functional magnetic resonance imaging (fMRI). Incentive motivation remarkably improved not only reaction times but also the peak grip force in subsequent grip responses. Although the reaction time has been used as a proxy for incentive motivation mediated by dopaminergic midbrain activity, the premovement activity of the mesocortical pathway is involved in controlling the force strength rather than the initiation of subsequent force generation. In this commentary, we review our recent findings and discuss remaining questions regarding the functional role of the mesocortical pathway in mind-motor interactions.

The Oct4-related PouV gene, pou5f3, mediates isthmus development in zebrafish by directly and dynamically regulating pax2a.

Using a transgenic zebrafish line harboring a heat-inducible dominant-interference pou5f3 gene (en-pou5f3), we reported that this PouV gene is involved in isthmus development at the midbrain-hindbrain boundary (MHB), which patterns the midbrain and cerebellum. Importantly, the functions of pou5f3 reportedly differ before and after the end of gastrulation. In the present study, we examined in detail the effects of en-pou5f3 induction on isthmus development during embryogenesis. When en-pou5f3 was induced around the end of gastrulation (bud stage), the isthmus was abrogated or deformed by the end of somitogenesis (24 hours post-fertilization). At this stage, the expression of MHB markers -- such as pax2a, fgf8a, wnt1, and gbx2 -- was absent in embryos lacking the isthmus structure, whereas it was present, although severely distorted, in embryos with a deformed isthmus. We further found that, after en-pou5f3 induction at late gastrulation, pax2a, fgf8a, and wnt1 were immediately and irreversibly downregulated, whereas the expression of en2a and gbx2 was reduced only weakly and slowly. Induction of en-pou5f3 at early somite stages also immediately downregulated MHB genes, particularly pax2a, but their expression was restored later. Overall, the data suggested that pou5f3 directly upregulates at least pax2a and possibly fgf8a and wnt1, which function in parallel in establishing the MHB, and that the role of pou5f3 dynamically changes around the end of gastrulation. We next examined the transcriptional regulation of pax2a using both in vitro and in vivo reporter analyses; the results showed that two upstream 1.0-kb regions with sequences conserved among vertebrates specifically drove transcription at the MHB. These reporter analyses confirmed that development of the isthmic organizer is regulated by PouV through direct regulation of pax2/pax2a in vertebrate embryos.

Midbrain sensitivity to auditory motion studied with dichotic sweeps of broadband noise.

Many neurons in the central nucleus of the inferior colliculus (IC) show sensitivity to interaural time differences (ITDs), which is thought to be relayed from the brainstem. However, studies with interaural phase modulation of pure tones showed that IC neurons have a sensitivity to changes in ITD that is not present at the level of the brainstem. This sensitivity has been interpreted as a form of sensitivity to motion. A new type of stimulus is used here to study the sensitivity of IC neurons to dynamic changes in ITD, in which broad- or narrowband stimuli are swept through a range of ITDs with arbitrary start-ITD, end-ITD, speed, and direction. Extracellular recordings were obtained under barbiturate anesthesia in the cat. We applied the same analyses as previously introduced for the study of responses to tones. We find effects of motion which are similar to those described in response to interaural phase modulation of tones. The size of the effects strongly depended on the motion parameters but was overall smaller than reported for tones. We found that the effects of motion could largely be explained by the temporal response pattern of the neuron such as adaptation and build-up. Our data add to previous evidence questioning true coding of motion at the level of the IC.

A Computational Model of Auditory Chirp-Velocity Sensitivity and Amplitude-Modulation Tuning in Inferior Colliculus Neurons.

We demonstrate a model of chirp-velocity sensitivity in the inferior colliculus (IC) that retains the tuning to amplitude modulation (AM) that was established in earlier models. The mechanism of velocity sensitivity is sequence detection by octopus cells of the posteroventral cochlear nucleus, which have been proposed in physiological studies to respond preferentially to the order of arrival of cross-frequency inputs of different amplitudes. Model architecture is based on coincidence detection of a combination of excitatory and inhibitory inputs. Chirp-sensitivity of the IC output is largely controlled by the strength and timing of the chirp-sensitive octopus-cell inhibitory input. AM tuning is controlled by inhibition and excitation that are tuned to the same frequency. We present several example neurons that demonstrate the feasibility of the model in simulating realistic chirp-sensitivity and AM tuning for a wide range of characteristic frequencies. Additionally, we explore the systematic impact of varying parameters on model responses. The proposed model can be used to assess the contribution of IC chirp-velocity sensitivity to responses to complex sounds, such as speech.

Micrographia after midbrain infarction alleviated by Japanese calligraphy-style writing: A case report.

•A 77-year-old right-handed man experienced an infarct in the right midbrain.•Ipsilesional progressive micrographia occurred after the midbrain infarct.•Micrographia improved when the patient wrote as if practicing Japanese calligraphy.•Further studies should confirm the utility of Japanese calligraphy in such cases.

A descending pathway from the lateral/ventrolateral PAG to the rostroventral medulla mediating the vasomotor response evoked by social defeat stress in rats.

The stress-induced cardiovascular response is based on the defensive reaction in mammals. It has been shown that the sympathetic vasomotor pathway of acute psychological stress is indirectly mediated via neurons in the rostroventral medulla (RVM) from the hypothalamic stress center. In this study, direct projections to the RVM and distribution of neuroexcitatory marker c-Fos-expressed neurons were investigated during social defeat stress (SDS) in conscious rats. The experimental rat that was injected with a neural tracer, FluoroGold (FG) into the unilateral RVM, was exposed to the SDS. Double-positive neurons of both c-Fos and FG were locally distributed in the lateral/ventrolateral periaqueductal gray matter (l/vl PAG) in the midbrain. These results suggest that the neurons in the l/vl PAG contribute to the defensive reaction evoked by acute psychological stress, such as the SDS. During the SDS period, arterial pressure (AP) and heart rate (HR) showed sustained increases in the rat. Therefore, we performed chemical stimulation by excitatory amino acid microinjection within the l/vl PAG and measured cardiovascular response and sympathetic nerve activity in some anesthetized rats. The chemical stimulation of neurons in the l/vl PAG caused significant increases in arterial pressure and renal sympathetic nerve activity. Taken together, our results suggest that neurons in the l/vl PAG are a possible candidate for the cardiovascular descending pathway that modulates sympathetic vascular resistance evoked by acute psychological stress, like the SDS.NEW & NOTEWORTHY The sympathetic vasomotor pathway of an acute psychological stress-induced cardiovascular response is mediated via neurons in the RVM indirectly from the hypothalamus. In this study, we showed the relaying area of the efferent sympathetic vasomotor pathway from the hypothalamus to the RVM. The results suggested that the pressor response during psychological stress is mediated via neurons in the lateral/ventrolateral PAG to the RVM.

ShuYu capsule alleviates emotional and physical symptoms of premenstrual dysphoric disorder: Impact on ALLO decline and GABAA receptor δ subunit in the PAG area.

Premenstrual dysphoric disorder (PMDD) is a severe subtype of premenstrual syndrome in women of reproductive age, with its pathogenesis linked to the heightened sensitivity of type A γ -aminobutyric acid receptors (GABAAR) to neuroactive steroid hormone changes, particularly allopregnanolone (ALLO). While a low dose of fluoxetine, a classic selective serotonin reuptake inhibitor, is commonly used as a first-line drug to alleviate emotional disorders in PMDD in clinical settings, its mechanism of action is related to ALLO-GABAA receptor function. However, treating PMDD requires attention to both emotional and physical symptoms, such as pain sensitivity. This study aims to investigate the efficacy of ShuYu capsules, a traditional Chinese medicine, in simultaneously treating emotional and physical symptoms in a rat model of PMDD. Specifically, our focus centres on the midbrain periaqueductal grey (PAG), a region associated with emotion regulation and susceptibility to hyperalgesia. Considering the underlying mechanisms of ALLO-GABAA receptor function in the PAG region, we conducted a series of experiments to evaluate and define the effects of ShuYu capsules and uncover the relationship between the drug's efficacy and ALLO concentration fluctuations on GABAA receptor function in the PAG region. Our findings demonstrate that ShuYu capsules significantly improved oestrous cycle-dependant depression-like behaviour and reduced stress-induced hyperalgesia in rats with PMDD. Similar to the low dose of fluoxetine, ShuYu capsules targeted and mitigated the sharp decline in ALLO, rescued the upregulation of GABAAR subunit function, and activated PAG neurons in PMDD rats. The observed effects of ShuYu capsules suggest a central mechanism underlying PMDD symptoms, involving ALLO_GABAA receptor function in the PAG region. This study highlights the potential of traditional Chinese medicine in addressing both emotional and physical symptoms associated with PMDD, shedding light on novel therapeutic approaches for this condition.

Noncortical cognition: integration of information for close-proximity behavioral problem-solving.

Animals face behavioral problems that can be conceptualized in terms of a gradient of spatial and temporal proximity. I propose that solving close-proximity behavioral problems involves integrating disparate types of information in complex and flexible ways. In this framework, the midbrain periaqueductal gray (PAG) is understood as a key region involved in close-proximity motivated cognition. Anatomically, the PAG has access to signals across the neuroaxis via extensive connectivity with cortex, subcortex, and brainstem. However, the flow of signals is not unidirectional, as the PAG projects to the cortex directly, and further ascending signal flow is attained via the midline thalamus. Overall, the anatomical organization of the PAG allows is to be a critical hub engaged in cognition "here and now".

Disruption of Electroencephalogram Coherence between Cortex/Striatum and Midbrain Dopaminergic Regions in the Knock-Out Mice with Combined Loss of Alpha, Beta, and Gamma Synucleins.

The malfunctioning of the brain synucleins is associated with pathogenesis of Parkinson's disease. Synucleins' ability to modulate various pre-synaptic processes suggests their modifying effects on the electroencephalogram (EEG) recorded from different brain structures. Disturbances in interrelations between them are critical for the onset and evolution of neurodegenerative diseases. Recently, we have shown that, in mice lacking several synucleins, differences between the frequency spectra of EEG from different brain structures are correlated with specificity of synucleins' combinations. Given that EEG spectra are indirect characteristics of inter-structural relations, in this study, we analyzed a coherence of instantaneous values for EEGs recorded from different structures as a direct measure of "functional connectivity" between them. METHODS: EEG data from seven groups of knock-out (KO) mice with combined deletions of alpha, beta, and gamma synucleins versus a group of wild-type (WT) mice were compared. EEG coherence was estimated between the cortex (MC), putamen (Pt), ventral tegmental area (VTA), and substantia nigra (SN) in all combinations. RESULTS: EEG coherence suppression, predominantly in the beta frequency band, was observed in KO mice versus WT littermates. The suppression was minimal in MC-Pt and VTA-SN interrelations in all KO groups and in all inter-structural relations in mice lacking either all synucleins or only beta synuclein. In other combinations of deleted synucleins, significant EEG coherence suppression in KO mice was dominant in relations with VTA and SN. CONCLUSION: Deletions of the synucleins produced significant attenuation of intra-cerebral EEG coherence depending on the imbalance of different types of synucleins.

Clinical Utility of Tectal Plate Measurements on Magnetic Resonance Imaging in Progressive Supranuclear Palsy.

BACKGROUND: Midbrain atrophy is a characteristic feature of progressive supranuclear palsy (PSP), observed in PSP-Richardson's syndrome (PSP-RS) and to a lesser extent PSP-parkinsonism (PSP-P). OBJECTIVE: Our aim was to critically evaluate the utility of manual magnetic resonance imaging measurements of the midbrain tectal plate as a diagnostic biomarker in PSP. METHODS: Length of the tectal plate and width of the superior and inferior colliculi were measured in 40 PSP (20 PSP-RS and 20 PSP-P) patients and compared with 20 Parkinson's disease and 20 healthy control subjects. RESULTS: Tectal plate length was reduced in both PSP groups compared with Parkinson's disease and control subjects and was most abnormal in PSP-RS followed by PSP-P. Reduced tectal plate length was associated with worse PSP Rating Scale scores. CONCLUSIONS: Simple manual measurements of tectal plate length show utility as a diagnostic biomarker in PSP, particularly for PSP-RS. © 2024 International Parkinson and Movement Disorder Society.

[Inhibition of glutamatergic neurons in the dorsomedial periaqueductal gray alleviates excessive defensive behaviors of mice with post-traumatic stress disorder].

OBJECTIVE: To investigate the role of glutamatergic neurons in the dorsomedial periaqueductal grey (dmPAG) in regulating excessive defensive behaviors in mice with post-traumatic stress disorder (PTSD). METHODS: Eight-week-old male C57BL/6 mice were subjected to stereotactic injections of different recombinant adeno- associated viral vectors (rAAV2/9-CaMKII-mCherry, rAAV2/9-CaMKII-hM3Dq-mCherry and rAAV2/9-CaMKII-hM4Di-mCherry) into the bilateral dmPAG for chemogenetic activation or inhibition of the glutamatergic neurons, followed 2 weeks later by PTSD modeling by single prolonged stress. The looming test, response to whisker stimulation test and contextual fear conditioning (CFC) test were used to observe changes in defensive behaviors of the PTSD mice. The activity of glutamatergic neurons in the dmPAG were observed using immunofluorescence staining. RESULTS: Compared with the control mice, the mouse models of PTSD showed a shortened latency of flights with increased time spent in the nest, response scores of defensive behaviors and freezing time (all P<0.01). Immunofluorescence staining revealed significantly increased c-fos-positive glutamatergic neurons in the dmPAG of PTSD mice with defensive behaviors. Activation of the glutamatergic neurons in the dmPAG (in PTSD hM3Dq group) did not cause significant changes in the latency of flights or time in nest but obviously increased response scores of defensive behaviors and freezing time of the mice, whereas inhibiting the glutamatergic neurons in the dmPAG (in PTSD hM4Di group) caused the reverse changes and obviously alleviated defensive behaviors in the PTSD mice (P<0.05 or 0.01). CONCLUSION: Inhibiting the activity of glutamatergic neurons in the dmPAG can alleviate defensive behaviors in mice with PTSD.

Delayed levodopa-responsive parkinsonism following acute midbrain injury.

Acute midbrain injury may cause both hyperkinetic movement disorders and parkinsonism. The temporal interval between the insult and the emergence of hyperkinetic disorders can last years. A delayed appearance of parkinsonism, on the other hand, was rarely described. We present three cases of male patients (50-, 58- and 28-year-old) who developed levodopa-responsive parkinsonism 20, 8 and two years, respectively, after acute brain insult involving the midbrain. Insults included subcortical intracerebral hemorrhage dissecting into the midbrain, embolic basilar occlusion and trauma. A fluorodopa scan, performed in two cases, revealed reduced striatal uptake. All individuals improved on low doses of levodopa and developed motor fluctuations shortly after levodopa was introduced. We conclude that delayed, levodopa-responsive parkinsonism following midbrain injury should be recognized in the relevant clinical setup. Possible mechanisms include age-related loss of dopaminergic neurons superimposed on acute injury and secondary neurodegeneration.

Quantitative brain stem assessment in discriminating neurodegenerative disorders from normal pressure hydrocephalus.

BACKGROUND AND PURPOSE: Differentiating idiopathic normal pressure hydrocephalus (iNPH) from neurodegenerative disorders such as progressive supranuclear palsy (PSP), Multiple System Atrophy-parkinsonian type (MSA-P), and vascular dementia (VaD) is challenging due to overlapping clinical and neuroimaging findings. This study assesses if quantitative brain stem and cerebellum metrics can aid in this differentiation. METHODS: We retrospectively compared the sagittal midbrain area, midbrain to pons ratio, MR parkinsonism index (MRPI), and cerebellar atrophy in 30 PSP patients, 31 iNPH patients, 27 MSA-P patients, 32 VaD patients, and 25 healthy controls. Statistical analyses determined group differences, sensitivity, specificity, and the area under the receiver operating characteristic curves. RESULTS: There was an overlap in midbrain morphology between PSP and iNPH, as assessed with MRPI, midbrain to pons ratio, and midbrain area. A cutoff value of MRPI > 13 exhibited 84% specificity in distinguishing PSP from iNPH and 100% in discriminating PSP from all other conditions. A cutoff value of midbrain to pons ratio at <0.15 yielded 95% specificity for differentiating PSP from iNPH and 100% from all other conditions. A cutoff value of midbrain area at <87 mm2 exhibited 97% specificity for differentiating PSP from iNPH and 100% from all other conditions. All measures showed low sensitivity. Cerebellar atrophy did not differ significantly among groups. CONCLUSION: Our study questions MRPI's diagnostic performance in distinguishing PSP from iNPH. Simpler indices such as midbrain to pons ratio and midbrain area showed similar or better accuracy. However, all these indices displayed low sensitivity despite significant differences among PSP, MSA-P, and VaD.