Repetitive pulsed-wave ultrasound stimulation suppresses neural activity by modulating ambient GABA levels via effects on astrocytes.

Ultrasound is highly biopermeable and can non-invasively penetrate deep into the brain. Stimulation with patterned low-intensity ultrasound can induce sustained inhibition of neural activity in humans and animals, with potential implications for research and therapeutics. Although mechanosensitive channels are involved, the cellular and molecular mechanisms underlying neuromodulation by ultrasound remain unknown. To investigate the mechanism of action of ultrasound stimulation, we studied the effects of two types of patterned ultrasound on synaptic transmission and neural network activity using whole-cell recordings in primary cultured hippocampal cells. Single-shot pulsed-wave (PW) or continuous-wave (CW) ultrasound had no effect on neural activity. By contrast, although repetitive CW stimulation also had no effect, repetitive PW stimulation persistently reduced spontaneous recurrent burst firing. This inhibitory effect was dependent on extrasynaptic-but not synaptic-GABAA receptors, and the effect was abolished under astrocyte-free conditions. Pharmacological activation of astrocytic TRPA1 channels mimicked the effects of ultrasound by increasing the tonic GABAA current induced by ambient GABA. Pharmacological blockade of TRPA1 channels abolished the inhibitory effect of ultrasound. These findings suggest that the repetitive PW low-intensity ultrasound used in our study does not have a direct effect on neural function but instead exerts its sustained neuromodulatory effect through modulation of ambient GABA levels via channels with characteristics of TRPA1, which is expressed in astrocytes.

Modulation of time in Parkinson's disease: a review and perspective on cognitive rehabilitation.

Time cognition is an essential function of human life, and the impairment affects a variety of behavioral patterns. Neuropsychological approaches have been widely demonstrated that Parkinson's disease (PD) impairs time cognitive processing. Many researchers believe that time cognitive deficits are due to the basal ganglia, including the striatum or subthalamic nucleus, which is the pathomechanism of PD, and are considered to produce only transient recovery due to medication effects. In this perspective, we focus on a compensatory property of brain function based on the improved time cognition independent of basal ganglia recovery and an overlapping structure on the neural network based on an improved inhibitory system by time cognitive training, in patients with PD. This perspective may lead to restoring multiple functions through single function training.

Activator of KAT3 histone acetyltransferase family ameliorates a neurodevelopmental disorder phenotype in the syntaxin 1A ablated mouse model.

Syntaxin-1A (stx1a) repression causes a neurodevelopmental disorder phenotype, low latent inhibition (LI) behavior, by disrupting 5-hydroxytryptaminergic (5-HTergic) systems. Herein, we discovered that lysine acetyltransferase (KAT) 3B increases stx1a neuronal transcription and TTK21, a KAT3 activator, induces stx1a transcription and 5-HT release in vitro. Furthermore, glucose-derived CSP-TTK21 could restore decreased stx1a expression, 5-HTergic systems in the brain, and low LI in stx1a (+/-) mice by crossing the blood-brain barrier, whereas the KAT3 inhibitor suppresses stx1a expression, 5-HTergic systems, and LI behaviors in wild-type mice. Finally, in wild-type and stx1a (-/-) mice treated with IKK inhibitors and CSP-TTK21, respectively, we show that KAT3 activator-induced LI improvement is a direct consequence of KAT3B-stx1a pathway, not a side effect. In conclusion, KAT3B can positively regulate stx1a transcription in neurons, and increasing neuronal stx1a expression and 5-HTergic systems by a KAT3 activator consequently improves the low LI behavior in the stx1a ablation mouse model.

Age- and sex-related oculomotor manifestation of dopamine deficiency in Segawa disease.

OBJECTIVE: To investigate the oculomotor manifestations of Segawa disease (SD), considered to represent mild dopamine deficiency and discuss their pathophysiological basis. METHODS: We recorded visually- (VGS) and memory-guided saccade (MGS) tasks in 31 SD patients and 153 age-matched control subjects to study how basal ganglia (BG) dysfunction in SD evolves with age for male and female subjects. RESULTS: SD patients were impaired in initiating MGS, showing longer latencies with occasional failure. Patients showed impaired ability to suppress reflexive saccades; saccades to cues presented in MGS were more frequent and showed a shorter latency than in control subjects. These findings were more prominent in male patients, particularly between 13 and 25 years. Additionally, male patients showed larger delay in MGS latency in trials preceded by saccades to cue than those unpreceded. CONCLUSIONS: The findings can be explained by a dysfunction of the BG-direct pathway impinging on superior colliculus (SC) due to dopamine deficiency. The disturbed inhibitory control of saccades may be explained by increased SC responsivity to visual stimuli. SIGNIFICANCE: Oculomotor abnormalities in SD can be explained by dysfunction of the BG inhibitory pathways reaching SC, with a delayed maturation in male SD patients, consistent with previous pathological/physiological studies.

Roles of the cerebellum and basal ganglia in temporal integration: Insights from a synchronized tapping task.

OBJECTIVE: The aim of this study was to clarify the roles of the cerebellum and basal ganglia for temporal integration. METHODS: We studied 39 patients with spinocerebellar degeneration (SCD), comprising spinocerebellar atrophy 6 (SCA6), SCA31, Machado-Joseph disease (MJD, also called SCA3), and multiple system atrophy (MSA). Thirteen normal subjects participated as controls. Participants were instructed to tap on a button in synchrony with isochronous tones. We analyzed the inter-tap interval (ITI), synchronizing tapping error (STE), negative asynchrony, and proportion of delayed tapping as indicators of tapping performance. RESULTS: The ITI coefficient of variation was increased only in MSA patients. The standard variation of STE was larger in SCD patients than in normal subjects, especially for MSA. Negative asynchrony, which is a tendency to tap the button before the tones, was prominent in SCA6 and MSA patients, with possible basal ganglia involvement. SCA31 patients exhibited normal to supranormal performance in terms of the variability of STE, which was surprising. CONCLUSIONS: Cerebellar patients generally showed greater STE variability, except for SCA31. The pace of tapping was affected in patients with possible basal ganglia pathology. SIGNIFICANCE: Our results suggest that interaction between the cerebellum and the basal ganglia is essential for temporal processing. The cerebellum and basal ganglia and their interaction regulate synchronized tapping, resulting in distinct tapping pattern abnormalities among different SCD subtypes.

The Pathophysiology of Gilles de la Tourette Syndrome: Changes in Saccade Performance by Low-Dose L-Dopa and Dopamine Receptor Blockers.

AIM: To elucidate the pathophysiology of Gilles de la Tourette syndrome (GTS), which is associated with prior use of dopamine receptor antagonists (blockers) and treatment by L-Dopa, through saccade performance. METHOD: In 226 male GTS patients (5-14 years), we followed vocal and motor tics and obsessive-compulsive disorder (OCD) after discontinuing blockers at the first visit starting with low-dose L-Dopa. We recorded visual- (VGS) and memory-guided saccades (MGS) in 110 patients and 26 normal participants. RESULTS: At the first visit, prior blocker users exhibited more severe vocal tics and OCD, but not motor tics, which persisted during follow-up. Patients treated with L-Dopa showed greater improvement of motor tics, but not vocal tics and OCD. Patients with and without blocker use showed similarly impaired MGS performance, while patients with blocker use showed more prominently impaired inhibitory control of saccades, associated with vocal tics and OCD. DISCUSSION: Impaired MGS performance suggested a mild hypodopaminergic state causing reduced direct pathway activity in the (oculo-)motor loops of the basal ganglia-thalamocortical circuit. Blocker use may aggravate vocal tics and OCD due to disinhibition within the associative and limbic loops. The findings provide a rationale for discouraging blocker use and using low-dose L-Dopa in GTS.

Comparison of the Molecular Motility of Tubulin Dimeric Isoforms: Molecular Dynamics Simulations and Diffracted X-ray Tracking Study.

Tubulin has been recently reported to form a large family consisting of various gene isoforms; however, the differences in the molecular features of tubulin dimers composed of a combination of these isoforms remain unknown. Therefore, we attempted to elucidate the physical differences in the molecular motility of these tubulin dimers using the method of measurable pico-meter-scale molecular motility, diffracted X-ray tracking (DXT) analysis, regarding characteristic tubulin dimers, including neuronal TUBB3 and ubiquitous TUBB5. We first conducted a DXT analysis of neuronal (TUBB3-TUBA1A) and ubiquitous (TUBB5-TUBA1B) tubulin dimers and found that the molecular motility around the vertical axis of the neuronal tubulin dimer was lower than that of the ubiquitous tubulin dimer. The results of molecular dynamics (MD) simulation suggest that the difference in motility between the neuronal and ubiquitous tubulin dimers was probably caused by a change in the major contact of Gln245 in the T7 loop of TUBB from Glu11 in TUBA to Val353 in TUBB. The present study is the first report of a novel phenomenon in which the pico-meter-scale molecular motility between neuronal and ubiquitous tubulin dimers is different.

Quadripulse transcranial magnetic stimulation inducing long-term depression in healthy subjects may increase seizure risk in some patients with intractable epilepsy.

Objective: This study aimed to assess the efficacy and safety of quadripulse transcranial magnetic stimulation-50 (QPS-50) in patients with intractable epilepsy. Methods: Four patients were included in the study. QPS-50, which induces long-term depression in healthy subjects, was administered for 30 min on a weekly basis for 12 weeks. Patients' clinical symptoms and physiological parameters were evaluated before, during, and after the repeated QPS-50 period. We performed two control experiments: the effect in MEP (Motor evoked potential) size after a single QPS-50 session with a round coil in nine healthy volunteers, and a follow-up study of physiological parameters by repeated QPS-50 sessions in four other healthy participants. Results: Motor threshold (MT) decreased during the repeated QPS-50 sessions in all patients. Epileptic symptoms worsened in two patients, whereas no clinical worsening was observed in the other two patients. In contrast, MT remained unaffected for 12 weeks in all healthy volunteers. Conclusions: QPS-50 may not be effective as a treatment for intractable epilepsy. Significance: In intractable epilepsy patients, administering repeated QPS-50 may paradoxically render the motor cortex more excitable, probably because of abnormal inhibitory control within the epileptic cortex. The possibility of clinical aggravation should be seriously considered when treating intractable epilepsy patients with non-invasive stimulation methods.

Abnormal saccade profiles in hereditary spinocerebellar degeneration reveal cerebellar contribution to visually guided saccades.

OBJECTIVE: To study how the pathophysiology underlying hereditary spinocerebellar degeneration (spinocerebellar ataxia; SCA) with pure cerebellar manifestation evolves with disease progression using saccade recordings. METHODS: We recorded visually- (VGS) and memory-guided saccade (MGS) task performance in a homogeneous population of 20 genetically proven SCA patients (12 SCA6 and eight SCA31 patients) and 19 normal controls. RESULTS: For VGS but not MGS, saccade latency and amplitude were increased and more variable than those in normal subjects, which correlated with cerebellar symptom severity assessed using the International Cooperative Ataxia Rating Scale (ICARS). Parameters with significant correlations with cerebellar symptoms showed an aggravation after disease stage progression (ICARS > 50). The saccade velocity profile exhibited shortened acceleration and prolonged deceleration, which also correlated with disease progression. The main sequence relationship between saccade amplitude and peak velocity as well as saccade inhibitory control were preserved. CONCLUSIONS: The cerebellum may be involved in initiating VGS, which was aggravated acutely during disease stage progression. Dysfunction associated with disease progression occurs mainly in the cerebellum and brainstem interaction but may also eventually involve cortical saccade processing. SIGNIFICANCE: Saccade recording can reveal cerebellar pathophysiology underlying SCA with disease progression.

How do patients with Parkinson's disease and cerebellar ataxia read aloud? -Eye-voice coordination in text reading.

Background: The coordination between gaze and voice is closely linked when reading text aloud, with the gaze leading the reading position by a certain eye-voice lead (EVL). How this coordination is affected is unknown in patients with cerebellar ataxia and parkinsonism, who show oculomotor deficits possibly impacting coordination between different effectors. Objective: To elucidate the role of the cerebellum and basal ganglia in eye-voice coordination during reading aloud, by studying patients with Parkinson's disease (PD) and spinocerebellar degeneration (SCD). Methods: Participants were sixteen SCD patients, 18 PD patients, and 30 age-matched normal subjects, all native Japanese speakers without cognitive impairment. Subjects read aloud Japanese texts of varying readability displayed on a monitor in front of their eyes, consisting of Chinese characters and hiragana (Japanese phonograms). The gaze and voice reading the text was simultaneously recorded by video-oculography and a microphone. A custom program synchronized and aligned the gaze and audio data in time. Results: Reading speed was significantly reduced in SCD patients (3.53 ± 1.81 letters/s), requiring frequent regressions to compensate for the slow reading speed. In contrast, PD patients read at a comparable speed to normal subjects (4.79 ± 3.13 letters/s vs. 4.71 ± 2.38 letters/s). The gaze scanning speed, excluding regressive saccades, was slower in PD patients (9.64 ± 4.26 letters/s) compared to both normal subjects (12.55 ± 5.42 letters/s) and SCD patients (10.81 ± 4.52 letters/s). PD patients' gaze could not far exceed that of the reading speed, with smaller allowance for the gaze to proceed ahead of the reading position. Spatial EVL was similar across the three groups for all texts (normal: 2.95 ± 1.17 letters/s, PD: 2.95 ± 1.51 letters/s, SCD: 3.21 ± 1.35 letters/s). The ratio of gaze duration to temporal EVL was lowest for SCD patients (normal: 0.73 ± 0.50, PD: 0.70 ± 0.37, SCD: 0.40 ± 0.15). Conclusion: Although coordination between voice and eye movements and normal eye-voice span was observed in both PD and SCD, SCD patients made frequent regressions to manage the slowed vocal output, restricting the ability for advance processing of text ahead of the gaze. In contrast, PD patients experience restricted reading speed primarily due to slowed scanning, limiting their maximum reading speed but effectively utilizing advance processing of upcoming text.

Early detection of cognitive decline in Alzheimer's disease using eye tracking.

Background: Patients with Alzheimer's disease (AD) are known to exhibit visuospatial processing impairment, as reflected in eye movements from the early stages of the disease. We investigated whether the pattern of gaze exploration during visual tasks could be useful for detecting cognitive decline at the earliest stage. Methods: Sixteen AD patients (age: 79.1 ± 7.9 years, Mini Mental State Examination [MMSE] score: 17.7 ± 5.3, mean ± standard deviation) and 16 control subjects (age: 79.4 ± 4.6, MMSE score: 26.9 ± 2.4) participated. In the visual memory task, subjects memorized presented line drawings for later recall. In the visual search tasks, they searched for a target Landolt ring of specific orientation (serial search task) or color (pop-out task) embedded among arrays of distractors. Using video-oculography, saccade parameters, patterns of gaze exploration, and pupil size change during task performance were recorded and compared between AD and control subjects. Results: In the visual memory task, the number of informative regions of interest (ROIs) fixated was significantly reduced in AD patients compared to control subjects. In the visual search task, AD patients took a significantly longer time and more saccades to detect the target in the serial but not in pop-out search. In both tasks, there was no significant difference in the saccade frequency and amplitude between groups. On-task pupil modulation during the serial search task was decreased in AD. The number of ROIs fixated in the visual memory task and search time and saccade numbers in the serial search task differentiated both groups of subjects with high sensitivity, whereas saccade parameters of pupil size modulation were effective in confirming normal cognition from cognitive decline with high specificity. Discussion: Reduced fixation on informative ROIs reflected impaired attentional allocation. Increased search time and saccade numbers in the visual search task indicated inefficient visual processing. Decreased on-task pupil size during visual search suggested decreased pupil modulation with cognitive load in AD patients, reflecting impaired function of the locus coeruleus. When patients perform the combination of these tasks to visualize multiple aspects of visuospatial processing, cognitive decline can be detected at an early stage with high sensitivity and specificity and its progression be evaluated.

Role of the subthalamic nucleus in perceiving and estimating the passage of time.

Sense of time (temporal sense) is believed to be processed by various brain regions in a complex manner, among which the basal ganglia, including the striatum and subthalamic nucleus (STN), play central roles. However, the precise mechanism for processing sense of time has not been clarified. To examine the role of the STN in temporal processing of the sense of time by directly manipulating STN function by switching a deep brain stimulation (DBS) device On/Off in 28 patients with Parkinson's disease undergoing STN-DBS therapy. The test session was performed approximately 20 min after switching the DBS device from On to Off or from Off to On. Temporal sense processing was assessed in three different tasks (time reproduction, time production, and bisection). In the three temporal cognitive tasks, switching STN-DBS to Off caused shorter durations to be produced compared with the switching to the On condition in the time production task. In contrast, no effect of STN-DBS was observed in the time bisection or time reproduction tasks. These findings suggest that the STN is involved in the representation process of time duration and that the role of the STN in the sense of time may be limited to the exteriorization of memories formed by experience.

Hand-foot coordination is significantly influenced by motion direction in individuals with autism spectrum disorder.

Generally, when individuals attempt to move two limbs rhythmically in the opposite direction (e.g., flex the left hand and extend the left foot along the sagittal plane), the movements tend to be instead performed in the same direction. This phenomenon, known as directional constraint, can be harnessed to examine the difficulties in movement coordination exhibited by most individuals with autism spectrum disorder (ASD). While such difficulties have already been investigated through standardized clinical assessments, they have not been examined through kinematic methods. Thus, we employed a clinical assessment scale in an experimentally controlled environment to investigate whether stronger directional constraint during the rhythmic movement of two limbs is more pronounced and associated with decreased movement coordination in individuals with ASD. ASD and typically developing (TD) participants were asked to rhythmically move two limbs either in the same or opposite directions. In addition, the coordination skills of participants were assessed using the Bruininks-Oseretsky Test of Motor Proficiency Second Edition (BOT-2). Subjects with ASD showed significantly stronger directional constraint than TD participants during the contralateral and ipsilateral movement of the hand and foot. According to the pooled data from both groups, participants who showed stronger directional constraint during these two movement conditions also exhibited poorer coordinated movement skills in the BOT-2. These results suggest that people with ASD may have difficulties in inhibiting the neural signals that synchronize the direction of inter-limb movements, thus resulting in coordination disabilities. LAY SUMMARY: Individuals with autism spectrum disorder (ASD) often exhibit difficulties in coordinated movements. We asked those with ASD and typically developing (TD) participants to move two limbs (e.g., left hand and left foot) either in the same or the opposite direction. Results demonstrated that participants with ASD had more difficulties in counteracting the tendency of their hand and foot to synchronously move in the same direction. Our findings suggested that difficulties to suppress synchronized movements of the hand and foot result in coordination disabilities.

Golgi stress induces upregulation of the ER-Golgi SNARE Syntaxin-5, altered ßAPP processing, and Caspase-3-dependent apoptosis in NG108-15 cells.

The involvement of secretory pathways and Golgi dysfunction in neuronal cells during Alzheimer's disease progression is poorly understood. Our previous overexpression and knockdown studies revealed that the intracellular protein level of Syntaxin-5, an endoplasmic reticulum-Golgi soluble N-ethylmaleimide-sensitive factor-attachment protein receptor (SNARE), modulates beta-amyloid precursor protein processing in neuronal cells. We recently showed that changes in endogenous Syntaxin-5 protein expression occur under stress induction. Syntaxin-5 was upregulated by endoplasmic reticulum stress but was degraded by Caspase-3 during apoptosis in neuronal cells. In addition, we showed that sustained endoplasmic reticulum stress promotes Caspase-3-dependent apoptosis during the later phase of the endoplasmic reticulum stress response in NG108-15 cells. In this study, to elucidate the consequences of secretory pathway dysfunction in beta-amyloid precursor protein processing that lead to neuronal cell death, we examined the effect of various stresses on endoplasmic reticulum-Golgi SNARE expression and beta-amyloid precursor protein processing. By using compounds to disrupt Golgi function, we show that Golgi stress promotes upregulation of the endoplasmic reticulum-Golgi SNARE Syntaxin-5, and prolonged stress causes Caspase-3-dependent apoptosis. Golgi stress induced intracellular beta-amyloid precursor protein accumulation and a concomitant decrease in total amyloid-beta production. We also examined the protective effect of the chemical chaperone 4-phenylbutylate on changes in amyloid-beta production and the activation of Caspase-3 induced by endoplasmic reticulum and Golgi stress. The compound alleviated the increase in the amyloid-beta 1-42/amyloid-beta 1-40 ratio induced by endoplasmic reticulum and Golgi stress. Furthermore, 4-phenylbutylate could rescue Caspase-3-dependent apoptosis induced by prolonged organelle stress. These results suggest that organelle stress originating from the endoplasmic reticulum and Golgi has a substantial impact on the amyloidogenic processing of beta-amyloid precursor protein and Caspase-3-dependent apoptosis, leading to neuronal cell death.

Inducing Cortical Plasticity to Manipulate and Consolidate Subjective Time Interval Production.

OBJECTIVES: Time awareness may change depending on the mental state or disease conditions, although each individual perceives his/her own sense of time as stable and accurate. Nevertheless, the processes that consolidate altered duration production remain unclear. The present study aimed to manipulate the subjective duration production via memory consolidation through the modulation of neural plasticity. MATERIALS AND METHODS: We first performed false feedback training of duration or length production and examined the period required for natural recovery from the altered production. Next, persistent neural plasticity was promoted by quadripulse transcranial magnetic stimulation (QPS) over the right dorsolateral prefrontal cortex (DLPFC), temporoparietal junction (TPJ), and primary motor cortex (M1). We conducted the same feedback training in the individual and studied how the time course of false learning changed. RESULTS: We observed that altered duration production after false feedback returned to baseline within two hours. Next, immediate exposure to false feedback during neural plasticity enhancement revealed that in individuals who received QPS over the right DLPFC, but not over TPJ or M1, false duration production was maintained for four hours; furthermore, the efficacy persisted for at least one week. CONCLUSION: These findings suggest that, while learned altered duration production decays over several hours, QPS over the right DLPFC enables the consolidation of newly learned duration production.

Temporal synchronization for in-phase and antiphase movements during bilateral finger- and foot-tapping tasks.

Appropriate motor performance, which must be precisely processed and timed to temporal and spatial requirements, can be studied using a synchronized tapping task. For gait rehabilitation, estimation of bilateral foot-tapping accuracy is important, as walking involves bilateral movements, usually antiphase, of the lower extremities. Rhythmic control of lower limb movements, such as gait, involves voluntary control and may also be automatically regulated by the central pattern generator. This study investigated the temporal synchronization of in-phase and antiphase movements using synchronized bilateral finger and foot-tapping tasks. Thirty healthy young adult volunteers were enrolled and instructed to tap the finger or foot button synchronously with the tones presented at fixed inter-stimulus intervals (ISIs). One of 10 different ISIs (250-4800 ms) was selected for each block, in which 110 tones were presented. Taps were performed by either unilateral or bilateral fingers or feet, either in-phase (to move bilateral fingers or ankles simultaneously) or antiphase (to move bilateral fingers or ankles alternately). The synchronization error (SE) and coefficient of variation (CV) of the inter-tap interval (ITI) were evaluated. In all trials with short ISIs, SEs were narrowly distributed, either clustered around 0 ms or with a slightly negative value. Although SE variability gradually increased with increasing ISI, the CV of ITI was significantly lower for antiphase movement than for unilateral or in-phase movement in the foot-tapping task, but not in the finger-tapping task. The preserved temporal synchronization for antiphase movement of the foot, but not finger tapping, may be due to the neural mechanisms underlying locomotion.

Quantitative Evaluation of Cerebellar Function in Multiple System Atrophy with Transcranial Magnetic Stimulation.

Objective evaluation of cerebellar dysfunction in neurodegenerative disorders is often difficult because of other overlapping symptoms. Cerebellar inhibition (CBI) tested by dual-coil transcranial magnetic stimulation (TMS) is anticipated as a promising measure to estimate cerebellar function. Cerebellar TMS inhibits the primary motor cortex (M1), which can be measured as the decrease of motor evoked potential (MEP) elicited by a single-pulse TMS over the M1. This study was conducted to quantify cerebellar dysfunction using CBI in cerebellar type multiple system atrophy (MSA-C) patients. First, CBI was measured using MEP elicited from a hand muscle by stimulating the hand motor area of M1. The amount of CBI was defined as the degree of decrease in the MEP amplitude in the presence of cerebellar stimulation compared with the condition of M1 stimulation alone. Results of the MSA-C patients were compared with those of healthy volunteers. Correlation between amounts of CBI and a clinical scale of ataxia, the International Cooperative Ataxia Scale Rating (ICARS), was assessed. Healthy volunteers showed more inhibition than MSA-C patients. Moreover, ICARS showed that the CBI amount in the patients is correlated with the degree of ataxia significantly. Results suggest that CBI can be a good marker of disease progression in MSA-C patients.

Deciphering the saccade velocity profile of progressive supranuclear palsy: A sign of latent cerebellar/brainstem dysfunction?

OBJECTIVE: To study whether the velocity profile of horizontal saccades could be used as an indicator of brainstem and cerebellar output dysfunction, depending on progressive supranuclear palsy (PSP) subtype. METHODS: We compared the velocity profiles in 32 PSP patients of various subtypes with 38 age-matched normal subjects, including Richardson syndrome (RS), PSP-parkinsonism (PSPp), and pure akinesia (PAGF), and cerebellar subtypes of PSP (PSPc). RESULTS: PSP patients showed reduced peak velocity along with increased duration, especially in the deceleration phase. This alteration was more prominent for larger target eccentricities (20-30 degrees), and correlated with disease severity. The changes were most pronounced in PSPc patients, with irregular increases and decreases in velocity profile, followed by RS patients, whereas the change was smaller in PSPp and normal in PAGF patients. CONCLUSIONS: Saccade velocity profile can be an indicator of brainstem and/or cerebellar output. Altered velocity profile of PSP patients may reflect the pathology in the brainstem, but may also reflect cerebellar dysfunction, most prominently in PSPc. SIGNIFICANCE: Saccade velocity profile may be used as an indicator of latent cerebellar/brainstem dysfunction.