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This paper gives an account of single Purkyně cell responses when three types of mechanical stimulation, as in the previous paper, are applied to the forefoot and hindfoot of the decerebrate unanesthetized cat. Attention was concentrated on the effects of brief mechanical pulses to the footpad. Recording was extracellular by glass microelectrodes and special precautions were taken in identifying the spike responses as being due to a single Purkyně cell and in securing its effective isolation for our computer averaging techniques, as described in the previous papers. All Purkyně cells were in the ipsilateral anterior lobe in the lateral vermis or pars intermedia of lobules III, IV, V, except for a few recordings in the extreme rostral zone of lobule VI. Mechanical pulses or taps evoked responses from many Purkyně cells which were pure excitatory, pure inhibitory or admixtures thereof. The latencies of onset were usually in the range of 12-20 msec from the onset of the tap, which tends to be a little longer than the observed latencies for mossy fiber responses described in the preceding paper. There was often a considerable difference in the sizes of the responses evoked from different pads of the same foot, and the usual threshold for response was below 0.2 mm amplitude. Durations of responses were usually 10-20 msec for excitation and 50-100 msec for inhibition. Pressure pulses to the central foot pads of 2 sec duration evoked a wide variety of responses: brief phasic at 'on' and 'off' that could be admixtures of excitation and inhibition; almost pure tonic excitations or inhibitions that were well maintained during the 2 sec; phasic-tonic responses in various relative degrees. Usually 500 g was maximally effective and the threshold was below 100 g. Hair receptors were stimulated preferentially by brief air jets, there being brief excitatory or inhibitory responses much as with taps, but with rather longer latency. The effective area was usually fairly extensive over the hairy skin of the foot. In general the effects on Purkyně cells by cutaneous mechanoreceptors acting via mossy fibers were in accord with the mossy fiber responses reported in the preceding paper and with the well-known excitatory and inhibitory effects that are exerted by mossy fiber inputs on Purkyně cells. [ABSTRACT FROM AUTHOR]

The 275 Purkyně cells identified by the criteria of the previous paper have been investigated with respect to their role as units integrating the input to the anterior lobe from various limb nerves. The discharges from single Purkyně cells have been studied in lightly anesthetized (pentothal) or in decerebrate unanesthetized cats, there being averaging usually of 128 responses in the form of post-stimulus time histograms and cumulative frequency distributions. Single Purkyně cells exhibited a wide variation in their responses to the diverse inputs from the various afferent nerves. Attention was focussed on excitatory and inhibitory responses evoked by mossy fibers with a short latency, usually 10-15 msec for hindlimb afferents. With most Purkyně cells these responses were predominantly evoked from cutaneous nerves, low threshold fibers being particularly effective. A few Purkyně cells were preponderantly excited by afferent volleys from muscle nerves, but there was a large group with a mixed input from cutaneous and muscle nerves. Graded strengths of stimulation of muscle nerves showed that sometimes group I volleys were prepotent, but other Purkyně cells were selectively excited by group II volleys. Though sometimes the afferent volleys from antagonistic muscles had a reciprocal action on a Purkyně cell, as on a motoneurone, it was more common to find similar actions. Also convergence of inputs from forelimb and hindlirnb nerves, both cutaneous and muscular, was not uncommon, particularly in marginal areas between hindlimb and forelimb zones. A special design feature is the convergence onto a Purkyně cell of mossy fiber and climbing fiber inputs evoked by the same afferent volley. This convergence was of particular interest along the parasagittal strip of hindlimb climbing fiber distribution in lobule V. It was not possible to translate the observations into some map of the cerebellar cortex on which are marked the territorial distributions from the various limb afferent nerves. Rather, there was an ill-defined patchy character, closely adjacent Purkyně cells often receiving very different subsets of the total input from the various limb nerves. The unitary integrations accomplished by the individual Purkyně cells are further integrated when their axons converge onto and inhibit the neurones of the cerebellar nuclei, and this integration by convergence would occur in each successive relay on the output pathways from the cerebellum. It is pointed out that the experimental findings on the integrative action of the individual Purkyně cells provide basic information for attempts to construct models simulating cerebellar performance and control. [ABSTRACT FROM AUTHOR]

This paper gives an account of the responses of cerebellar fastigial cells to various afferent inputs from ipsilateral forelimb or hindlimb. Most of the preparations (17 out of 25) have been decerebrate and unanesthetized. The remainder were under anesthesia - chloralose, pentothal or surital. The afferent inputs have been provided by stimulation of predominantly cutaneous limb nerves or by three types of mechanical stimulation: taps to foot pads; pressure on foot pads; air jets to hairy skin. Recording from single fastigial cells was extracellular by glass microelectrodes, and computer averaging techniques of spike responses were employed as described in previous papers. Identification of fastigial cells was simply from location in the large fastigial nucleus, this location being later confirmed by identification of microelectrode tracks in histological sections. Fastigial cells display a fairly steady background discharge, the mean being 37 Hz for the decerebrate and considerably lower for the anesthetized. Pad taps usually evoked a diphasic (excitatory-inhibitory) response, but in some cases the inhibitory was dominant, in others the excitatory. The threshold was below 0.2 mm, and several fastigial cells were excited or inhibited by taps of only 0.01 mm. Air jet stimulation of hairy skin of the foot evoked similar responses. Durations of excitation were usually about 10 msec but inhibition was longer, usually about 50 msec. Nerve stimulation evoked responses of comparable type, but the latency was at least 4 msec shorter, corresponding to the more direct and shorter pathways from the site of stimulation. With some fastigial cells steady pressure to central foot pads of 2 sec duration evoked only brief phasic responses (excitatory or inhibitory) at 'on' and 'off'. With other cells there were tonic responses - excitation or inhibition or admixtures thereof - for the whole duration of the pressure. Usually 500 g was almost maximally effective, and the threshold was always below 100 g. In an indeterminate type of response (the semitonic) the excitation or inhibition at 'on' persisted for up to 500 msec, an effect matching the response of the rapidly adapting receptors of the pads. With repetitive stimulation both the excitatory and inhibitory responses to pad taps were reduced with frequencies above 1 Hz and greatly depressed at 5 to 7 Hz. However a small inhibition was observed to persist during tap frequencies as high as 65 Hz. In a preliminary study both the background and the evoked responses of fastigial cells were found to be very sensitive to barbiturate anesthesia. [ABSTRACT FROM AUTHOR]

This paper gives an account of single mossy fiber responses when three types of mechanical stimulation are applied to the forefoot and hindfoot of the cat which is either decerebrate and unanesthetized or lightly anesthetized by pentothal or chloralose. The mechanical stimuli were applied either to footpads (brief pulses, taps, or longer square pulses or ramps) or to the hairy skin by air jets. Recording of single mossy fibers was extracellular by glass microelectrodes that were inserted into the granular layer of the cerebellar cortex or the subjacent white matter. As described in previous papers computer averaging techniques usually of 64 responses have been employed to enhance reliability. Taps evoked pure excitatory responses from many mossy fibers, which were usually brief high frequency bursts resembling those evoked by nerve volleys. Usually the threshold displacement was less than 0.2 mm and thresholds as low as 0.01 mm were observed. There were often considerable differences in the intensities of responses from different pads of the same foot. Successive pulses of mechanical stimulation evoked mossy fiber responses of diminished intensity. Longer mechanical stimuli with square or ramp onsets evoked various admixtures of phasic and tonic responses. Hair stimulation was often a very effective excitant, the receptive field for a single mossy fiber usually covering a considerable area of foot and leg. Taps and pressure to the pads were also effective in inhibiting the background discharge of some mossy fibers, and admixtures of excitatory and inhibitory actions were observed. The results are discussed in relationship to the discharges evoked in primary afferent fibers by cutaneous mechanoreceptor stimulation. They provide an intermediate stage of information between mechanoreceptor stimulation and the response of Purkyně cells as described in the next paper. [ABSTRACT FROM AUTHOR]

In the preceding paper ( Appelberg and Molander 1967) the caudal part of the red nucleus and parts of the inferior olivary nucleus were shown to cause increased dynamic sensitivity of muscle spindles when stimulated repetitively. The results to be presented will show that single shock electrical stimulation in the caudal part of the red nucleus evoked a field potential in the inferior olivary nucleus. This response seemed to be monosynaptically evoked and was observed only in parts of the olive where repetitive stimulation caused increased dynamic sensitivity of muscle spindles. Stimulation in the red nucleus as well as single shock stimulation in the actual part of the inferior olive also caused a potential in the vermis of the posterior cerebellar lobe. In conditioning - test experiments with the two stimuli the conditioning shock was seen to cause alternating periods of decreased and increased responsiveness in the pathway concerned. The same type of interaction was seen between two responses caused by double shock stimulation in the red nucleus. It is concluded that information from the caudal part of the red nucleus reaches dynamic fusimotor neurones in the spinal cord via a relay in the inferior olivary nucleus; an additional relay in the pathway is also predicted. The cerebellum seems to receive information about ongoing activity in the pathway but mesencephalic stimulation was seen to cause spindle effects also in decerebellated animals. [ABSTRACT FROM AUTHOR]

Voluntary movements induce postural perturbations, which are counteracted by anticipatory postural adjustments (APAs) that preserve body equilibrium. Little is known about the neural structures generating APAs, but several studies suggested a role of sensory-motor areas, basal ganglia, supplementary motor area and thalamus. However, the role of the cerebellum still remains an open question. The aim of this present paper is to shed further light on the role of cerebellum in APAs organization. Thus, APAs that stabilize the arm when the index finger is briskly flexed were recorded in 13 ataxic subjects (seven sporadic cases, four dominant ataxia type III and two autosomal recessive), presenting a slowly progressive cerebellar syndrome with four-limb dysmetria, and compared with those obtained in 13 healthy subjects. The pattern of postural activity was similar in the two groups [excitation in triceps and inhibition in biceps and anterior deltoid (AD)], but apparent modifications in timing were observed in all ataxic subjects in which, on average, triceps brachii excitation lagged the onset of the prime mover flexor digitorum superficialis by about 27 ms and biceps and AD inhibition were almost synchronous to it. Instead, in normal subjects, triceps onset was synchronous to the prime mover and biceps and AD anticipated it by about 40 ms. The observed disruption of the intra-limb APA organization confirms that the cerebellum is involved in APA control and, considering cerebellar subjects as a model of dysmetria, also supports the view that a proper APA chain may play a crucial role in refining movement metria. [ABSTRACT FROM AUTHOR]

This paper reviews results that support a model in which memory for VOR gain is initially encoded in the flocculus, and in which cerebellar LTD and LTP are responsible for gain increases and gain decreases, respectively. We also review data suggesting that after it is encoded, motor memory can either be disrupted, possibly by a local mechanism, or else consolidated. We show that consolidation can be rapid, in which case the frequency dependence of learning is unchanged and we will argue that this is consistent with a local mechanism of consolidation. In the longer term, however, the available evidence supports the transfer of memory out of the flocculus. In new experiments reported here, we address the mechanism of memory encoding. Pharmacological evidence shows that both mGluR1 and GABA receptors in the flocculus are necessary for gain-up, but not for gain-down learning. Immunohistochemical experiments show that the two receptors are largely segregated on different dendritic spines on Purkinje cells. Together with what is already known of the mechanisms of cerebellar LTD and LTP, our data suggest that the direction of learning may be determined by interactions among groups of spines. Our results also provide new evidence for the existence of frequency channels for vestibular signals within the cerebellar cortex. [ABSTRACT FROM AUTHOR]

It is known that the medio-posterior cerebellar lobules VI/VII of the vermis and caudal part of the fastigial nucleus (cFN) are involved in the control of saccadic displacements of the visual axis in space (gaze). We have recently shown in the head-unrestrained cat that inactivation of the cFN severely impairs the accuracy of orienting gaze shifts toward visual targets by altering the amplitude of both eye and head components. In the present paper, we report additional data that indicate that the deficits induced by cFN inactivation are not restricted to saccadic gaze shifts but extend to the forward reaching movement of the whole body toward a visual target. Indeed, the path followed by the animal walking toward a visible food target was systematically curved toward the inactivated side. This deficit could largely be accounted for by an angular bias in the heading direction used by the animal to reach the target. These data suggest that pharmacological inactivation of the cFN leads to a general deficit in spatial orientation. [ABSTRACT FROM AUTHOR]

The time-course of human adaptation to spatial perturbations of visuomotor function (e.g. with prisms) is very short. However, it is not clear how rapid the adaptation to other aspects of perturbed feedback is. In this paper we report the adaptation to delayed visual feedback. Three groups of six subjects tracked unpredictable, continuously moving targets using a hand-held joystick while visual feedback of the joystick position was delayed (0 ms, 200 ms or 300 ms). Subjects clearly adapted to the delay, with a significant drop in tracking error, but changes in more subtle aspects of their tracking behaviour (such as changes in intermittency and their "impulse response functions") were not consistently observed. We suggest that the adaptation seen was consistent with the idea of there being a "delay component" in the internal processes used in manual tracking, as proposed in models such as the Smith predictor model. [ABSTRACT FROM AUTHOR]

The study addresses the issue of the role of the cerebellum in human withdrawal-reflex conditioning by comparing data from patients with pure cerebellar diseases (CBL, n=10) and from cerebellar patients showing additional extracerebellar symptoms (CBL+, n=10 ) with those from 11 control subjects (CTRL). During recording sessions, the standard delay-conditioning paradigm with paired-trials was used with tone as the conditioned stimulus (CS). Parameters of the conditioned muscle responses are analyzed in an accompanying paper. Here, we focus on the unconditioned muscle response. A train of current pulses (unconditioned stimulus, US) evoked a lower-limb withdrawal reflex (unconditioned response, UR), which was recorded electromyographically from leg muscles. During the recording sessions with CTRL subjects, UR amplitudes decayed from initially 100% to approximately 50% at the end of the session. This type of decay was clearly less pronounced in the CBL group and minimal in the CBL+ group. Furthermore, the CBL group exhibited UR onsets that were delayed by 20 ms compared with those from CTRL subjects. Although the ranges of measurements characterizing the URs of a given cerebellar patient tested in the paired-trial paradigm overlapped with those of control subjects, the statistically significant differences observed at the group level suggest deficits in the performance of the reflex responses. The delayed URs in patients and the different type of decay of UR amplitudes in repetitively evoked withdrawal reflexes constitute evidence that the cerebellum is critically involved in the control of these UR parameters. [ABSTRACT FROM AUTHOR]

This paper reports the effect of limb movement speed on dorsal spinocerebellar tract (DSCT) activity recorded while the cat hindlimb was passively moved through two types of foot trajectories (figure eight and step cycle) at different speeds. While nearly all the DSCT neurons sampled (151/159; 94.5%) were significantly modulated by the direction of foot movement in these trajectories, they were only modestly influenced by movement speed. We quantified the speed effect and also accounted for intrinsic cell variability by computing a variability index (VI) between pairs of responses to trajectories made either at the same or at different speeds. The distribution of same-speed VIs across cells indicated a mean variability of about 10% over a trajectory cycle, whereas the two-speed distributions indicated a mean change of about 25% for a two- to fourfold change in movement speed. We also examined the relative contribution of movement speed to the activity of each DSCT cell by means of a multivariate regression model that also included as predictors the position, movement direction, and interactions between movement and position. We found that 28 of 103 (27.2%) neurons were not sensitive to movement speed. The rest were modulated in varying degrees by changes in speed, and the speed modulation depended on limb position for most of them (54/75). Overall, DSCT speed sensitivity resembles the 0.3-power relationship used to describe the velocity sensitivity of muscle spindles for large muscle stretches. We examined this by recording muscle spindle activity during these passive foot trajectories and found that their speed sensitivity was within the range observed for the DSCT and explained by the 0.3-power law. In total, movement speed accounted for about 15% of the variance in DSCT activity across cells, while the directional component of movement accounted for about 45%. The results suggest a separate processing of sensory information about the two components of movement velocity: namely, its direction and magnitude. [ABSTRACT FROM AUTHOR]

The spatial coincidence of somatosensory cerebral cortex (SI) and trigeminal projections to the cerebellar hemisphere has been previously demonstrated. In this paper we describe the temporal relationship between tactilely-evoked responses in SI and in the granule cell layer of the cerebellar hemisphere, in anesthetized rats. We simultaneously recorded field potentials in areas of common receptive fields of SI and of the cerebellar folium crus IIa after peripheral tactile stimulation of the corresponding facial area. Response of the cerebellar granule cell layer to a brief tactile stimulation consisted of two components at different latencies. We found a strong correlation between the latency of the SI response and that of the second (long-latency) cerebellar component following facial stimulation. No such relationship was found between the latency of the SI response and that of the first (short-latency) cerebellar component, originating from a direct trigeminocerebellar pathway. In addition, lidocaine pressure injection in SI, cortical ablation, and decerebration all significantly affected the second cerebellar peak but not the first. Further, when tactile stimuli were presented 75 ms apart, the response in SI failed, as did the second cerebellar peak, while the shortlatency cerebellar response still occurred. We found a wide spatial distribution of the upper lip response beyond the upper lip area in crus IIa for the long-latency component of the cerebellar response. Our results demonstrate that SI is the primary contributor to the cerebellar long-latency response to peripheral tactile stimulation. These results are discussed in the context of Purkinje cell responses to tactile input. [ABSTRACT FROM AUTHOR]

Specificity testing should be performed under conditions identical to or closely similar to those of the immunocytochemical procedure. This paper describes a new model system that meets this requirement for postembedding immunocytochemistry of amino acids at the light- and electron microscopic levels. Test conjugates, obtained by reacting different amino acids with brain macromolecules in the presence of glutaraldehyde, were freeze-dried and embedded in an epoxy resin (Durcupan) exactly as for brain tissue. One section from each of the embedded amino acid conjugates and from a brain protein-glutaraldehyde conjugate (without amino acid) were piled on top of each other and embedded anew. Transverse semithin (0.5 μm) and ultrathin sections were cut through the stack. These test sections, in which all the different conjugates were represented, were then processed in the same drops of sera as the tissue sections to permit identical conditions for testing and immunocytochemistry. After immunogold labelling for electron microscopy, a quantitative expression of crossreactivity was obtained by computer-assisted calculation of gold particle densities over the different conjugates. The antisera used in the present study (glutamate anti-serum 13, taurine antiserum 20, and GABA antiserum 26) showed highly selective labelling of the respective amino acid conjugates and produced distinct labelling patterns in simultaneously processed cerebellar sections. [ABSTRACT FROM AUTHOR]

Previous unpublished experiments from this laboratory had revealed only post-activation depression effects in the cerebellar cortex when its inputs were activated by high frequency trains. In the experiments reported in this paper, we found reliable long-term potentiation (LTP) effects in the deep nuclei (interpositus and vestibular) when stimulation trains were applied to the white matter at the point where inferior peduncle fibers enter the cerebellum. LTP effects were found in both acute and chronic preparations. In the chronic preparations, LTP lasted for at least 8 days in all but one animal. [ABSTRACT FROM AUTHOR]

Primary electroreceptor afferents terminate in the posterior lateral line lobe (PLLL) in electroreceptive teleosts. This paper examines the central connections of PLLL in fish of the family Mormyridae using horseradish peroxidase and tritiated amino acid tracing techniques. Some connections of the closely related lobus caudalis of the cerebellum are also examined. There are three zones on each side of the mormyrid PLLL cortex. Two receive input from mormyromast receptors, and one from ampullary receptors. An intrazonal projection system, intrinsic to PLLL, connects neighboring points within each zone. It also joins corresponding zones on the two sides of the body via commissural fibers. An interzonal system connects the two mormyromast zones on the same side of the midline. Central structures which project to PLLL include lobus caudalis, nucleus paratrigeminalis lateralis, and nucleus praeeminentialis. Nucleus praeeminentialis projects bilaterally and somatotopically to the lower molecular layer of PLLL. PLLL cortex projects bilaterally and somatotopically to two major mesencephalic sites: n. praeeminentialis, and n. lateralis. Somatotopically corresponding points in each zone of PLLL cortex project to the same small region of n. lateralis. Nucleus lateralis has a large and somatotopically organized projection to n. praeeminentialis. The afferent and efferent connections of lobus caudalis are similar to those of PLLL, indicating its close association with the electrosensory system. The anatomical results show that there is ample opportunity for electrosensory information arising on left and right sides of the body to interact centrally. One can suggest that comparison of afferent input from the two sides would reduce the non-significant variability which affects both of them equally. The results also show the presence of several somatotopically organized feedback lops which return the results of higher order processing of electrosensory information to earlier stages. [ABSTRACT FROM AUTHOR]

The preceding two papers gave accounts of mossy fiber (MF) or of climbing fiber (CF) inputs to Purkyně cells under conditions where the other input was depressed by the experimental procedure. By utilizing either chloralose anesthesia or decerebration with sparing of the pyramidal tracts it has been possible to study the convergence of MF and CF inputs onto single Purkyně cells. The stimulation of cutaneous mechanoreceptors, the recording procedures for unitary Purkyně cell discharges and the computer averaging techniques were as previously described. Testing by taps to the footpads evoked a combined MF and CF response more commonly than either response alone, and often both inputs were very effective. There was a tendency for such phasic CF responses to be more frequently observed than the tonic responses to pad pressure, but such responses did occur. Purkyně cells were located by the usual procedure along the microelectrode tracks later identified in serial sections. Those cells activated by the fast MF inputs from the pad receptors were found to be closely associated in groups or colonies. The delayed MF inputs probably via spino-reticular pathways were more widely dispersed. The topographical relationships of these colonies are displayed on maps of the unfolded cerebellar cortex for lobules II to VI of both vermis and pars intermedia. In general these distributions of Purkyně cells activated from forefoot and hindfoot appear as islands in the larger fields that degeneration procedures exhibit for the cuneocerebellar and dorsal spinocerebellar tracts respectively. The CF inputs from the footpads also project to these same colonies, so that there are conjoint MF and CF colonies. The several modalities of the cutaneous mechanoreceptors of the forefoot or hindfoot often participate in the receptive fields of individual Purkyně cells. Such a field may be restricted to one or other side of the foot, all tested cutaneous mechanoreceptors then sharing approximately in the same restriction. Finally it is shown how these experimental findings relate to the theories of cerebellar function, particularly to the dynamic loop hypothesis. [ABSTRACT FROM AUTHOR]

This paper is the first of a series in which the processing of information in the cerebellum has been studied by investigating the effects that known inputs from limb nerves produce on the unitary spike potentials in the cerebellar cortex. These spikes have been recorded extracellularly at all depths along microelectrode tracks in the 5th, 4th and 3rd lobules of the anterior lobe in the lateral vermis or in the pars intermedia. These units have a background frequency of discharge, often very irregular, and computer averaging techniques have been employed in order to derive reliable information on the time course and intensity of the excitatory and/or inhibitory actions produced by the input against this background. Most of the spike responses recorded from the granular layer fall into two classes, one characteristic of impulses in mossy fibers, and the other of impulse discharges from granule cells. Both in the spontaneous background and in the response to afferent volleys in limb nerves the mossy fibers exhibit a performance in close accord with that described for the discharges up the spino-cerebellar tracts. The short latency of 6-9 msec for hindlimb stimuli and the high frequency burst response of 2-4 impulses are characteristic. The mossy fibers displayed a wide variety of responses to the wide range of testing inputs, there being various combinations of excitatory and inhibitory responses and also delayed excitatory actions, all of which must be assumed to be reflections of synaptic influences on the cells of origin of the mossy fibers in the spinal cord. Granule cells have a longer latency by several milliseconds, 9-20 msec for the hindlimb, and a slower frequency in their burst response which tended to be longer and more irregular. The small unitary spike potentials are more difficult to isolate. Also with repetitive stimulation granule cells are more readily depressed than are mossy fibers. Usually a granule cell exhibits a wider range of response to the various cutaneous and muscular afferents of a limb. Both mossy fibers and granule cells may display reciprocal responses to volleys from muscle nerves to antagonistic muscles. This attempt to define properties of the mossy fiber and granule cell spike potentials should help in their identification in future investigations. [ABSTRACT FROM AUTHOR]

Neural processing in the basal ganglia is critical for normal movement. Diseases of the basal ganglia, such as Parkinson's disease, produce a variety of movement disorders including akinesia and bradykinesia. Many believe that the basal ganglia influence movement via thalamic projections to motor areas of the cerebral cortex and through projections to the cerebellum, which also projects to the motor cortex via the thalamus. However, lesions that interrupt these thalamic pathways to the cortex have little effect on many movements, including limb movements. Yet, limb movements are severely impaired by basal ganglia disease or damage to the cerebellum. We can explain this impairment as well as the mild effects of thalamic lesions if basal ganglia and cerebellar output reach brainstem motor regions without passing through the thalamus. In this report, we describe several brainstem pathways that connect basal ganglia output to the cerebellum via nucleus reticularis tegmenti pontis (NRTP). Additionally, we propose that widespread afferent and efferent connections of NRTP with the cerebellum could integrate processing across cerebellar regions. The basal ganglia could then alter movements via descending projections of the cerebellum. Pathways through NRTP are important for the control of normal movement and may underlie deficits associated with basal ganglia disease. [ABSTRACT FROM AUTHOR]

Recordings from over the posterior fossa following impulsive acceleration stimuli have shown short latency evoked potentials of presumed cerebellar origin. In this study, we investigated the effect of posture on these cerebellar evoked potentials (CEPs) and their relationship to postural reflexes recorded from the leg muscles evoked by the same stimuli. Nine healthy subjects were tested during lying (supine and prone), sitting and standing. Impulsive accelerations were applied at the mastoid and to truncal (both C7 and sternal) stimulation sites. The effect of vision, eyes open or closed, was investigated for all three stimuli. For the truncal stimuli, the effect of differing leaning conditions during standing was also recorded. CEP amplitudes were correlated for the three stimuli. For C7 stimulation during standing, both CEPs and postural reflexes scaled as the threat to postural stability increased. However, CEPs for all stimuli were present during lying, sitting and standing with amplitude and latency parameters mainly unaffected by posture or vision. In contrast, postural reflexes from the leg muscles were attenuated when not standing, with the effect being more marked for truncal stimuli. We conclude that CEPs evoked by axial and vestibular stimuli are not systematically gated by posture, in contrast to the reflex responses evoked by the same stimuli. [ABSTRACT FROM AUTHOR]

Anodal cerebellar transcranial direct current stimulation (tDCS) is known to enhance motor learning, and therefore, has been suggested to hold promise as a therapeutic intervention. However, the neural mechanisms underpinning the effects of cerebellar tDCS are currently unknown. We investigated the neural changes associated with cerebellar tDCS using magnetic resonance spectroscopy (MRS). 34 healthy participants were divided into two groups which received either concurrent anodal or sham cerebellar tDCS during a visuomotor adaptation task. The anodal group underwent an additional session involving MRS in which the main inhibitory and excitatory neurotransmitters: GABA and glutamate (Glu) were measured pre-, during, and post anodal cerebellar tDCS, but without the behavioural task. We found no significant group-level changes in GABA or glutamate during- or post-tDCS compared to pre-tDCS levels, however, there was large degree of variability across participants. Although cerebellar tDCS did not affect visuomotor adaptation, surprisingly cerebellar tDCS increased motor memory retention with this being strongly correlated with a decrease in cerebellar glutamate levels during tDCS across participants. This work provides novel insights regarding the neural mechanisms which may underlie cerebellar tDCS, but also reveals limitations in the ability to produce robust effects across participants and between studies. [ABSTRACT FROM AUTHOR]

Transcranial direct current stimulation (tDCS) is a non-invasive form of brain stimulation, which allows for selective inhibition or excitation of neural structures. It has demonstrated some efficacy in the treatment of mood disorders. However, these studies have predominately focused on stimulation of the prefrontal cortex (PFC). The cerebellum has an increasingly recognized role in emotional control, affective state, and some psychopathologies. As such, tDCS research into mood modulation needs to expand beyond conventional PFC-focused paradigms. Using a contralateral stimulation electrode placement [anodal left dorsolateral(dl)PFC, cathodal right cerebellum], and a single-blind, repeated-measures design, we initially assessed changes in the mood of healthy participants in response to acute stimulation (n = 44) and three repeated stimulations delivered second-daily (n = 21). In a second experiment, we separately investigated the influence of reversed polarity upon these same measures, in response to acute stimulation (n = 23) and repeated stimulation (n = 11). We observed a systematic elevation of mood in both active conditions following single and repeated tDCS, the latter of which displayed a progressive elevation of mood from baseline. No mood change was noted in response to either single or repeated stimulation in the sham condition. Frontocerebellar tDCS stimulation advantageously influences mood in healthy participants, with an accumulative and potentiated effect following successive stimulations. The possibility that frontocerebellar stimulation may provide a novel therapeutic adjunctive or pre-emptive intervention in stress-related disorders and mood-related psychopathologies should be considered. [ABSTRACT FROM AUTHOR]

Gulf War Illness (GWI) is a multisystem disorder that has affected a substantial number of veterans who served in the 1990-1991 Gulf War. The brain is prominently affected, as manifested by the presence of neurological, cognitive and mood symptoms. Although brain dysfunction in GWI has been well documented (EBioMedicine 12:127-32, 2016), abnormalities in brain structure have been debated. Here we report a substantial (~10%) subcortical brain atrophy in GWI comprising mainly the brainstem, cerebellum and thalamus, and, to a lesser extent, basal ganglia, amygdala and diencephalon. The highest atrophy was observed in the brainstem, followed by left cerebellum and right thalamus, then by right cerebellum and left thalamus. These findings indicate graded atrophy of regions anatomically connected through the brainstem via the crossed superior cerebellar peduncle (left cerebellum → right thalamus, right cerebellum → left thalamus). This distribution of atrophy, together with the observed systematic reduction in volume of other subcortical areas (basal ganglia, amygdala and diencephalon), resemble the distribution of atrophy seen in toxic encephalopathy (Am J Neuroradiol 13:747-760, 1992) caused by a variety of substances, including organic solvents. Given the potential exposure of Gulf War veterans to 'a wide range of biological and chemical agents including sand, smoke from oil-well fires, paints, solvents, insecticides, petroleum fuels and their combustion products, organophosphate nerve agents, pyridostigmine bromide, ...' (Institute of Medicine National Research Council. Gulf War and Health: Volume 1. Depleted uranium, pyridostigmine bromide, sarin, and vaccines. National Academies Press, Washington DC, 2000), it is reasonable to suppose that such exposures, alone or in combination, could underlie the subcortical atrophy observed. [ABSTRACT FROM AUTHOR]

Despite several pieces of evidence, which suggest that the human brain employs internal models for motor control and learning, the location of these models in the brain is not yet clear. In this study, we used transcranial direct current stimulation (tDCS) to manipulate right cerebellar function, while subjects adapt to a visuomotor task. We investigated the effect of this manipulation on the internal forward and inverse models by measuring two kinds of behavior: generalization of training in one direction to neighboring directions (as a proxy for inverse models) and localization of the hand position after movement without visual feedback (as a proxy for forward model). The experimental results showed no effect of cerebellar tDCS on generalization, but significant effect on localization. These observations support the idea that the cerebellum is a possible brain region for internal forward, but not inverse model formation. We also used a realistic human head model to calculate current density distribution in the brain. The result of this model confirmed the passage of current through the cerebellum. Moreover, to further explain some observed experimental results, we modeled the visuomotor adaptation process with the help of a biologically inspired method known as population coding. The effect of tDCS was also incorporated in the model. The results of this modeling study closely match our experimental data and provide further evidence in line with the idea that tDCS manipulates FM's function in the cerebellum. [ABSTRACT FROM AUTHOR]

The origin of the internal 'sensory conflict' stimulus causing motion sickness has been debated for more than four decades. Recent studies show a subclass of neurons in the vestibular nuclei and deep cerebellar nuclei that respond preferentially to passive head movements. During active movement, the semicircular canal and otolith input ('reafference') to these neurons are canceled by a mechanism comparing the expected consequences of self-generated movement (estimated with an internal model-presumably located in the cerebellum) with the actual sensory feedback. The un-canceled component ('exafference') resulting from passive movement normally helps compensate for unexpected postural disturbances. Notably, the existence of such vestibular 'sensory conflict' neurons had been postulated as early as 1982, but their existence and putative role in posture control and motion sickness have been long debated. Here, we review the development of 'sensory conflict' theories in relation to recent evidence for brainstem and cerebellar reafference cancelation, and identify some open research questions. We propose that conditions producing persistent activity of these neurons, or their targets, stimulate nearby brainstem emetic centers-via an as yet unidentified mechanism. We discuss how such a mechanism is consistent with the notable difference in motion sickness susceptibility of drivers as opposed to passengers, human immunity to normal self-generated movement and why head restraint or lying horizontal confers relative immunity. Finally, we propose that fuller characterization of these mechanisms and their potential role in motion sickness could lead to more effective, scientifically based prevention and treatment for motion sickness. [ABSTRACT FROM AUTHOR]

To examine the mechanisms of functional bimanual synchronization in goal-directed movements, we studied the movement kinematics of motorically unimpaired subjects while they performed repetitive prehension movements (either unimanually or bimanually) to small food items. Compared to unimanual conditions, bimanual movement execution yielded a significantly prolonged mouth contact phase. We hypothesized that this threefold prolongation led to a proper functional synchronization of the movement onsets of both hands at the beginning of each new movement cycle. That these temporal adjustments occurred in the movement phase with maximal haptic input points to the importance of sensory feedback for bimanual coordination. These results are discussed with respect to the important role of sensory feedback in the timing of coordinated bimanual movements. Furthermore, we propose that time-based coordinating schemas, which are implemented by the cerebellum and the posterior parietal cortex using sensory feedback, underlie functional inter-limb coordination. [ABSTRACT FROM AUTHOR]

We recorded from over 280 single cortical neurons throughout the medial anterior lobe of the cat cerebellum during passive movements of the hindlimbs resembling stepping on a moving treadmill. We used three stepping patterns, unilateral stepping of either the ipsilateral or contralateral leg and bipedal stepping in an alternating gait pattern. We found that over 60% of the neurons, mostly Purkinje cells, responded to stepping of one or both legs, and over 40% to more than one type of stepping pattern. Responsive cells were distributed throughout the five anterior lobules, and the highest concentration was found in traditional hindlimb areas in lobules 2 and 3. A comparison of response waveforms showed that they are similar for neighboring cells in many parts of the cerebellar cortex, and they tend to form local blob-like groupings. Response patterns, i.e., relationship among responses to each stepping type, tended to be similar within a local group. The groupings extend further in the parasagittal dimension (up to about a third of a lobule) than in the transverse dimension (about 1 mm), and they may form functional modules. A principal component analysis also showed that the responses were composed of a four basis waveforms (principal components) that explained about 80% of the response waveform variance that were nearly identical to those derived from dorsal spinocerebellar tract (DSCT) responses to similar stepping movements. We reconstructed the locations of the recorded neurons on a 2D map of the cerebellar cortex showing the spatial distribution of responsive cells according to their response characteristics. We propose, on the basis of these results, that the sensory input to the cerebellum from the hindlimbs is distributed to multiple zones that may each contribute to a different component of cerebellar function. [ABSTRACT FROM AUTHOR]

Motor learning ensures the accuracy of our daily movements. However, we know relatively little about its mechanisms, particularly for voluntary movements. Saccadic eye movements serve to bring the image of a visual target precisely onto the fovea. Their accuracy is maintained not by on-line sensory feedback but by a learning mechanism, called saccade adaptation. Recent studies on saccade adaptation have provided valuable additions to our knowledge of motor learning. This review summarizes what we know about the characteristics and neural mechanisms of saccade adaptation, emphasizing recent findings and new ideas. Long-term adaptation, distinct from its short-term counterpart, seems to be present in the saccadic system. Accumulating evidence indicates the involvement of the oculomotor cerebellar vermis as a learning site. The superior colliculus is now suggested not only to generate saccade commands but also to issue driving signals for motor learning. These and other significant contributions have advanced our understanding of saccade adaptation and motor learning in general. [ABSTRACT FROM AUTHOR]