Closing the loop: Novel quantitative fMRI approach for manipulation of the sensorimotor loop in tremor.

Tremor is thought to be an effect of oscillatory activity within the sensorimotor network. To date, the underlying pathological brain networks are not fully understood. Disentangling tremor activity from voluntary motor output and sensorimotor feedback systems is challenging. To better understand the intrinsic sensorimotor fingerprint underlying tremor, we aimed to disentangle the sensorimotor system into driving (motor) and feedback/compensatory (sensory) neuronal involvement, and aimed to pinpoint tremor activity in essential tremor (ET) and tremor-dominant Parkinson's disease (PD) with a novel closed-loop approach. Eighteen ET patients, 14 tremor-dominant PD patients, and 18 healthy controls were included. An MR-compatible wrist manipulator was employed during functional MRI (fMRI) while muscle activity during (in)voluntary movements was concurrently recorded using electromyography (EMG). Tremor was quantified based on EMG and correlated to brain activity. Participants performed three tasks: an active wrist motor task, a passive wrist movement task, and rest (no wrist movement). The results in healthy controls proved that our experimental paradigm activated the expected motor and sensory networks separately using the active (motor) and passive (sensory) task. ET patients showed similar patterns of activation within the motor and sensory networks. PD patients had less activity during the active motor task in the cerebellum and basal ganglia compared to ET and healthy controls. EMG showed that in ET, tremor fluctuations correlated positively with activity in the inferior olive region, and that in PD tremor fluctuations correlated positively with cerebellar activity. Our novel approach with an MR-compatible wrist manipulator, allowed to investigate the involvement of the motor and sensory networks separately, and as such to better understand tremor pathophysiology. In ET sensorimotor network function did not differ from healthy controls. PD showed less motor-related activity. Focusing on tremor, our results indicate involvement of the inferior olive in ET tremor modulation, and cerebellar involvement in PD tremor modulation.

Cerebral dopamine deficiency, plasma monoamine alterations and neurocognitive deficits in adults with phenylketonuria.

BACKGROUND: Phenylketonuria (PKU), a genetic metabolic disorder that is characterized by the inability to convert phenylalanine to tyrosine, leads to severe intellectual disability and other cerebral complications if left untreated. Dietary treatment, initiated soon after birth, prevents most brain-related complications. A leading hypothesis postulates that a shortage of brain monoamines may be associated with neurocognitive deficits that are observable even in early-treated PKU. However, there is a paucity of evidence as yet for this hypothesis. METHODS: We therefore assessed in vivo striatal dopamine D2/3 receptor (D2/3R) availability and plasma monoamine metabolite levels together with measures of impulsivity and executive functioning in 18 adults with PKU and average intellect (31.2 ± 7.4 years, nine females), most of whom were early and continuously treated. Comparison data from 12 healthy controls that did not differ in gender and age were available. RESULTS: Mean D2/3R availability was significantly higher (13%; p = 0.032) in the PKU group (n = 15) than in the controls, which may reflect reduced synaptic brain dopamine levels in PKU. The PKU group had lower plasma levels of homovanillic acid (p < 0.001) and 3-methoxy-4-hydroxy-phenylglycol (p < 0.0001), the predominant metabolites of dopamine and norepinephrine, respectively. Self-reported impulsivity levels were significantly higher in the PKU group compared with healthy controls (p = 0.033). Within the PKU group, D2/3R availability showed a positive correlation with both impulsivity (r = 0.72, p = 0.003) and the error rate during a cognitive flexibility task (r = 0.59, p = 0.020). CONCLUSIONS: These findings provide further support for the hypothesis that executive functioning deficits in treated adult PKU may be associated with cerebral dopamine deficiency.

A monozygotic twin pair with highly discordant Gaucher phenotypes.

We describe monozygotic twin sisters, born to consanguineous Moroccan parents, who are highly discordant for the manifestations of Gaucher disease. Both carry Gaucher genotype N188S/N188S. One has severe visceral involvement, epilepsy, and a cerebellar syndrome. Her twin does not manifest any symptoms or signs of Gaucher disease but suffers from type 1 diabetes mellitus. The concurrence of a mild Gaucher mutation with a severe phenotype, as well as the occurrence of highly discordant phenotypes in a pair of monozygotic twins, is discussed.

Directionality of corticomuscular coupling in essential tremor and cortical myoclonic tremor.

OBJECTIVE: A role of the motor cortex in tremor generation in essential tremor (ET) is assumed, yet the directionality of corticomuscular coupling is unknown. Our aim is to clarify the role of the motor cortex. To this end we also study 'familial cortical myoclonic tremor with epilepsy' (FCMTE) and slow repetitive voluntary movements with a known cortical drive. METHODS: Directionality of corticomuscular coupling (EEG-EMG) was studied with renormalized partial directed coherence (rPDC) during tremor in 25 ET patients, 25 healthy controls (mimicked) and in seven FCMTE patients; and during a self-paced 2 Hz task in eight ET patients and seven healthy controls. RESULTS: Efferent coupling around tremor frequency was seen in 33% of ET patients, 45.5% of healthy controls, all FCMTE patients, and, around 2 Hz, in all ET patients and all healthy controls. Ascending coupling, seen in the majority of all participants, was weaker in ET than in healthy controls around 5-6 Hz. CONCLUSIONS: Possible explanations are that tremor in ET results from faulty subcortical output bypassing the motor cortex; rate-dependent transmission similar to generation of rhythmic movements; and/or faulty feedforward mechanism resulting from decreased afferent (sensory) coupling. SIGNIFICANCE: A linear cortical drive is lacking in the majority of ET patients.

Age-related changes in motor unit number estimates in adult patients with Charcot-Marie-Tooth type 1A.

BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) is known as a demyelinating hereditary neuropathy. Secondary axonal dysfunction is the most important determinant of disease severity. In adult patients, clinical progression may be because of further axonal deterioration as was shown with compound muscle action potential (CMAP) amplitude reductions over time. The motor unit number estimation (MUNE) technique may be more accurate to determine the number of axons as it is not disturbed by the effect of reinnervation. The purpose of this study was to investigate the number and size of motor units in relation to age in patients and controls. METHODS: In a cross-sectional design, we assessed arm and hand strength and performed electrophysiological examinations, including CMAP amplitudes and MUNE of the thenar muscles using high-density surface EMG in 69 adult patients with CMT1A and 55 age-matched healthy controls. RESULTS: In patients, lower CMAP amplitudes and MUNE values were related to hand weakness. The CMAP amplitude and MUNE value of the thenar muscles were significantly lower in patients than in controls. CMAP amplitudes declined with age in controls, but not in patients. MUNE values declined with age in both patients and controls. CONCLUSIONS: The age-dependent decrease in the number of motor units was not significantly different between patients with CMT1A and controls, indicating that loss of motor units in adult patients is limited.

The intermuscular 3-7 Hz drive is not affected by distal proprioceptive input in myoclonus-dystonia.

In dystonia, both sensory malfunctioning and an abnormal intermuscular low-frequency drive of 3-7 Hz have been found, although cause and effect are unknown. It is hypothesized that sensory processing is primarily disturbed and induces this drive. Accordingly, experimenter-controlled sensory input should be able to influence the frequency of the drive. In six genetically confirmed myoclonus-dystonia (MD) patients and six matched controls, the low-frequency drive was studied with intermuscular coherence analysis. External perturbations were applied mechanically to the wrist joint in small frequency bands (0-4, 4-8 and 8-12 Hz; 'angle' protocol) and at single frequencies (1, 5, 7 and 9 Hz; 'torque' protocol). The low-frequency drive was found in the neck muscles of 4 MD patients. In these patients, its frequency did not shift due to the perturbation. In the torque protocol, the externally applied frequencies could be detected in all controls and in the two patients without the common drive. The common low-frequency drive was not be affected by external perturbations in MD patients. Furthermore, the torque protocol did not induce intermuscular coherences at the applied frequencies in these patients, as was the case in healthy controls and in patients without the drive. This suggests that the dystonic 3-7 Hz drive is caused by a sensory-independent motor drive and sensory malfunctioning in MD might rather be a consequence than a cause of dystonia.

Increased saccadic rate during smooth pursuit eye movements in patients at Ultra High Risk for developing a psychosis.

Abnormalities in eye tracking are consistently observed in schizophrenia patients and their relatives and have been proposed as an endophenotype of the disease. The aim of this study was to investigate the performance of patients at Ultra High Risk (UHR) for developing psychosis on a task of smooth pursuit eye movement (SPEM). Forty-six UHR patients and twenty-eight age and education matched controls were assessed with a task of SPEM and psychiatric questionnaires. Our results showed that both the corrective and non-corrective saccadic rates during pursuit were higher in the UHR group. There were however no differences in smooth pursuit gain between the two groups. The saccadic rate was related to positive UHR symptoms. Our findings indicate that abnormalities in SPEM are already present in UHR patients, prior to a first psychotic episode. These abnormalities occur only in the saccadic system.

Oculomotor abnormalities in myoclonic tremor: a comparison with spinocerebellar ataxia type 6.

In the present study, eye movements are recorded in two patient groups with an autosomal dominantly inherited cerebellar disorder, i.e. spinocerebellar ataxia type 6 (SCA6) and familial cortical myoclonic tremor with epilepsy (FCMTE). In SCA6 and FCMTE patients striking similarities with the extensive Purkinje cell changes in the cerebellar cortex were described, but the two disorders have a distinctive clinical picture. SCA6 is a late-onset cerebellar syndrome, with relatively minimal brain stem and cerebral cortex symptoms. In contrast, FCMTE is clinically characterized by cortical symptomatology with a distal cortical myoclonic tremor and infrequent epileptic attacks without cerebellar dysarthria and limb ataxia. Comparison of oculomotor function of six FCMTE patients, five SCA6 patients and 18 healthy controls demonstrated both in SCA6 patients and FCMTE patients square wave jerks, downbeat nystagmus (DBN) and a stronger reduced downward smooth pursuit gain than an upward smooth pursuit gain. Only in SCA6 patients horizontal smooth pursuit gain was reduced. Except for the downward direction mean saccadic gain in both patient groups was reduced. This is consistent with cerebellar cortical pathology in both disorders. Subsequently, both patient groups showed increase of DBN with hyperventilation. As a novel finding, only the FCMTE patients showed a significantly increased amount of express saccades in the pro-saccade paradigm.

Eye movement abnormalities in essential tremor versus tremor dominant Parkinson's disease.

OBJECTIVE: To show that eye movement abnormalities differ between essential tremor (ET) and tremor dominant Parkinson's disease (PD-T), and that these abnormalities reflect cerebellar dysfunction in ET and basal ganglia pathology in PD-T. METHODS: In this exploratory study, in 23 patients with ET, 21 age-matched patients with PD-T, and 19 age-matched healthy controls (HCs), we investigated visually guided saccades, antisaccades, and smooth pursuit eye movements (SPEM). RESULTS: While the ET group had a normal gain (saccade amplitude/target amplitude) and latency of saccades, the PD-T group had hypometric visually guided saccades, and a prolonged latency of visually guided saccades and antisaccades. The SPEM gain was similarly low in both ET and PD-T and was significantly lower in both patient groups than in the HC group. CONCLUSIONS: In ET, SPEM gain was reduced in the presence of normal saccades, whereas in PD-T, the reduced SPEM gain was accompanied by delayed saccade initiation and hypometric saccades, in line with cerebellar dysfunction in ET and basal ganglia dysfunction in PD-T. SIGNIFICANCE: These findings support the presumed cerebellar pathology in ET. In addition, the difference in saccade features may contribute to the groundwork for a quantitative diagnostic test to differentiate between these disorders.

A meta-analysis of P50 studies in patients with schizophrenia and relatives: differences in methodology between research groups.

OBJECTIVE: To determine whether patients with schizophrenia as well as their relatives show deficits in sensory gating reflected by an abnormal P50 ratio and to quantify the differences from controls. METHODS: A systematic search on articles published between 1982 and 2006 was conducted. 28 patient studies that were suitable for analysis including 891 patients and 686 controls were retrieved. Six studies on P50 of relatives of schizophrenic patients were identified, including 317 relatives and 294 controls. RESULTS: In the patient studies we found an P50 effect size of 1.28 (SD=0.72). We confirmed high variability in outcomes across studies. Almost half of the studies included where published by one laboratory of the University of Colorado and these results differed significantly from the results found in studies performed in other laboratories. We found correlations between effect size outcome and sound intensity, filter settings and subjects' position which could be explained by differences between the Colorado laboratory and the other groups. In the relative studies we found a mean P50 effect size of 0.85 (+/-0.42). CONCLUSIONS: The differences in methodology and lack of reported demographics and methodology including raters blinding in some studies makes it hard to compare results across studies and to evaluate the validity and reliability of P50 as a candidate endophenotype for schizophrenia. There are large differences in outcomes from Colorado studies and non-Colorado studies. In contrast to the Colorado studies in the non-Colorado studies P50 suppression would not qualify as an endophenotype for schizophrenia. These differences might be explained by the differences in methodology e.g. lower levels of sound intensity, differences in filter settings and subjects' position. Finally we make some recommendations for future research based on the outcomes of this meta-analysis.

Failure to find P50 suppression deficits in young first-episode patients with schizophrenia and clinically unaffected siblings.

OBJECTIVE: To evaluate whether the P50 gating deficit is present in young first-episode patients with schizophrenia and their healthy young siblings. METHODS: An auditory paired-click paradigm was used to assess P50 gating in 53 patients, 27 unaffected siblings, and 28 healthy controls. P50 parameters were compared between patients, sibs, and unrelated controls by a mixed-effects regression model. RESULTS: P50 gating was not significantly impaired in patients with schizophrenia and healthy siblings as compared with controls. CONCLUSIONS: P50 gating was not found to be significantly impaired in young first-episode schizophrenia patients and in healthy young siblings. These results are in contrast with the existing literature. We suggest that P50 gating impairment may be developmentally or age dependent.

Directional Recording of Subthalamic Spectral Power Densities in Parkinson's Disease and the Effect of Steering Deep Brain Stimulation.

BACKGROUND: A new 32-contacts deep brain stimulation (DBS) lead, capable of directionally steering stimulation, was tested intraoperatively. OBJECTIVE: The aim of this pilot study was to perform recordings from the multidirectional contacts and to investigate the effect of directional current steering on the local field potentials (LFPs). METHODS: In eight patients with Parkinson's disease, after standard microelectrode recording and clinical testing, the new lead was temporarily implanted. The 32-channel LFP recordings were measured simultaneously at different depths and directions before and after directional stimulation. RESULTS: The spatial distribution of LFPs power spectral densities across the contact array at baseline marked the borders of the subthalamic nucleus (STN) with a significant increase in beta power and with a mean accuracy of approximately 0.6 mm in four patients.The power in the 18.5-30 Hz frequency band varied across different directions in all patients. In the three cases that showed improvement of rigidity, this was higher when current was steered toward the direction with the highest LFP power in the beta band. Subthalamic LFPs in six patients showed a differential frequency-dependent suppression/enhancement of the oscillatory activity in the 10-45 Hz frequency band after four different 'steering' modes as compared to ring mode, suggesting a higher specificity. CONCLUSIONS: Through a new 32-contact DBS lead it is possible to record simultaneous subthalamic LFPs at different depths and directions, providing confirmation of adequate lead placement and multidirectional spatial-temporal information potentially related to pathological subthalamic electrical activity and to the effect of stimulation. Although further research is needed, this may improve the efficiency of steering stimulation.

Tic related local field potentials in the thalamus and the effect of deep brain stimulation in Tourette syndrome: Report of three cases.

OBJECTIVE: Three patients with intractable Tourette syndrome (TS) underwent thalamic deep brain stimulation (DBS). To investigate the role of thalamic electrical activity in tic generation, local field potentials (LFP), EEG and EMG simultaneously were recorded. METHODS: Event related potentials and event related spectral perturbations of EEG and LFP, event related cross-coherences between EEG/LFP and LFP/LFP were analyzed. As time locking events, the tic onsets were used. Spontaneous tics were compared to voluntary tic mimicking. The effect of tic suppression and DBS on thalamic LFPs was evaluated. RESULTS: All three patients showed time-locked and prior to onset of spontaneous motor tics thalamic synchronization and thalamo-cortical cross-coherence. Also in three patients, not time-locked to motor tics, increased intra-thalamic coherences in the 1-8Hz frequency band were found. In one patient it was demonstrated that voluntary mimicked tics were preceded by premotor cortical and thalamic potentials. In this patient unilateral thalamic DBS contralaterally decreased the background thalamic activity. CONCLUSIONS: The present study in three cases with TS shows that spontaneous tics in TS are preceded by repetitive coherent thalamo-cortical discharges, indicating that preceding a tic the basal ganglia circuits are "charged up", ultimately leading to a motor tic. SIGNIFICANCE: Thalamic LFP recording may lead to more insight in underlying pathophysiological mechanisms in TS.

Spectral analysis of the EEG and 99m-Tc-HMPAO SPECT-scan in Alzheimer's disease.

99m-technetium-hexamethylpropylene-amineoxine (99m-Tc-HMPAO) single-photon-emission-computer-tomography (SPECT)-scans and spectral analyzed electroencephalogram (EEGs) of 20 patients with Alzheimer's disease (AD) were studied. A significant correlation was found between the temporoparietal-cerebellar-ratio (TP/C-ratio) of the SPECT-scan and the peak frequencies of leads T3-T5, C3-P3, and C4-P4 of the EEG. In addition a significant negative correlation between the TP/C-ratio and the theta/alpha-ratio (t/a-ratio) of leads T3-T5, T4-T6, C3-P3, and C4-P4 was demonstrated. Our study demonstrates that slowing of the EEG parallels a decrease in blood flow in the temporoparietal regions in AD-patients. Both findings could be parallel phenomena of regional hypometabolism.

Neuropsychological and clinical correlates of antisaccade task performance in schizophrenia.

OBJECTIVES: To elucidate pathophysiologic mechanisms involved in abnormal antisaccade task performance in schizophrenia by investigating a possible relationship among antisaccade task performance, neuropsychological test results, and symptomatology in a group of young patients with recent-onset schizophrenia; to compare the effects of olanzapine and risperidone on antisaccades and reflexive saccades. BACKGROUND: Patients with schizophrenia consistently perform worse than controls on the antisaccade task in which the subject is required to inhibit a reflexive saccade to a suddenly appearing visual target and look in the opposite direction. METHODS: In 37 young (mean age 21 years), medicated patients with recent-onset schizophrenia the authors assessed antisaccades, reflexive saccades, neuropsychological test performance, and symptomatology. A subgroup of 18 patients was treated with olanzapine, and 15 patients were treated with risperidone. Reflexive-saccade and antisaccade task results were compared with those obtained in 13 control subjects. RESULTS: The antisaccade error rate was significantly higher in the patients than in the control subjects. In the patients, poor working memory function was related to increased antisaccade error rate. Severity of disorganization symptoms at intake was related to prolonged mean latency of the correct antisaccades. Patients on risperidone had a prolonged mean latency in the reflexive saccade task compared with patients using olanzapine. CONCLUSIONS: Abnormal antisaccade task performance is already present in early schizophrenia and may reflect working memory dysfunction. In future studies, medication effects should be considered in interpreting eye movement test results of patients with schizophrenia.

Soleus H-reflex tests in causalgia-dystonia compared with dystonia and mimicked dystonic posture.

Dystonia in the causalgia-dystonia syndrome is characterized by a fixed dystonic posture. To identify involvement of central pathophysiologic mechanisms, we analyzed soleus H-reflex tests in five patients with causalgia-dystonia. Soleus H-reflex test results in these patients differed from those in healthy controls but were similar to those in purely dystonic patients and healthy controls mimicking dystonic posture. The results suggest involvement of supraspinal mechanisms in the abnormal posture of causalgia-dystonia.

Dopa-responsive dystonia and normalization of soleus H-reflex test results with treatment.

We studied the ratio of the maximal H-reflex to maximal direct muscle potential (H/M ratio), late facilitation and late inhibition in the recovery curve, and vibratory inhibition of the soleus H-reflex in three consecutive patients with hereditary dopa-responsive dystonia, before and during treatment with levodopa. In one patient, we repeated the H-reflex tests twice after withdrawal of levodopa. The results were compared with those in a group of 48 healthy subjects. In the patients before treatment, the soleus H-reflex recovery curve showed increased late facilitation and depressed late inhibition, reflecting alterations in postsynaptic interneuronal activity. Vibratory inhibition, predominantly reflecting presynaptic inhibitory action, was depressed. Normalization of these test results occurred during levodopa treatment, concurrent with a clear clinical response. The H/M ratio, reflecting the excitability state of the motoneuron pool, was similar during and without levodopa treatment. In the one patient tested after levodopa withdrawal, enhancement of late facilitation and decrease of vibratory inhibition paralleled the reoccurrence of dystonia most clearly. Since soleus H-reflex tests mainly reflect mechanisms operating at the spinal level, spinal aminergic or dopaminergic systems are probably involved in dopa-responsive dystonia.

Selective broad-band spatial frequency loss in contrast sensitivity functions. Comparison with a model based on optical transfer functions.

PURPOSE: Contrast sensitivity functions (CSFs) were measured under various optical conditions in healthy observers together with CSFs from selected patients. Threshold increases across the spatial frequency range were compared with predictions of a theoretical optical model based on modulation transfer functions. METHODS: Contrast thresholds for various spatial frequencies were determined with a computer-automated method of ascending limits in a control group and a group of patients with various visual pathway diseases ranging from retinal disorders, such as diabetic retinopathy, to neural disorders, such as multiple sclerosis. For normal control subjects, simulated contrast sensitivity losses also were effected by manipulating pupil diameter and dioptric blur. Modulation transfer functions of the eye's optics in polychromatic light were calculated. The wave aberration function included standard spherical aberration, coma, and small amounts of irregular aberrations. RESULTS: Experimentally, slight dioptric blur (e.g., 0.4 to 0.75 D) introduced increased CSF thresholds within either a narrow or broad bandwidth. For the latter, decreased CSF sensitivity occurred across a spatial frequency range as broad as 1 log unit, from low spatial frequencies (2 cyc/deg), and for pupil sizes equal to or larger than 3 mm. Predictions based on an optical model are qualitatively and quantitatively in agreement with these findings. Contrast sensitivity losses of the patients were neither specific nor selective to the pathologic condition at hand. Furthermore, various CSF losses optically induced in the control subjects were indistinguishable from nonoptically induced pathologic CSF profiles. CONCLUSIONS: Selective broad-band contrast sensitivity loss may be optically induced by slight refractive error. As a result, selective contrast sensitivity loss at lower and intermediate spatial frequencies concurrent in patients with various pathologic, neuro-ophthalmologic conditions cannot be a priori attributed to neural factors without carefully controlled and well-defined optical variables.

Clinical and neuropsychological correlates of the P300 in schizophrenia.

We investigated the relationship between the P300, neuropsychological test performance and symptomatology in recent-onset schizophrenic patients (n = 45) to gain insight into underlying mechanisms of abnormal P300 in schizophrenia. The P300 was recorded in two sessions with an intermission of five minutes, at the midline frontal, central and parietal electrode site. P300 amplitude and latency were compared with those obtained in 25 controls. Twenty patients were treated with olanzapine and 19 patients with risperidone. P300 amplitude was smaller and latency longer in patients than in controls. In the patient group, parietal P300 amplitude reduction was related to poorer performance on neuropsychological tests of memory. Frontal P300 amplitude reduction was related to impaired selective attention. In patients with negative symptomatology, P300 amplitude was reduced in the second P300 session compared with the first. Patients on risperidone demonstrated a smaller parietal P300 amplitude than patients using olanzapine. Reduced parietal P300 amplitude could signify a dysfunction in the continuous memory updating of current events. Negative symptomatology may be associated with a time dependent decrease in neuronal firing, as indicated by reduced P300 amplitude in the second P300 session.

Posterior tibial nerve somatosensory evoked potentials in slowly progressive spastic paraplegia: a comparative study with clinical signs.

Clinical and neurophysiological examinations were performed on seven patients with hereditary spastic paraplegia and on eight patients with primary lateral sclerosis. The results were compared with those obtained from a group of 39 control subjects. Prolonged latency times and decreased amplitudes of the posterior tibial nerve (PTN) somatosensory evoked potentials (SEPs) were found in the majority of the patients. The SEP changes occurred without sensory impairment or with loss of vibration sense only. There was no significant relation between the PTN SEP abnormalities and the severity of pyramidal signs for the whole patient group, nor longitudinally for the individual subjects. Analyses of PTN SEPs in patients suffering from slowly progressive spastic paraplegia (SP), therefore, seem to be a method to indicate a feature of spinal cord dysfunction that is not related to the severity of clinical signs. Considering the neuropathology of the spinal cord in SP patients, we furthermore argue that the ascending spinal pathway involved in conducting impulses for PTN SEPs probably uses other routes as well as the funiculus gracilis.