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.

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.

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.

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.

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.

Multiparametric MRI features of granulomatous prostatitis and tubercular prostate abscess.

The authors report the diffusion and contrast-enhanced MRI appearance of five cases of granulomatous prostatitis (GP), non-specific (two cases) and infectious post-Bacillus Calmette-Guerin (BCG) therapy (three cases, with a tubercular abscess in two of them). All patients had raising PSA levels and abnormal DRE. History of BCG therapy or acute prostatitis was present in four patients. Multiparametric MRI (T2W-MRI, DW-MRI and DCE-MRI) was performed before biopsies. Diagnosis was confirmed by TRUS-guided biopsies in four cases and by transurethral resection in one case. MRI showed a tumor-like appearance in three cases, an abscess-like appearance in one case and a combined tumor/abscess-like appearance in one case. Extraprostatic fat was infiltrated in three patients, simulating T3a disease. Histologically, caseous necrosis was found when MRI showed abcedation. Demonstration of occult tubercular abscesses in post-BCG GP may have therapeutic implications and MRI is useful prior to surgical or interventional drainage of large caseous abscesses.

Functional neuronal activity and connectivity within the subthalamic nucleus in Parkinson's disease.

OBJECTIVE: Characterization of the functional neuronal activity and connectivity within the subthalamic nucleus (STN) in patients with Parkinson's disease (PD). METHODS: Single units were extracted from micro-electrode recording (MER) of 18 PD patients who underwent STN deep brain stimulation (DBS) surgery. The firing rate and pattern of simultaneously recorded spike trains and their coherence were analyzed. To provide a precise functional assignment of position to the observed activities, for each patient we mapped its classified multichannel STN MERs to a generic atlas representation with a sensorimotor part and a remaining part. RESULTS: Within the sensorimotor part we found significantly higher mean firing rate (P < 0.05) and significantly more burst-like activity (P < 0.05) than within the remaining part. The proportion of significant coherence in the beta band (13-30 Hz) is significantly higher in the sensorimotor part of the STN than elsewhere (P = 0.015). CONCLUSIONS: The STN sensorimotor part distinguishes itself from the remaining part with respect to beta coherence, firing rate and burst-like activity and postoperatively was found as the preferred target area. SIGNIFICANCE: Our firing behavior analysis may help to discriminate the STN sensorimotor part for the placement of the DBS electrode.

Imaging in lower urinary tract infections.

In epididymo-orchitis, a sonogram shows a non-homogenous and hypertrophied epididymis and testis, with increased vascularisation seen on a Doppler sonogram. Abscesses must be investigated using sonography so that a necrotic tumour is not misdiagnosed. In prostatitis, sonography is indicated to investigate urine retention and where treatment has failed (to look for a blockage, an abscess, or pyelonephritis). Endorectal sonography is the best imaging modality for analysing the parenchyma, but otherwise has limited value. Chronic prostatitis is the main differential diagnosis from prostate cancer; the two may be distinguished using diffusion MRI. In cases of cystitis, imaging is indicated when a patient has recurrent cystitis (to investigate what the causative factors might be), or an infection with a less common bacterium (to look for calcifications, emphysema, any involvement of the upper urinary tract), and in cases of cystitis with pseudotumour.

From Parkinsonian thalamic activity to restoring thalamic relay using deep brain stimulation: new insights from computational modeling.

We present a computational model of a thalamocortical relay neuron for exploring basal ganglia thalamocortical loop behavior in relation to Parkinson's disease and deep brain stimulation (DBS). Previous microelectrode, single-unit recording studies demonstrated that oscillatory interaction within and between basal ganglia nuclei is very often accompanied by synchronization at Parkinsonian rest tremor frequencies (3-10 Hz). These oscillations have a profound influence on thalamic projections and impair the thalamic relaying of cortical input by generating rebound action potentials. Our model describes convergent inhibitory input received from basal ganglia by the thalamocortical cells based on characteristics of normal activity, and/or low-frequency oscillations (activity associated with Parkinson's disease). In addition to simulated input, we also used microelectrode recordings as inputs for the model. In the resting state, and without additional sensorimotor input, pathological rebound activity is generated for even mild Parkinsonian input. We have found a specific stimulation window of amplitudes and frequencies for periodic input, which corresponds to high-frequency DBS, and which also suppresses rebound activity for mild and even more prominent Parkinsonian input. When low-frequency pathological rebound activity disables the thalamocortical cell's ability to relay excitatory cortical input, a stimulation signal with parameter settings corresponding to our stimulation window can restore the thalamocortical cell's relay functionality.

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.

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.

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.

Robust EMG-fMRI artifact reduction for motion (FARM).

OBJECTIVE: Current template-based artifact reduction methods are inadequate to reduce irregular volume- and slice-artifacts induced by limb motion in combined (surface) EMG-fMRI (electromyography-functional magnetic resonance imaging) studies. In addition, artifacts are not removed adequately for EMG frequencies above 50 Hz. We present a new fMRI artifact reduction algorithm for motion (FARM) and compare it with standard artifact correction as implemented in fMRI artifact slice-template removal (FASTR). METHODS: One control subject generated motion artifacts during EMG-fMRI. Low-frequency motion artifacts and volume-artifacts were removed prior to slice-artifact correction. Slice-artifacts were phase-shifted and removed with motion adaptive templates (FARM). EMG data were also corrected applying FASTR. RESULTS: Time traces demonstrate that artifacts related to sudden changes in wire position are contained to shorter time periods. EMG power spectra from neck and arm muscles show that FARM has improved performance at higher frequencies. CONCLUSIONS: High-pass filtering, volume-artifact removal, phase-shifting and adaptation of slice-templates to motion improve the quality of artifact-corrected EMG recorded during limb motion. SIGNIFICANCE: The improved accuracy at which EMG-fMRI data can be obtained opens up new ways to directly relate self-paced movements to brain activations and to study patients suffering from movement disorders.

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.

Automatic noise-level detection for extra-cellular micro-electrode recordings.

Extra-cellular neuro-recording signals used for functional mapping in deep brain stimulation (DBS) surgery and invasive brain computer interfaces, may suffer from poor signal to noise ratio. Therefore, a reliable automatic noise estimate is essential to extract spikes from recordings. We show that current methods are biased toward overestimation of noise-levels with increasing neuronal activity or artifacts. An improved and novel method is proposed that is based on an estimate of the mode of the distribution of the signal envelope. Our method makes use of the inherent characteristics of the noise distribution. For band-limited Gaussian noise the envelope of the signal is known to follow the Rayleigh distribution. The location of the peak of this distribution provides a reliable noise-level estimate. It is demonstrated that this new 'envelope' method gives superior performance both on simulated data, and on actual micro-electrode recordings made during the implantation surgery of DBS electrodes for the treatment of Parkinson's disease.

Normal cortical excitability in Myoclonus-Dystonia--a TMS study.

OBJECTIVE: The aim of the present study is to investigate cortical excitability in patients with DYT 11 positive Myoclonus-Dystonia (M-D), using transcranial magnetic stimulation (TMS). METHODS: Silent period, motor evoked potential (MEP) recruitment curve, short interval intracortical inhibition (SICI), intracortical facilitation (ICF) and short interval intracortical facilitation (SICF), with short interstimulus intervals (ISIs) ranging from 1.2 to 3.2 ms, were studied in 15 DYT 11-positive M-D patients and their matched controls. In four patients and matched controls peripheral double pulse electrical nerve stimulation was performed. RESULTS: All TMS parameters of cortical excitability were normal compared to healthy controls. In the SICF protocol we observed more variable and polyphasic MEPs in M-D patients. Cross-covariance analysis of MEP area revealed a significant correlation difference at ISI 2.2 and 2.8 ms. This increased variability was not seen in other TMS protocols or with peripheral nerve stimulation. CONCLUSIONS: In contrast with other types of dystonia, no changes in cortical excitability were found in DYT 11 patients. Our findings suggest that M-D is both clinically and pathophysiologically a separate entity from other dystonic disorders. Polyphasic MEPs during the SICF protocol in M-D patients could reflect central neuron membrane instability. Application of the SICF protocol in other patient groups has to prove its value in movement disorders.

P300 deficits are present in young first-episode patients with schizophrenia and not in their healthy young siblings.

OBJECTIVE: To evaluated P300 (P3b) abnormalities in young first episode patients with schizophrenia and their healthy young siblings. METHODS: An auditory oddball paradigm was used to assess P300 in 53 patients, 27 unaffected siblings and 28 healthy controls. Amplitude and latency of the three midline sites (Fz, Cz, and Pz) were compared between patients, siblings, and controls by a mixed-effects regression model. RESULTS: P300 amplitude was significantly reduced in patients with schizophrenia but not in healthy siblings, when compared to healthy controls. P300 latency did not significantly differ between the three groups. CONCLUSIONS: P300 amplitude but not latency was found to be affected in young patients with recent onset schizophrenia. However, P300 amplitude and latency were found not to be affected in healthy unaffected young siblings and, therefore, did not qualify as an endophenotype for schizophrenia. SIGNIFICANCE: The failure to find the P300 (P3b) abnormality in healthy siblings of patients with schizophrenia is an important finding and should be added to P300 literature.

Potential efficacy of enzyme replacement and substrate reduction therapy in three siblings with Gaucher disease type III.

We report three siblings with Gaucher disease type III, born between 1992 and 2004. During this period, new developments resulted in different potential therapies, changing clinical practice. The two eldest siblings received enzyme replacement therapy (ERT) from the age of 24 and 5 months respectively, later followed by an increase in dosage. ERT was combined with substrate reduction therapy (SRT) from the ages of 12 and 8 years, respectively. In the youngest sibling the combination of high-dose ERT and SRT was given from the age of 5 months. The two eldest siblings showed significant neurological impairment from the age of 1.5 years, starting with a convergent strabismus and partial oculomotor apraxia, followed by cognitive decline and an abnormal EEG and BAER. In contrast, the neurological development in the youngest sibling is almost completely normal. At the age of 3 years, cognitive development, EEG and BAER are all normal. Disturbed saccadic eye movements, which were already present at the start of therapy, remained stable. In addition to the clinical efficacy, we report on the biochemical response to therapy. Based on our results, the combination of high-dose ERT and SRT should be considered as a possible therapeutic approach for GD III, especially if started at a young age. Further follow-up studies are necessary to explore the long-term therapeutic effects.

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.