Christian K. E. Moll

Invasive recordings from the human brain: clinical insights and beyond

Although non-invasive methods such as functional magnetic resonance imaging, electroencephalograms and magnetoencephalograms provide most of the current data about the human brain, their resolution is insufficient to show physiological processes at the cellular level. Clinical approaches sometimes allow invasive recordings to be taken from the human brain, mainly in patients with epilepsy or with movement disorders, and such recordings can sample neural activity at spatial scales ranging from single cells to distributed cell assemblies. In addition to their clinical relevance, these recordings can provide unique insights into brain functions such as movement control, perception, memory, language and even consciousness.

Different Subtypes of Striatal Neurons Are Selectively Modulated by Cortical Oscillations

The striatum is the key site for cortical input to the basal ganglia. Cortical input to striatal microcircuits has been previously studied only in the context of one or two types of neurons. Here, we provide the first description of four putative types of striatal neurons (medium spiny, fast spiking, tonically active, and low-threshold spiking) in a single data set by separating extracellular recordings of sorted single spikes recorded under halothane anesthesia using waveform and burst parameters. Under halothane, the electrocorticograms and striatal local field potential displayed spontaneous oscillations at both low (2–9 Hz) and high (35–80 Hz) frequencies. Putative fast spiking interneurons were significantly more likely to phase lock to high-frequency cortical oscillations and displayed significant cross-correlations in this frequency range. These findings suggest that, as in neocortex and hippocampus, the coordinated activity of fast spiking interneurons may specifically be involved in mediating oscillatory synchronization in the striatum.

Activity parameters of subthalamic nucleus neurons selectively predict motor symptom severity in Parkinson's disease.

Parkinsons disease (PD) is a heterogeneous disorder that leads to variable expression of several different motor symptoms. While changes in firing rate, pattern, and oscillation of basal ganglia neurons have been observed in PD patients and experimental animals, there is limited evidence linking them to specific motor symptoms. Here we examined this relationship using extracellular recordings of subthalamic nucleus neurons from 19 PD patients undergoing surgery for deep brain stimulation. For each patient, ≥10 single units and/or multi-units were recorded in the OFF medication state. We correlated the proportion of neurons displaying different activities with preoperative Unified Parkinsons Disease Rating Scale subscores (OFF medication). The mean spectral power at sub-beta frequencies and percentage of units oscillating at beta frequencies were positively correlated with the axial and limb rigidity scores, respectively. The percentage of units oscillating at gamma frequency was negatively correlated with the bradykinesia scores. The mean intraburst rate was positively correlated with both bradykinesia and axial scores, while the related ratio of interspike intervals below/above 10 ms was positively correlated with these symptoms and limb rigidity. None of the activity parameters correlated with tremor. The grand average of all the significantly correlated subthalamic nucleus activities accounted for >60% of the variance of the combined bradykinetic-rigid and axial scores. Our results demonstrate that the occurrence of alterations in the rate and pattern of basal ganglia neurons could partly underlie the variability in parkinsonian phenotype.

Corticostriatal Coordination through Coherent Phase-Amplitude Coupling

The corticostriatal axis is the main input stage of the basal ganglia and is crucial for their role in motor behavior. Synchronized oscillations might mediate interactions between cortex and striatum during behavior, yet direct evidence remains sparse. Here, we show that, during motor behavior, low- and high-frequency oscillations jointly couple cortex and striatum via cross-frequency interactions. We investigated neuronal oscillations along the corticostriatal axis in rats during rest and treadmill running. We found prominent theta and gamma oscillations in cortex and striatum, the peak frequencies of which scaled with motor demand. Theta and gamma oscillations were functionally coupled through phase-amplitude coupling. Furthermore, theta oscillations were phase coupled between structures. Together, local phase-amplitude coupling and corticostriatal theta phase coupling mediated the temporal correlation of gamma bursts between the cortex and striatum. The coordination of fast oscillations through coherent phase-amplitude coupling may be a general mechanism to regulate neuronal interactions along the corticostriatal axis and beyond.

Effects of DBS, premotor rTMS, and levodopa on motor function and silent period in advanced Parkinson's disease†

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a widely used and highly effective treatment for patients with advanced Parkinsons disease (PD). Repetitive TMS (rTMS) applied to motor cortical areas has also been shown to improve symptoms in PD and modulate motor cortical excitability. Here, we compared clinical and neurophysiological effects of STN stimulation with those of 1 Hz rTMS given to the dorsal premotor cortex (PMd) and those following intake of levodopa in a group of PD patients with advanced disease. Ten PD patients were studied on 2 consecutive days before and after surgery. Clinical effects were determined using the UPDRS motor score. Motor thresholds, motor‐evoked potential (MEP) amplitudes during slight voluntary contraction, and the cortical silent periods (SP) were measured using TMS. Before surgery effects of levodopa and 1 Hz PMd rTMS and after surgery those of STN stimulation with or without additional levodopa were determined. Levodopa significantly improved clinical symptoms and increased the SP duration. STN stimulation improved clinical symptoms without changing the SP duration. In contrast, 1 Hz PMd rTMS was not effective clinically but normalized the SP duration. Whereas levodopa had widespread effects at different levels of an abnormally active motor network in PD, STN stimulation and PMd rTMS led to either clinical improvement or SP normalization, i.e., only partially reversed abnormal motor network activity.

The anterior ectosylvian visual area of the ferret: a homologue for an enigmatic visual cortical area of the cat?

The present paper describes the results of electrophysiological mapping experiments focused on the anterior limb of the ectosylvian gyrus of the ferret (Mustela putorius). The aim was to determine if the ferret possessed a homologous cortical area to the anterior ectosylvian visual area (AEV) of the domestic cat, but not clearly delineated in any other mammal studied to date. We were able to gather data on the visuotopic organization of a region that we consider to be a homologue of cat AEV. The visual map in this area showed a distinct visuotopic organization and covered a large extent of the visual field. Within the ferret AEV there were clusters of bimodal recording sites (somato‐visual and audio‐visual) that were located adjacent to surrounding unimodal cortical areas (such as the second somatosensory area and primary and secondary auditory areas). The ferret AEV, like that of the cat, was topographically isolated from other visual cortical areas by intervening auditory and somatosensory areas. Taken together these features suggest that the region described here as AEV in the ferret is indeed a direct homologue of the previously described cat AEV.

Asymmetric pallidal neuronal activity in patients with cervical dystonia

The origin of asymmetric clinical manifestation of symptoms in patients suffering from cervical dystonia (CD) is hitherto poorly understood. Dysregulated neuronal activity in the basal ganglia has been suggested to have a role in the pathophysiology of CD. Here, we re-assessed the question to what extent relative changes occur in the direct vs. indirect basal ganglia pathway in CD, whether these circuit changes are lateralized, and how these alterations relate to CD symptoms. To this end, we recorded ongoing single cell and local field potential (LFP) activity from the external (GPe) and internal pallidal segment (GPi) of 13 CD patients undergoing microelectrode-guided stereotactic surgery for deep brain stimulation in the GPi. We compared pallidal recordings from CD patients operated under local anaesthesia (LA) with those obtained in CD patients operated under general anaesthesia (GA). In awake patients, mean GPe discharge rate (52 Hz) was lower than that of GPi (72 Hz). Mean GPi discharge ipsilateral to the side of head turning was higher than contralateral and correlated with torticollis symptom severity. Lateralized differences were absent at the level of the GPe and in recordings from patients operated under GA. Furthermore, in the GPi of CD patients there was a subpopulation of theta-oscillatory cells with unique bursting characteristics. Power and coherence of GPe– and GPi–LFPs were dominated by a theta peak and also exhibited band-specific interhemispheric differences. Strong cross-frequency coupling of low-gamma amplitude to theta phase was a feature of pallidal LFPs recorded under LA, but not GA. These results indicate that CD is associated with an asymmetric pallidal outflow. Based on the finding of symmetric neuronal discharges in the GPe, we propose that an imbalanced interhemispheric direct pathway gain may be involved in CD pathophysiology.

Clinical neuroimaging and electrophysiological assessment of three DYT6 dystonia families.

The purpose of the study was to delineate clinical and electrophysiological characteristics as well as laryngoscopical and transcranial ultrasound (TCS) findings in THAP1 mutation carriers (MutC). According to recent genetic studies, DYT6 (THAP1) gene mutations are an important cause of primary early‐onset dystonia. In contrast to DYT1 mutations, THAP1 mutations are associated with primary early‐onset segmental or generalised dystonia frequently involving the craniocervical region and the larynx. Blood samples from twelve individuals of three German families with DYT6 positive index cases were obtained to test for THAP1 mutations. Eight THAP1 MutC were identified. Of these, six (three symptomatic and three asymptomatic) THAP1 MutC could be clinically evaluated. Laryngoscopy was performed to evaluate laryngeal dysfunction in patients. Brainstem echogenicity was investigated in all MutC using TCS. Two of the patients had undergone bilateral pallidal DBS. In all three symptomatic MutC, early‐onset laryngeal dystonia was a prominent feature. Laryngeal assessment demonstrated adductor‐type dystonia in all of them. On clinical examination, the three asymptomatic MutC also showed subtle signs of focal or segmental dystonia. TCS revealed increased substantia nigra (SN) hyperechogenicity in all MutC. Intraoperative microelectrode recordings under general anesthesia in two of the patients showed no difference between THAP1 and previously operated DYT1 MutC. The presence of spasmodic dysphonia in patients with young‐onset segmental or generalised dystonia is a hallmark of DYT6 dystonia. SN hyperechogenicity on TCS may represent an endophenotype in these patients. Pallidal DBS in two patients was unsatisfactory.

Location, architecture, and retinotopy of the anteromedial lateral suprasylvian visual area ~AMLS! of the ferret ~Mustela putorius!

The present paper describes the results of architectural and electrophysiological mapping observations of the medial bank of the suprasylvian sulcus of the ferret immediately caudal to somatosensory regions. The aim was to determine if the ferret possessed a homologous cortical area to the anteromedial lateral suprasylvian visual area (AMLS) of the domestic cat. We studied the architectural features and visuotopic organization of a region that we now consider to be a homologue to the cat AMLS. This area showed a distinct architecture and retinotopic organization. The retinotopic map was complex in nature with a bias towards representation of the lower visual field. These features indicate that the region described here as AMLS in the ferret is indeed a direct homologue of the previously described cat AMLS and forms part of a hierarchy of cortical areas processing motion in the ferret visual cortex. With the results of the present study and those of earlier studies a total of twelve cortical visual areas have been determined presently for the ferret, all of which appear to have direct homologues with visual cortical areas in the cat (which has a total of eighteen areas).

Waking up the brain: a case study of stimulation-induced wakeful unawareness during anaesthesia

Hitherto, little is known about the specific functional contributions of extrathalamic arousal systems to the regulation of wakefulness in humans. Here, we describe a 42-year-old woman with treatment resistant tremulous cervical dystonia who underwent microelectrode-guided stereotactic implantation of deep brain stimulation (DBS) electrodes in the internal segment of the globus pallidus internus (GPi) under general anaesthesia. Acute unilateral DBS of circumscribed sites within the subpallidal fibre-field with 130 Hz caused a transient state of wakefulness with an increased responsiveness to external stimuli but without detectable signs of conscious awareness. The extent of behavioural arousal could be titrated as a function of stimulus intensity. At lower stimulation intensities, bilateral eye opening occurred in response to verbal commands or tactile stimulation. At suprathreshold intensities, the patients eyes remained open and conjugated throughout the stimulation period. The arousal effect ceased abruptly when DBS was discontinued. Behavioural arousal was accompanied by global cortical EEG activation in the gamma-frequency range (40-120 Hz) and by autonomic activation as evidenced by increased heart rate. The observed effect was reproducible in both hemispheres and topographically restricted to 6 out of 15 tested sites in the fibre-field between the GPi and the posterior aspect of the basal nucleus of Meynert. We conclude that the stimulated neural substrate in the subpallidal basal forebrain is involved in the premotor control of lid and eye position and the control of the activation state of the human neocortex. It may thus be important for the induction and maintenance of anaesthesia-induced unconsciousness in humans. It is suggested that subpallidal DBS released a downstream arousal circuit from anaesthesia-related inhibitory modulation either by direct excitation of an arousal nucleus or by inhibition of a sleep-promoting centre in the basal forebrain.