Oscillatory Neuronal Activity Research Articles

Properties of oscillatory neuronal activity in the basal ganglia and thalamus in patients with Parkinson\u2019s disease

BackgroundThe cardinal features of Parkinson’s disease (PD) are bradykinesia, rigidity and rest tremor. Abnormal activity in the basal ganglia is predicted to underlie the mechanism of motor symptoms. This study aims to characterize properties of oscillatory activity in the basal ganglia and motor thalamus in patients with PD.MethodsTwenty-nine patients with PD who underwent bilateral or unilateral electrode implantation for subthalamic nucleus (STN) DBS (n = 11), unilateral pallidotomy (n = 9) and unilateral thalamotomy (n = 9) were studied. Microelectrode recordings in the STN, globus pallidus internus (GPi) and ventral oral posterior/ventral intermediate of thalamus (Vop/Vim) were performed. Electromyography of the contralateral limbs was recorded. Single unit characteristics including interspike intervals were analyzed. Spectral and coherence analyses were assessed. Mean spontaneous firing rate (MSFR) of neurons was calculated. Analysis of variance and X2 test were performed.ResultsOf 76 STN neurons, 39.5% were 4–6 Hz band oscillatory neurons and 28.9% were β frequency band (βFB) oscillatory neurons. The MSFR was 44.2 ± 7.6 Hz. Of 62 GPi neurons, 37.1% were 4–6 Hz band oscillatory neurons and 27.4% were βFB neurons. The MSFR was 80.9 ± 9.6 Hz. Of 44 Vop neurons, 65.9% were 4–6 Hz band oscillatory neurons and 9% were βFB neurons. The MSFR was 24.4 ± 4.2 Hz. Of 30 Vim oscillatory neurons, 70% were 4–6 Hz band oscillatory neurons and 13.3% were βFB neurons. The MSFR was 30.3 ± 3.6 Hz. Further analysis indicated that proportion of βFB oscillatory neurons in STN and GPi was higher than that of similar neurons in the Vop and Vim (P < 0.05). Conversely, the proportion of 4–6 Hz band oscillatory neurons and tremor related neurons in the Vim and Vop was higher than that of STN and GPi (P < 0.05). The highest MSFR was for GPi oscillatory neurons whereas the lowest MSFR was for Vop oscillatory neurons (P < 0.005).ConclusionThe alterations in neuronal activity in basal ganglia play a critical role in generation of parkinsonism. β oscillatory activity is more prominent in basal ganglia than in thalamus suggesting that the activity likely results from dopaminergic depletion. While both basal ganglia and thalamus have tremor activity, the thalamus appears to play a more important role in tremor production, and basal ganglia β oscillatory activity might be the trigger.

Modulation of neuronal oscillatory activity in the beta- and gamma-band is associated with current individual anxiety levels

Human faces are among the most salient visual stimuli and act both as socially and emotionally relevant signals. Faces and especially faces with emotional expression receive prioritized processing in the human brain and activate a distributed network of brain areas reflected, e.g., in enhanced oscillatory neuronal activity. However, an inconsistent picture emerged so far regarding neuronal oscillatory activity across different frequency-bands modulated by emotionally and socially relevant stimuli. The individual level of anxiety among healthy populations might be one explanation for these inconsistent findings. Therefore, we tested the hypothesis whether oscillatory neuronal activity is associated with individual anxiety levels during perception of faces with neutral and fearful facial expressions. We recorded neuronal activity using magnetoencephalography (MEG) in 27 healthy participants and determined their individual state anxiety levels. Images of human faces with neutral and fearful expressions, and physically matched visual control stimuli were presented while participants performed a simple color detection task. Spectral analyses revealed that face processing and in particular processing of fearful faces was characterized by enhanced neuronal activity in the theta- and gamma-band and decreased activity in the beta-band in early visual cortex and the fusiform gyrus (FFG). Moreover, the individuals' state anxiety levels correlated positively with the gamma-band response and negatively with the beta response in the FFG and the amygdala. Our results suggest that oscillatory neuronal activity plays an important role in affective face processing and is dependent on the individual level of state anxiety. Our work provides new insights on the role of oscillatory neuronal activity underlying processing of faces.

F61. Oscillatory neuronal activity in the basal ganglia and the ventral thalamus in patients with Parkinson’s disease

Parkinson’s disease (PD) is characterized by tremor, rigidity, bradykinesia. According to the classic model of PD, the dopamine deficit in the SNc results in alterations of neuronal activity in the basal ganglia motor circuit, leading to parkinsonian symptoms. The purpose of the study was to characterize oscillatory neurons in the STN, the GPi and the Vop/Vim nuclei in PD patients, the firing rates and proportion of oscillatory neurons in the three nuclei were compared. Twenty-nine patients with PD underwent STN DBS, pallidotomy and thalamotomy were studied. Microelectrode recordings in the STN, GPi and Vop/Vim and EMG on limbs were performed. The interspike intervals were assessed. Spectral analysis was used to evaluate neuronal oscillatory activities. Coherence was performed. Mean spontaneous firing rates (MSFR) and proportions of STN, GPi and Vop/Vim oscillatory neurons were compared. Of 76 STN neurons identified, 39.5% were tremor frequency oscillatory (TFB) neurons and 28.9% were ß frequency oscillatory (ßFB) neurons. Their MSFR was 44.2 ± 7.6 Hz. Of 62 GPi neurons identified, 37.1% were TFB neurons and 27.4% were ßFB oscillatory neurons. Their MSFR was 80.9 ± 9.6 Hz. Of 74 thalamic neurons identified, 45 were Vop neurons and 29 were Vim neurons. Of 45 Vop neurons, 66.7% was TFB oscillatory neurons and 9.0% was ßFB oscillatory neurons. Of 29 Vim neurons, 69% were TFB oscillatory neurons and 13.7% was ßFB oscillatory neurons. Their MSFR was 24.5 ± 4.1 Hz for Vop and 30.8 ± 3.7 Hz for Vim. Further comparisons of MSFR and proportions of TFB, βFB oscillatory neurons in STN, GPi and Vop/Vim found that there were significant other differences among the nuclei. TFB oscillatory neurons predominantly distributed in Vop (66.7%) and Vim (69%) as compared to STN (28.9%) and GPi (27.4%). In contrast, ßFB oscillatory neurons distributed in the STN (28.9%) and GPi (27.4%) as compared to Vop (9%) and Vim (13.7%). There were also significant differences of MSFR of TFB and βFB oscillatory neurons among the four nuclei. The comparisons showed that the highest MSFR was GPi oscillatory neurons (80.9 ± 9.6 Hz), then STN neurons (44.2 ± 7.6 Hz) and Vim neurons (30.8 ± 3.7 Hz), and the lowest rate was Vop neurons (24.5 ± 4.1 Hz). All comparisons were p < 0.05. 1. In comparison to normal animal model, significant increased MSFR of GPi, STN neurons and decreased MSFR of Vop neurons in PD patients supports the prediction of the classic model of PD. 2. The proportions of STN and GPi βFB oscillatory neurons were higher than that of Vop/Vim oscillatory neurons suggesting that dopamine deficits likely increase β frequency oscillations in PD. 3. The TFB oscillatory neurons exist in basal ganglia nuclei STN, GPi and the Vop and Vim as well. Particularly, the highest proportion of TFB oscillatory neuron was observed in Vim suggests that both the basal ganglia and cerebello-thalamic circuits are involved in generation of tremor, cerebello-thalamic circuits seeming to be more important.

3.1 ENHANCED PARVALBUMIN NETWORK ACTIVITY PROLONGS CRITICAL PERIOD PLASTICITY

BackgroundOscillations in neuronal activity tie the pathophysiology of schizophrenia to alterations in local processing and large-scale coordination, and these alterations in turn can lead to the cognitive and perceptual disturbances observed in schizophrenia. Here, we focus on the dual role of fast-spiking, parvalbumin (PV+) networks in the generation of gamma oscillations and critical periods of brain plasticity.MethodsWe generated a mouse model of reduced recurrent inhibition only within local PV+ cell networks by selective removal of GABAA receptor alpha1 subunits (PV-α1 KO mice). Electroencephalography (EEG), PV+ immunohistochemistry, perineuronal net (PNN) labeling and redox balance were compared to cortical measures of brain plasticity (loss of visual acuity, formation of preference behaviors) that are typically limited to a critical period early in life.ResultsPV-α1 KO mice exhibit chronically enhanced gamma-oscillations and extended juvenile forms of cortical plasticity into adulthood. Acute pharmacological suppression of excitatory input restored E-I balance onto these disinhibited PV+ cells and returned baseline EEG power to normal levels, preventing the extended plasticity. Enhanced gamma oscillations were further found to compromise the integrity of perineuronal nets (PNNs) surrounding PV+ cells, elevating oxidative stress and the turnover of metallopeptidases and structural components of the PNN. All of these aspects were also reversed by pharmacological dampening of excitation onto PV+ cells.DiscussionCortical gamma oscillations are associated with plasticity and cognition. Our results provide a cellular explanation of how elevated gamma oscillations may promote ectopic brain plasticity by regulating the extracellular matrix which normally stabilizes cortical circuitry. These results carry broad implications for subjects at-risk for schizophrenia who exhibit heightened gamma oscillations prior to psychosis onset (see talk by P Uhlhaas).

18.1 MITOCHONDRIAL ALTERATIONS WITHIN THE PYRAMIDAL-PARVALBUMIN CELL MICROCIRCUIT IN THE PREFRONTAL CORTEX IN SCHIZOPHRENIA

BackgroundWorking memory, a core cognitive function impaired in schizophrenia, depends upon gamma oscillatory neuronal activity in the prefrontal cortex (PFC). Accordingly, individuals with schizophrenia show lower power of gamma oscillations in the PFC during tasks that involve working memory. Gamma oscillations emerge from the fast and coordinated activity of layer 3 excitatory pyramidal cells and inhibitory parvalbumin (PV) cells. As such, gamma oscillations have a particularly high energetic demand that is met by ATP production via oxidative phosphorylation (OXPHOS) within pyramidal and PV cell mitochondria. PFC layer 3 pyramidal cells have prominent reductions in OXPHOS-related gene pathways in schizophrenia. Importantly, OXPHOS can be regulated by two distinct processes: ATP demand to support neuronal firing, or upstream deficits in OXPHOS enzyme expression. Layer- and cell type-specific transcriptomic analyses of OXPHOS enzymes and ultrastructural analyses of mitochondrial morphology can help to distinguish between these two possibilities. Reduced ATP demand due to reduced neuronal firing is associated with 1) correlated expression levels of OXPHOS enzyme complexes, 2) lower expression of all subunits comprising Complex IV, the terminal and rate-limiting OXPHOS enzyme complex, and 3) normal mitochondrial morphology. Defective OXPHOS results in 1) elimination of correlated expression of OXPHOS enzyme complexes, 2) variable and inconsistent effects on Complex IV subunit expression, and 3) abnormal mitochondrial morphology.To determine which upstream factor is likely operative in the illness, we quantified OXPHOS enzyme complex transcripts in layer 3 pyramidal and PV cells, and performed ultrastructural analyses of mitochondrial morphology within pyramidal and PV axon boutons in layer 3 of the PFC in schizophrenia and unaffected comparison subjects.MethodsFor mRNA analyses, frozen tissue sections of area 9 from 36 pairs of schizophrenia and comparison subjects were stained for Nissl substance to identify pyramidal cells, or labeled using immunoperoxidase for aggrecan to identify PV cells. Layer 3 pyramidal and PV somata were dissected using laser capture microdissection. Transcriptome profiling was performed by microarray using Affymetrix GeneChips. Analysis of Complexes I, IV, and V expression in each neuronal population was assessed at q<0.05 in covariate- and multiple comparisons-corrected analyses.Electron microscopic analyses were performed in area 46 of 2 matched pairs of schizophrenia and comparison subjects. Mitochondria in pyramidal and PV cell boutons were classified as normal or abnormal using established criteria. Chi-square analysis was used to examine whether the percentages of each type differed between groups.ResultsThe expression of subunits comprising Complexes I, IV, and V in layer 3 pyramidal and PV cells was significantly lower in subjects with schizophrenia relative to unaffected comparison subjects. In both cell populations, expression of Complexes I, IV, and V were correlated (r=0.8-0.9) in unaffected comparison and schizophrenia subjects. Complex IV subunits showed 11–26% reductions in pyramidal cells, and 7-31% reductions in PV cells in schizophrenia. In both unaffected comparison and schizophrenia subjects, ≥99% of mitochondria in pyramidal cell boutons and ≥97% of mitochondria in PV cell boutons exhibited normal morphology.DiscussionThe current findings are most consistent with the interpretation that lower measures of OXPHOS in schizophrenia reflect lower demand for ATP production due to less neuronal firing.

O3.1. NEUROTYPING UNTREATED FIRST EPISODE SCHIZOPHRENIA ON THE BASIS OF SLOW-WAVE RESTING-STATE DYNAMICS

BackgroundCoherence in the phase of oscillatory neuronal activity indicates functional interaction among brain regions at rest. Infra-slow fluctuations in BOLD signal (band 5 - 0.01 to 0.027 Hz - and band 4 - 0.027 to 0.073 Hz) has been observed using resting state fMRI when employing frequency-domain analysis, and has been previously shown to be altered in schizophrenia. In the current study, we examined the strength and the dynamic variance of phase coherence in these 2 bands (using a sliding window approach) among 6 large-scale brain networks (default-mode, fronto-parietal, salience, sensorimotor, visual, cerebellar) in 129 drug-naïve patients with schizophrenia and 197 healthy controls. Our motivation was to exploit the large-scale resting-state slow-wave oscillatory dynamics to parse the heterogeneity of schizophrenia.MethodsFour 6*6 matrices depicting patient vs. control differences in dynamic variance and mean of phase coherence (vPC and mPC respectively) in the slow 4 and slow 5 bands were constructed from resting state fMRI time series obtained from 6 networks based on 160 nodes of Dosenbach’s atlas. Deviations in mean/variance of phase coherence among the 6 networks were identified after FDR correction for each matrix (p<0.05). A latent profile analysis (LPA) was undertaken on the basis of the identified deviant features in the patient group. LPA is a Finite Mixture Modelling approach to identify naturally occurring sub-groups of patients on the basis of multivariable data. The identified subgroups were compared in terms of the severity of clinical symptoms across van der Gaag’s 5 factors of PANSS scale.ResultsPatients with schizophrenia showed increased vPC between salience-sensorimotor and visual-cerebellar networks in band 5; decreased vPC between DMN-sensorimotor and DMN-cerebellar networks in band 4. Patients also had a decrease in mPC between DMN-visual and DMN-cerebellar networks in band 5. We were able to identify 3 subgroups of patients using LPA. SZ1 (n=28) and SZ2 (n=45) had higher overall burden of symptoms compared to SZ3 (n=56). SZ2 had the highest burden of negative syndrome score and showed most deviance from healthy controls (5 out of 7 features significantly different from the healthy cohort). SZ1 had the highest burden of positive syndrome scores and had 4 out of 7 features deviant from HC. In contrast, SZ3 had least deviation from HC (3 out of 7 features) and also had less symptom burden across all symptom dimensions.DiscussionVarious abnormalities have been reported in the interactions among the large-scale networks in schizophrenia, with lack of consistency ascribed to syndromic heterogeneity. We illustrate how deviations in time-varying nature of slow-wave oscillations in resting state fMRI can be exploited to meaningfully reduce heterogeneity of this illness. The 3 subgroups thus identified not only show differential symptom burden but also exhibit hierarchical deviation from a normative group of healthy controls (SZ2>SZ1>SZ3>HC). To our knowledge this is the first attempt to stratify ‘neurotypes’ among drug-naïve patients with schizophrenia on the basis of large-scale network dynamics. Given the widespread availability of resting-fMRI data, we anticipate independent replication of our results in the near future.

Phase of beta-frequency tACS over primary motor cortex modulates corticospinal excitability

The assessment of corticospinal excitability by means of transcranial magnetic stimulation-induced motor evoked potentials is an established diagnostic tool in neurophysiology and a widely used procedure in fundamental brain research. However, concern about low reliability of these measures has grown recently. One possible cause of high variability of MEPs under identical acquisition conditions could be the influence of oscillatory neuronal activity on corticospinal excitability. Based on research showing that transcranial alternating current stimulation can entrain neuronal oscillations we here test whether alpha or beta frequency tACS can influence corticospinal excitability in a phase-dependent manner. We applied tACS at individually calibrated alpha- and beta-band oscillation frequencies, or we applied sham tACS. Simultaneous single TMS pulses time locked to eight equidistant phases of the ongoing tACS signal evoked MEPs. To evaluate offline effects of stimulation frequency, MEP amplitudes were measured before and after tACS. To evaluate whether tACS influences MEP amplitude, we fitted one-cycle sinusoids to the average MEPs elicited at the different phase conditions of each tACS frequency. We found no frequency-specific offline effects of tACS. However, beta-frequency tACS modulation of MEPs was phase-dependent. Post hoc analyses suggested that this effect was specific to participants with low (<19 Hz) intrinsic beta frequency. In conclusion, by showing that beta tACS influences MEP amplitude in a phase-dependent manner, our results support a potential role attributed to neuronal oscillations in regulating corticospinal excitability. Moreover, our findings may be useful for the development of TMS protocols that improve the reliability of MEPs as a meaningful tool for research applications or for clinical monitoring and diagnosis.

Towards Revealing a Cooperative Mechanism of Camp Binding to HCN2 Cyclic Nucleotide Binding Domains at the Single-Molecule Level

Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels are critical for oscillatory neuronal activity in the brain and pacemaking in the heart. Although activation of these tetrameric channels can be driven solely by hyperpolarizing voltages, the binding of cyclic nucleotides to their intracellular cyclic nucleotide binding domains (CNBDs) enhances their voltage-dependence of activation through a mechanism that remains unclear. Previous studies dissecting the cooperative nature of subunit activation upon cAMP binding have relied on macroscopic methods, such as ensemble channel currents or fluorescence. Although these studies provide pivotal information in determining the gating-mechanism of HCN channels, they both afford only ensemble-averaged data, which obscures the resolution of individual binding steps. Herein, we aim to circumvent this limitation and determine the cooperative mechanism of cAMP binding to HCN2 CNBDs at the single-molecule level. By tethering an artificially-linked tetrameric CNBD construct into nanofabricated devices called zero-mode waveguides, we resolve the stepwise binding of fluorescent cAMP molecules to all four binding sites of our complex. Using hidden Markov modeling of our idealized single-molecule fluorescence time series, we begin to reveal a cooperative mechanism of cAMP binding to HCN2 CNBDs.

Loss of Balance between Striatal Feedforward Inhibition and Corticostriatal Excitation Leads to Tremor.

Fast-spiking interneurons (FSIs) exert powerful inhibitory control over the striatum and are hypothesized to balance the massive excitatory cortical and thalamic input to this structure. We recorded neuronal activity in the dorsolateral striatum and globus pallidus (GP) concurrently with the detailed movement kinematics of freely behaving female rats before and after selective inhibition of FSI activity using IEM-1460 microinjections. The inhibition led to the appearance of episodic rest tremor in the body part that depended on the somatotopic location of the injection within the striatum. The tremor was accompanied by coherent oscillations in the local field potential (LFP). Individual neuron activity patterns became oscillatory and coherent in the tremor frequency. Striatal neurons, but not GP neurons, displayed additional temporal, nonoscillatory correlations. The subsequent reduction in the corticostriatal input following muscimol injection to the corresponding somatotopic location in the primary motor cortex led to disruption of the tremor and a reduction of the LFP oscillations and individual neuron's phase-locked activity. The breakdown of the normal balance of excitation and inhibition in the striatum has been shown previously to be related to different motor abnormalities. Our results further indicate that the balance between excitatory corticostriatal input and feedforward FSI inhibition is sufficient to break down the striatal decorrelation process and generate oscillations resulting in rest tremor typical of multiple basal ganglia disorders.SIGNIFICANCE STATEMENT Fast-spiking interneurons (FSIs) play a key role in normal striatal processing by exerting powerful inhibitory control over the network. FSI malfunctions have been associated with abnormal processing of information within the striatum that leads to multiple movement disorders. Here, we study the changes in neuronal activity and movement kinematics following selective inhibition of these neurons. The injections led to the appearance of episodic rest tremor, accompanied by coherent oscillations in neuronal activity, which was reversed following corticostriatal inhibition. These results suggest that the balance between corticostriatal excitation and feedforward FSI inhibition is crucial for maintaining the striatal decorrelation process, and that its breakdown leads to the formation of oscillations resulting in rest tremor typical of multiple basal ganglia disorders.

Disparate Effects of Lithium and a GSK-3 Inhibitor on Neuronal Oscillatory Activity in Prefrontal Cortex and Hippocampus.

Glycogen synthase kinase-3 (GSK-3) plays a critical role in cognitive dysfunction associated with Alzheimer’s disease (AD), yet the mechanism by which GSK-3 alters cognitive processes in other disorders, such as schizophrenia, remains unknown. In the present study, we demonstrated a role for GSK-3 in the direct regulation of neuronal oscillations in hippocampus (HIP) and prelimbic cortex (PL). A comparison of the GSK-3 inhibitors SB 216763 and lithium demonstrated disparate effects of the drugs on spatial memory and neural oscillatory activity in HIP and PL. SB 216763 administration improved spatial memory whereas lithium treatment had no effect. Analysis of neuronal local field potentials in anesthetized animals revealed that whereas both repeated SB 216763 (2.5 mg/kg) and lithium (100 mg/kg) induced a theta frequency spike in HIP at approximately 10 Hz, only SB 216763 treatment induced an overall increase in theta power (4–12 Hz) compared to vehicle. Acute administration of either drug suppressed slow (32–59 Hz) and fast (61–100 Hz) gamma power. In PL, both drugs induced an increase in theta power. Repeated SB 216763 increased HIP–PL coherence across all frequencies except delta, whereas lithium selectively suppressed delta coherence. These findings demonstrate that GSK-3 plays a direct role in the regulation of theta oscillations in regions critically involved in cognition, and highlight a potential mechanism by which GSK-3 may contribute to cognitive decline in disorders of cognitive dysfunction.

Hypoxia regulates the level of glutamic acid decarboxylase enzymes and interrupts inhibitory synapse stability in primary cultured neurons

Gamma-aminobutyric acid (GABA) is the main neurotransmitter of inhibitory synaptic transmission, which is critical for oscillatory activity and synchronization of neurons in neural networks. GABA is synthesized by glutamic acid decarboxylase (GAD) enzymes in the inhibitory neuron and, thus, the deregulation of GAD enzymes and subsequent change of GABAergic activity are involved in various neurological and neuropsychiatric diseases. Under hypoxic conditions, neurons undergo neuropathological alterations which can be subtle or severe. Many studies have focused on the alteration of excitatory neurons by hypoxic injury, while inhibitory neuronal changes have not been well determined. Here, we demonstrated that hypoxic conditions decrease the expression of inhibitory neuron-related proteins, including GAD enzymes, through transcript downregulation and proteasomal degradation. Hif-1α induction and glutamate release under hypoxic conditions were implicated in the mechanism of GAD enzyme level reduction. Surprisingly, these conditions altered the density and size of inhibitory synapses, which was irreversible by reoxygenation, but was mediated by glutamate activity. Our findings suggest that potential implication of the compositional and structural alterations of inhibitory neuron in the pathogenesis of various hypoxic injuries.

Neuronal beta band oscillatory activity in the basal ganglia reflecting rigidity in Parkinson’s disease patients

Neuronal beta band oscillatory activity in the basal ganglia reflecting rigidity in Parkinson’s disease patients

Hippocampal sharp-wave ripples in awake mice are entrained by respiration

Several recent studies have shown that respiration modulates oscillatory neuronal activity in the neocortex and hippocampus on a cycle-by-cycle basis. It was suggested that this respiratory influence on neuronal activity affects cognitive functions, including memory. Sharp-wave ripples (SWRs) are high-frequency local field potential activity patterns characteristic for the hippocampus and implicated in memory consolidation and recall. Here we show that the timing of SWR events is modulated by the respiratory cycle, with a significantly increased probability of SWRs during the early expiration phase. This influence of respiration on SWR occurrence was eliminated when olfactory bulb activity was inhibited. Our findings represent a possible neuronal mechanism for a direct influence of the respiratory cycle on memory function.

Granger causality supports abnormal functional connectivity of beta oscillations in the dorsolateral striatum and substantia nigra pars reticulata in hemiparkinsonian rats.

Synchronized oscillatory neuronal activity in the beta frequency range has been reported in the basal ganglia (BG) of patients with Parkinson disease (PD) and PD animal models. The coherent abnormal oscillatory activities in the dorsolateral striatum (dStr) and substantia nigra pars reticulata (SNr) that accompany parkinsonian states have not been resolved. In this study, we recorded local field potentials (LFPs) in the dStr and SNr of 6-hydroxydopamine (6-OHDA)-induced dopamine (DA)-lesioned rats in an awake, resting state. Analyses of power spectral density and coherence data demonstrated augmented LFP power in the 24-36-Hz (high beta) range in both the dStr and SNr together with increased dStr-SNr coherence in the 24-36-Hz range, relative to sham controls; both effects were reversed by levodopa (L-dopa) treatment. Partial Granger causality analysis revealed a dStr→SNr propagation directionality of these beta oscillations. These findings support the involvement of increased synchronization of high beta activity in the dStr and the SNr, and suggest that dorsolateral striatal activity plays a determinant role in leading the coherent activity with the SNr in the development of parkinsonian pathophysiology.

Dopamine acting at D1-like, D2-like and α1-adrenergic receptors differentially modulates theta and gamma oscillatory activity in primary motor cortex.

The loss of dopamine (DA) in Parkinson’s is accompanied by the emergence of exaggerated theta and beta frequency neuronal oscillatory activity in the primary motor cortex (M1) and basal ganglia. DA replacement therapy or deep brain stimulation reduces the power of these oscillations and this is coincident with an improvement in motor performance implying a causal relationship. Here we provide in vitro evidence for the differential modulation of theta and gamma activity in M1 by DA acting at receptors exhibiting conventional and non-conventional DA pharmacology. Recording local field potentials in deep layer V of rat M1, co-application of carbachol (CCh, 5 μM) and kainic acid (KA, 150 nM) elicited simultaneous oscillations at a frequency of 6.49 ± 0.18 Hz (theta, n = 84) and 34.97 ± 0.39 Hz (gamma, n = 84). Bath application of DA resulted in a decrease in gamma power with no change in theta power. However, application of either the D1-like receptor agonist SKF38393 or the D2-like agonist quinpirole increased the power of both theta and gamma suggesting that the DA-mediated inhibition of oscillatory power is by action at other sites other than classical DA receptors. Application of amphetamine, which promotes endogenous amine neurotransmitter release, or the adrenergic α1-selective agonist phenylephrine mimicked the action of DA and reduced gamma power, a result unaffected by prior co-application of D1 and D2 receptor antagonists SCH23390 and sulpiride. Finally, application of the α1-adrenergic receptor antagonist prazosin blocked the action of DA on gamma power suggestive of interaction between α1 and DA receptors. These results show that DA mediates complex actions acting at dopamine D1-like and D2-like receptors, α1 adrenergic receptors and possibly DA/α1 heteromultimeric receptors to differentially modulate theta and gamma activity in M1.

Theta oscillations locked to intended actions rhythmically modulate perception.

Ongoing brain oscillations are known to influence perception, and to be reset by exogenous stimulations. Voluntary action is also accompanied by prominent rhythmic activity, and recent behavioral evidence suggests that this might be coupled with perception. Here, we reveal the neurophysiological underpinnings of this sensorimotor coupling in humans. We link the trial-by-trial dynamics of EEG oscillatory activity during movement preparation to the corresponding dynamics in perception, for two unrelated visual and motor tasks. The phase of theta oscillations (~4 Hz) predicts perceptual performance, even >1 s before movement. Moreover, theta oscillations are phase-locked to the onset of the movement. Remarkably, the alignment of theta phase and its perceptual relevance unfold with similar non-monotonic profiles, suggesting their relatedness. The present work shows that perception and movement initiation are automatically synchronized since the early stages of motor planning through neuronal oscillatory activity in the theta range.

Abnormalities in Dynamic Brain Activity Caused by Mild Traumatic Brain Injury Are Partially Rescued by the Cannabinoid Type-2 Receptor Inverse Agonist SMM-189

Mild traumatic brain injury (mTBI) can cause severe long-term cognitive and emotional deficits, including impaired memory, depression, and persevering fear, but the neuropathological basis of these deficits is uncertain. As medial prefrontal cortex (mPFC) and hippocampus play important roles in memory and emotion, we used multi-site, multi-electrode recordings of oscillatory neuronal activity in local field potentials (LFPs) in awake, head-fixed mice to determine if the functioning of these regions was abnormal after mTBI, using a closed-skull focal cranial blast model. We evaluated mPFC, hippocampus CA1, and primary somatosensory/visual cortical areas (S1/V1). Although mTBI did not alter the power of oscillations, it did cause increased coherence of θ (4-10 Hz) and β (10-30 Hz) oscillations within mPFC and S1/V1, reduced CA1 sharp-wave ripple (SWR)-evoked LFP activity in mPFC, downshifted SWR frequencies in CA1, and enhanced θ-γ phase-amplitude coupling (PAC) within mPFC. These abnormalities might be linked to the impaired memory, depression, and persevering fear seen after mTBI. Treatment with the cannabinoid type-2 (CB2) receptor inverse agonist SMM-189 has been shown to mitigate functional deficits and neuronal injury after mTBI in mice. We found that SMM-189 also reversed most of the observed neurophysiological abnormalities. This neurophysiological rescue is likely to stem from the previously reported reduction in neuron loss and/or the preservation of neuronal function and connectivity resulting from SMM-189 treatment, which appears to stem from the biasing of microglia from the proinflammatory M1 state to the prohealing M2 state by SMM-189.

Tonic and phasic changes in anteromedial globus pallidus activity in Tourette syndrome.

Tourette syndrome is a hyperkinetic neurodevelopmental disorder characterized by tics. Assess the neuronal changes in the associative/limbic GP associated with Tourette syndrome. Neurophysiological recordings were performed from the anterior (associative/limbic) GPe and GPi of 8 awake patients during DBS electrode implantation surgeries. The baseline firing rate of the neurons was low in a state-dependent manner in both segments of the GP. Tic-dependent transient rate changes were found in the activity of individual neurons of both segments around the time of the tic. Neither oscillatory activity of individual neurons nor correlations in their interactions were observed. The results demonstrate the involvement of the associative/limbic pathway in the underlying pathophysiology of Tourette syndrome and point to tonic and phasic modulations of basal ganglia output as a key mechanisms underlying the abnormal state of the disorder and the expression of individual tics, respectively. © 2017 International Parkinson and Movement Disorder Society.

Only Three Fingers Write, but the Whole Brain Works: A High-Density EEG Study Showing Advantages of Drawing Over Typing for Learning.

Are different parts of the brain active when we type on a keyboard as opposed to when we draw visual images on a tablet? Electroencephalogram (EEG) was used in young adults to study brain electrical activity as they were typing or describing in words visually presented PictionaryTM words using a keyboard, or as they were drawing pictures of the same words on a tablet using a stylus. Analyses of temporal spectral evolution (time-dependent amplitude changes) were performed on EEG data recorded with a 256-channel sensor array. We found that when drawing, brain areas in the parietal and occipital regions showed event related desynchronization activity in the theta/alpha range. Existing literature suggests that such oscillatory neuronal activity provides the brain with optimal conditions for learning. When describing the words using the keyboard, upper alpha/beta/gamma range activity in the central and frontal brain regions were observed, especially during the ideation phase. However, since this activity was highly synchronized, its relation to learning remains unclear. We concluded that because of the benefits for sensory-motor integration and learning, traditional handwritten notes are preferably combined with visualizations (e.g., small drawings, shapes, arrows, symbols) to facilitate and optimize learning.

Dopamine Induces Oscillatory Activities in Human Midbrain Neurons with Parkin Mutations

Locomotor symptoms in Parkinson's disease (PD) are accompanied by widespread oscillatory neuronal activities in basal ganglia. Here, we show that activation of dopamine D1-class receptors elicits a large rhythmic bursting of spontaneous excitatory postsynaptic currents (sEPSCs) in midbrain neurons differentiated from induced pluripotent stem cells (iPSCs) of PD patients with parkin mutations, but not normal subjects. Overexpression of wild-type parkin, but not its PD-causing mutant, abolishes the oscillatory activities in patient neurons. Dopamine induces a delayed enhancement in the amplitude of spontaneous, but not miniature, EPSCs, thus increasing quantal content. The results suggest that presynaptic regulation of glutamatergic transmission by dopamine D1-class receptors is significantly potentiated by parkin mutations. The aberrant dopaminergic regulation of presynaptic glutamatergic transmission in patient-specific iPSC-derived midbrain neurons provides a mechanistic clue to PD pathophysiology, and it demonstrates the usefulness of this model system in understanding how mutations of parkin cause movement symptoms in Parkinson's disease.