Restoring thalamocortical circuit dysfunction by correcting HCN channelopathy in Shank3 mutant mice.

Thalamocortical (TC) circuits are essential for sensory information processing. Clinical and preclinical studies of autism spectrum disorders (ASDs) have highlighted abnormal thalamic development and TC circuit dysfunction. However, mechanistic understanding of how TC dysfunction contributes to behavioral abnormalities in ASDs is limited. Here, our study on a Shank3 mouse model of ASD reveals TC neuron hyperexcitability with excessive burst firing and a temporal mismatch relationship with slow cortical rhythms during sleep. These TC electrophysiological alterations and the consequent sensory hypersensitivity and sleep fragmentation in Shank3 mutant mice are causally linked to HCN2 channelopathy. Restoring HCN2 function early in postnatal development via a viral approach or lamotrigine (LTG) ameliorates sensory and sleep problems. A retrospective case series also supports beneficial effects of LTG treatment on sensory behavior in ASD patients. Our study identifies a clinically relevant circuit mechanism and proposes a targeted molecular intervention for ASD-related behavioral impairments.

Heterozygous GABAA receptor ß3 subunit N110D knock-in mice have epileptic spasms.

OBJECTIVE: Infantile spasms is an epileptic encephalopathy of childhood, and its pathophysiology is largely unknown. We generated a heterozygous knock-in mouse with the human infantile spasms-associated de novo mutation GABRB3 (c.A328G, p.N110D) to investigate its molecular mechanisms and to establish the Gabrb3+/N110D knock-in mouse as a model of infantile spasms syndrome. METHODS: We used electroencephalography (EEG) and video monitoring to characterize seizure types, and a suite of behavioral tests to identify neurological and behavioral impairment in Gabrb3+/N110D knock-in mice. Miniature inhibitory postsynaptic currents (mIPSCs) were recorded from layer V/VI pyramidal neurons in somatosensory cortex, and extracellular multi-unit recordings from the ventral basal nucleus of the thalamus in a horizontal thalamocortical slice were used to assess spontaneous thalamocortical oscillations. RESULTS: The infantile spasms-associated human de novo mutation GABRB3 (c.A328G, p.N110D) caused epileptic spasms early in development and multiple seizure types in adult Gabrb3+/N110D knock-in mice. Signs of neurological impairment, anxiety, hyperactivity, social impairment, and deficits in spatial learning and memory were also observed. Gabrb3+/N110D mice had reduced cortical mIPSCs and increased duration of spontaneous oscillatory firing in the somatosensory thalamocortical circuit. SIGNIFICANCE: The Gabrb3+/N110D knock-in mouse has epileptic spasms, seizures, and other neurological impairments that are consistent with infantile spasms syndrome in patients. Multiple seizure types and abnormal behaviors indicative of neurological impairment both early and late in development suggest that Gabrb3+/N110D mice can be used to study the pathophysiology of infantile spasms. Reduced cortical inhibition and increased duration of thalamocortical oscillatory firing suggest perturbations in thalamocortical circuits.

Large-scale biophysically detailed model of somatosensory thalamocortical circuits in NetPyNE.

The primary somatosensory cortex (S1) of mammals is critically important in the perception of touch and related sensorimotor behaviors. In 2015, the Blue Brain Project (BBP) developed a groundbreaking rat S1 microcircuit simulation with over 31,000 neurons with 207 morpho-electrical neuron types, and 37 million synapses, incorporating anatomical and physiological information from a wide range of experimental studies. We have implemented this highly detailed and complex S1 model in NetPyNE, using the data available in the Neocortical Microcircuit Collaboration Portal. NetPyNE provides a Python high-level interface to NEURON and allows defining complicated multiscale models using an intuitive declarative standardized language. It also facilitates running parallel simulations, automates the optimization and exploration of parameters using supercomputers, and provides a wide range of built-in analysis functions. This will make the S1 model more accessible and simpler to scale, modify and extend in order to explore research questions or interconnect to other existing models. Despite some implementation differences, the NetPyNE model preserved the original cell morphologies, electrophysiological responses and spatial distribution for all 207 cell types; and the connectivity properties of all 1941 pathways, including synaptic dynamics and short-term plasticity (STP). The NetPyNE S1 simulations produced reasonable physiological firing rates and activity patterns across all populations. When STP was included, the network generated a 1 Hz oscillation comparable to the original model in vitro-like state. By then reducing the extracellular calcium concentration, the model reproduced the original S1 in vivo-like states with asynchronous activity. These results validate the original study using a new modeling tool. Simulated local field potentials (LFPs) exhibited realistic oscillatory patterns and features, including distance- and frequency-dependent attenuation. The model was extended by adding thalamic circuits, including 6 distinct thalamic populations with intrathalamic, thalamocortical (TC) and corticothalamic connectivity derived from experimental data. The thalamic model reproduced single known cell and circuit-level dynamics, including burst and tonic firing modes and oscillatory patterns, providing a more realistic input to cortex and enabling study of TC interactions. Overall, our work provides a widely accessible, data-driven and biophysically-detailed model of the somatosensory TC circuits that can be employed as a community tool for researchers to study neural dynamics, function and disease.

The mediodorsal thalamus supports adaptive responding based on stimulus-outcome associations.

The ability to engage into flexible behaviors is crucial in dynamic environments. We recently showed that in addition to the well described role of the orbitofrontal cortex (OFC), its thalamic input from the submedius thalamic nucleus (Sub) also contributes to adaptive responding during Pavlovian degradation. In the present study, we examined the role of the mediodorsal thalamus (MD) which is the other main thalamic input to the OFC. To this end, we assessed the effect of both pre- and post-training MD lesions in rats performing a Pavlovian contingency degradation task. Pre-training lesions mildly impeded the establishment of stimulus-outcome associations during the initial training of Pavlovian conditioning without interfering with Pavlovian degradation training when the sensory feedback provided by the outcome rewards were available to animals. However, we found that both pre- and post-training MD lesions produced a selective impairment during a test conducted under extinction conditions, during which only current mental representation could guide behavior. Altogether, these data suggest a role for the MD in the successful encoding and representation of Pavlovian associations.

Focal thalamocortical circuit abnormalities in sleep related epilepsy caused by focal cortical dysplasia type II.

Purpose To investigate the variations of the thalamocortical circuit between the focal cortical dysplasia (FCD) type II patients with sleep-related epilepsy (SRE) and those without SRE (non-SRE). Methods Patients with epilepsy who had histologically proven FCD type II were enrolled. Those without diffusion tensor image and 3-dimensional (3D) T1 MRI sequences were excluded. Thalamocortical structural connectivity to lesion and non-lesion regions was quantified using probabilistic tractography. Fractional anisotropy (FA) and mean diffusivity (MD) were computed. Results A total of 30 consecutive patients were included. Among them, 18 patients (60%) had SRE. Analysis of covariance showed that smaller lesion size was significantly associated with SRE (p=0.048). Compared to patients with non-SRE, patients with SRE showed a significant decrease in FA of thalamocortical projections to the lesion region (p=0.007). No difference was observed in the thalamocortical connectivity to the non-lesion region between patients with SRE and non-SRE. Among the patients with SRE, a significant decrease in FA of thalamocortical projections to the lesion region was noted compared with the contralateral homotopic non-lesion region (p=0.026). Conclusion The data provide evidence of disparity in thalamocortical projections to the lesion regions between SRE and non-SRE. This might indicate the underlying pathophysiology or neuroanatomical substrates of SRE related to the FCD type II.

The anterior limb of the internal capsule: Anatomy, function, and dysfunction.

The last two decades have seen a re-emergence of neurosurgery for severe, refractory psychiatric diseases, largely due to the advent of more precise and safe operative techniques. Nevertheless, the optimal targets for these surgeries remain a matter of debate, and are often grandfathered from experiences in the late 20th century. To better explore the rationale for one target in particular - the anterior limb of the internal capsule (ALIC) - we comprehensively reviewed all available literature on its role in the pathophysiology and treatment of mental illness. We first provide an overview of its functional anatomy, followed by a discussion on its role in several prevalent psychiatric diseases. Given its structural integration into the limbic system and involvement in a number of cognitive and emotional processes, the ALIC is a robust target for surgical treatment of refractory psychiatric diseases. The advent of novel neuroimaging techniques, coupled with image-guided therapeutics and neuromodulatory treatments, will continue to enable study on the ALIC in mental illness.

Thalamocortical connectivity in electroconvulsive therapy for major depressive disorder.

BACKGROUND: Electroconvulsive therapy (ECT) can lead to rapid and effective responses in major depressive disorder (MDD). However, the precise neural mechanisms of ECT for MDD are still unclear. Previous work has confirmed that thalamocortical circuits play an important role in emotion and cognition. However, the relationship between mechanisms of ECT for MDD and thalamocortical connectivity has not yet been investigated. METHOD: Thalamocortical functional connectivity analysis was performed on resting-state functional magnetic resonance imaging (fMRI) data collected from 28 MDD patients both pre- and post-ECT treatment, as well as 20 healthy controls. The cortex was parceled into six regions of interest (ROIs), which were used as seeds to assess the functional connectivity between the cortex and each voxel in the thalamus. Then, functional connectivity between the identified thalamic subregions and the rest of the brain was quantified to better localize thalamocortical connectivity related to ECT. Structural connectivity among the functionally abnormal regions was also determined using probabilistic tractography from diffusion tensor imaging (DTI) data. RESULTS: There was decreased parietal cortex-left pulvinar and left pulvinar-bilateral precuneus functional connectivity in post-ECT MDD patients, compared to pre-ECT MDD patients. Furthermore, functional connectivity strength of parietal cortex-left pulvinar and left pulvinar-bilateral precuneus was negative correlation with verbal fluency test scores in post-ECT MDD patients. No significant change was found in structural connectivity analysis. LIMITATIONS: The sample size of our study was not large. CONCLUSION: Our findings implicate that the specific abnormalities in thalamocortical circuit may be associated with cognitive impairment induced by ECT.

The role of coupling connections in a model of the cortico-basal ganglia-thalamocortical neural loop for the generation of beta oscillations.

Excessive neural synchronization in the cortico-basal ganglia-thalamocortical circuits in the beta (ß) frequency range (12-35 Hz) is closely associated with dopamine depletion in Parkinson's disease (PD) and correlated with movement impairments, but the neural basis remains unclear. In this work, we establish a double-oscillator neural mass model for the cortico-basal ganglia-thalamocortical closed-loop system and explore the impacts of dopamine depletion induced changes in coupling connections within or between the two oscillators on neural activities within the loop. Spectral analysis of the neural mass activities revealed that the power and frequency of their principal components are greatly dependent on the coupling strengths between nuclei. We found that the increased intra-coupling in the basal ganglia-thalamic (BG-Th) oscillator contributes to increased oscillations in the lower ß frequency band (12-25 Hz), while increased intra-coupling in the cortical oscillator mainly contributes to increased oscillations in the upper ß frequency band (26-35 Hz). Interestingly, pathological upper ß oscillations in the cortical oscillator may be another origin of the lower ß oscillations in the BG-Th oscillator, in addition to increased intra-coupling strength within the BG-Th network. Lower ß oscillations in the BG-Th oscillator can also change the dominant oscillation frequency of a cortical nucleus from the upper to the lower ß band. Thus, this work may pave the way towards revealing a possible neural basis underlying the Parkinsonian state.

Thalamocortical processing of the head-direction sense.

Our thoughts and sensations are examples of cognitive processes that emerge from the collective activity of billions of neurons in the brain. Thalamocortical circuits form the canonical building-blocks of the brain networks supporting the most complex cognitive functions. How these neurons communicate and interact has been the focus of extensive research in "classical" sensory systems. Similar to visual, auditory or somatosensory thalamic pathways, one primary nucleus in the anterior (limbic) thalamus - the antero-dorsal nucleus - conveys a low-level input, the head-direction (HD) signal, to the cortex. Its activity is controlled in large part by the vestibular system and is relayed by a serially connected group of subcortical nuclei to the thalamus. HD cells serve as the brain's internal 'compass' and each of them is tuned to the specific direction the animal is facing. Recently, recordings of HD neuronal populations in the antero-dorsal nucleus and its main cortical target, the post-subiculum, have revealed that neuronal activity in the thalamocortical HD network are largely invariant to brain states at three levels: static (preserved functional organization), temporal (same drifting speed during exploration and Rapid Eye Movement sleep) and inter-area interaction (from thalamus to cortex). These observations suggest that HD neurons are certainly more driven by intrinsic wiring and dynamics than by sensory inputs and that the information flows bottom-up, even during sleep. Altogether, thalamic HD cells convey a highly reliable, near-noiseless signal that broadly influences the emergence of spatial maps in the cortex and may play a key role in sleep-dependent memory processes.

Augmented Reticular Thalamic Bursting and Seizures in Scn1a-Dravet Syndrome.

Loss of function in the Scn1a gene leads to a severe epileptic encephalopathy called Dravet syndrome (DS). Reduced excitability in cortical inhibitory neurons is thought to be the major cause of DS seizures. Here, in contrast, we show enhanced excitability in thalamic inhibitory neurons that promotes the non-convulsive seizures that are a prominent yet poorly understood feature of DS. In a mouse model of DS with a loss of function in Scn1a, reticular thalamic cells exhibited abnormally long bursts of firing caused by the downregulation of calcium-activated potassium SK channels. Our study supports a mechanism in which loss of SK activity causes the reticular thalamic neurons to become hyperexcitable and promote non-convulsive seizures in DS. We propose that reduced excitability of inhibitory neurons is not global in DS and that non-GABAergic mechanisms such as SK channels may be important targets for treatment.

Greater widespread functional connectivity of the caudate in older adults who practice kripalu yoga and vipassana meditation than in controls.

There has been a growing interest in understanding how contemplative practices affect brain functional organization. However, most studies have restricted their exploration to predefined networks. Furthermore, scientific comparisons of different contemplative traditions are largely lacking. Here we explored differences in whole brain resting state functional connectivity between experienced yoga practitioners, experienced meditators, and matched controls. Analyses were repeated in an independent sample of experienced meditators and matched controls. Analyses utilizing Network-Based Statistics (Zalesky et al., 2010) revealed difference components for yoga practitioners > controls and meditators > controls in which the right caudate was a central node. Follow up analyses revealed that yoga practitioners and meditators had significantly greater degree centrality in the caudate than controls. This greater degree centrality was not driven by single connections but by greater connectivity between the caudate and numerous brain regions. Findings of greater caudate connectivity in meditators than in controls was replicated in an independent dataset. These findings suggest that yoga and meditation practitioners have stronger functional connectivity within basal ganglia cortico-thalamic feedback loops than non-practitioners. Although we could not provide evidence for its mechanistic role, this greater connectivity might be related to the often reported effects of meditation and yoga on behavioral flexibility, mental health, and well-being.

Neurophysiologic predictors of response to atomoxetine in young adults with attention deficit hyperactivity disorder: a pilot project.

Atomoxetine is a non-stimulant medication with sustained benefit throughout the day, and is a useful pharmacologic treatment option for young adults with Attention-Deficit/Hyperactivity Disorder (ADHD). It is difficult to determine, however, those patients for whom atomoxetine will be both effective and advantageous. Patients may need to take the medication for several weeks before therapeutic benefit is apparent, so a biomarker that could predict atomoxetine effectiveness early in the course of treatment could be clinically useful. There has been increased interest in the study of thalamocortical oscillatory activity using quantitative electroencephalography (qEEG) as a biomarker in ADHD. In this study, we investigated qEEG absolute power, relative power, and cordance, which have been shown to predict response to reuptake inhibitor antidepressants in Major Depressive Disorder (MDD), as potential predictors of response to atomoxetine. Forty-four young adults with ADHD (ages 18-30) enrolled in a multi-site, double-blind placebo-controlled study of the effectiveness of atomoxetine and underwent serial qEEG recordings at pretreatment baseline and one week after the start of medication. qEEG measures were calculated from a subset of the sample (N = 29) that provided useable qEEG recordings. Left temporoparietal cordance in the theta frequency band after one week of treatment was associated with ADHD symptom improvement and quality of life measured at 12 weeks in atomoxetine-treated subjects, but not in those treated with placebo. Neither absolute nor relative power measures selectively predicted improvement in medication-treated subjects. Measuring theta cordance after one week of treatment could be useful in predicting atomoxetine treatment response in adult ADHD.

Study of cerebello-thalamocortical pathway by transcranial magnetic stimulation in Parkinson's disease.

BACKGROUND: Although functional changes in the activation of the cerebellum in Parkinson's disease (PD) patients have been consistently described, it is still debated whether such altered cerebellar activation is a natural consequence of PD pathophysiology or rather it involves compensatory mechanisms. OBJECTIVE/HYPOTHESIS: We used different forms of cerebellar transcranial magnetic stimulation to evaluate the hypothesis that altered cerebello-cortical interactions can be observed in PD patients and to evaluate the role of dopaminergic treatment. METHODS: We studied the effects of a single cerebellar magnetic pulse over the excitability of the contralateral primary motor cortex tested with motor-evoked potentials (MEPs) (cerebellar-brain inhibition-CBI) in a group of 16 PD patients with (ON) and without dopaminergic treatment (OFF), and in 16 age-matched healthy controls. Moreover, we also tested the effects of cerebellar continuous theta-burst stimulation (cTBS) on MEP amplitude, short intracortical inhibition (SICI) and short intracortical facilitation (SICF) tested in the contralateral M1 in 13 PD patients in ON and OFF and in 16 age-matched healthy controls. RESULTS: CBI was evident in controls but not in PD patients, even when tested in both ON and OFF conditions. Similarly, cerebellar cTBS reduced MEP amplitude and SICI in controls but not in PD patients under any condition. CONCLUSION(S): These results demonstrate that PD patients have deficient short-latency and long-lasting cerebellar-thalamocortical inhibitory interactions that cannot be promptly restored by standard dopaminergic medication.