Unexpected median SEPs fluctuations during brain cavernous malformation resection with no post-operative deficit.

Median nerve somatosensory evoked potentials (SEPs) may present changes during cavernous malformation (CM) resection unrelated to new post-operative sensory deficits. We performed intraoperative neurophysiological monitoring of median SEPs (m-SEPs) in three patients who underwent CM resection (surgery) near the sensory-motor cortex. The only preoperative clinical manifestations in all patients were seizures. All patients presented m-SEPs alterations on the side of the lesion during the procedure. Two patients presented permanent changes in the cortical potentials. In the third patient, the cortical and subcortical components suffered temporal fluctuations to return to baselines at the end of the surgery. None of these patients developed new post-operative clinical deficits. During brain cavernous malformation resection, significant fluctuations in the amplitude of different components of m-SEPs may occur. These changes may be due to excitability variations on m-SEP generators and do not translate into new post-operative neurological deficits.

Distinct effects of the basal ganglia and cerebellum on the thalamocortical pathway in idiopathic generalized epilepsy.

The aberrant thalamocortical pathways of epilepsy have been detected recently, while its underlying effects on epilepsy are still not well understood. Exploring pathoglytic changes in two important thalamocortical pathways, that is, the basal ganglia (BG)-thalamocortical and the cerebellum-thalamocortical pathways, in people with idiopathic generalized epilepsy (IGE), could deepen our understanding on the pathological mechanism of this disease. These two pathways were reconstructed and investigated in this study by combining diffusion and functional MRI. Both pathways showed connectivity changes with the perception and cognition systems in patients. Consistent functional connectivity (FC) changes were observed mainly in perception regions, revealing the aberrant integration of sensorimotor and visual information in IGE. The pathway-specific FC alterations in high-order regions give neuroimaging evidence of the neural mechanisms of cognitive impairment and epileptic activities in IGE. Abnormal functional and structural integration of cerebellum, basal ganglia and thalamus could result in an imbalance of inhibition and excitability in brain systems of IGE. This study located the regulated cortical regions of BG and cerebellum which been affected in IGE, established possible links between the neuroimaging findings and epileptic symptoms, and enriched the understanding of the regulatory effects of BG and cerebellum on epilepsy.

Thalamocortical neural responses during hyperthermia: a resting-state functional MRI study.

The neural responses during hyperthermia, once thought of as simple physiological processes (e.g. thermal sensation and regulation), have now been recognised involving more cognitive processes, which would be of high importance to the management of those occupations during heavy heat exposure. Previous studies have demonstrated altered activity in localised subcortical clusters for thermal sensation and regulation, as well as cortical-cortical activity for behavioural tasks during hyperthermia. However, the involvement of cortical-subcortical activity during hyperthermia has not been investigated. In this study, we performed exploratory analyses comparing thalamocortical functional connectivity during whole body hyperthermic condition for an hour at 50 °C and normothermic condition at 25 °C. We found weakened functional connectivity of cortical fronto-polar/anterior cingulate cortex and prefrontal areas with the corresponding thalamic nuclei during hyperthermic versus normothermic comparisons. On the contrary, the motor/premotor, somatosensory and temporal cortical subdivisions showed increased connectivity with thalamic nuclei during hyperthermia. Thalamocortical connectivity changes in the prefrontal were identified to be correlated with the behavioural reaction time during psychomotor vigilance test after controlling for physiological variables. These distinct thalamocortical pathway alterations might reflect physiologically thermal sensation and regulation, as well as psychologically neural behaviour changes underlying cortical-subcortical activity during hyperthermia.

Parallel inputs from the mediodorsal thalamus to the prefrontal cortex in the rat.

There is a growing interest in determining the functional contribution of thalamic inputs to cortical functions. In the context of adaptive behaviours, identifying the precise role of the mediodorsal thalamus (MD) in particular remains difficult despite the large amount of experimental data available. A better understanding of the thalamocortical connectivity of this region may help to capture its functional role. To address this issue, this study focused exclusively on the specific connections from the MD to the prefrontal cortex (PFC) by means of direct comparisons of labelling produced by single and dual injections of retrograde tracers in the different subdivisions of the PFC in the rat. We show that at least three parallel and essentially separate thalamocortical pathways originate from the MD, as follows: projections to the dorsal (1) and the ventral (2) subdivisions of the mPFC follow a mediolateral topography at the thalamic level (i.e. medial thalamic neurons target the mPFC ventrally whereas lateral thalamic neurons project dorsally), whereas a considerable innervation to the OFC (3) includes thalamic cells projecting to both the lateral and the ventral OFC subdivisions. These observations provide new insight on the functions of the MD and suggest a specific focus on each of these pathways for future functional studies.

A Novel Gliotransmitter, L-ß-Aminoisobutyric Acid, Contributes to Pathophysiology of Clinical Efficacies and Adverse Reactions of Clozapine.

Clozapine is listed as one of the most effective antipsychotics and has been approved for treating treatment-resistant schizophrenia (TRS); however, several type A and B adverse reactions, including weight gain, metabolic complications, cardiotoxicity, convulsions, and discontinuation syndromes, exist. The critical mechanisms of clinical efficacy for schizophrenia, TRS, and adverse reactions of clozapine have not been elucidated. Recently, the GABA isomer L-ß-aminoisobutyric acid (L-BAIBA), a protective myokine in the peripheral organs, was identified as a candidate novel transmission modulator in the central nervous system (CNS). L-BAIBA activates adenosine monophosphate-activated protein kinase (AMPK) signalling in both the peripheral organs and CNS. Activated AMPK signalling in peripheral organs is an established major target for treating insulin-resistant diabetes, whereas activated AMPK signalling in the hypothalamus contributes to the pathophysiology of weight gain and metabolic disturbances. Clozapine increases L-BAIBA synthesis in the hypothalamus. In addition, the various functions of L-BAIBA in the CNS have recently been elucidated, including as an activator of GABA-B and group-III metabotropic glutamate (III-mGlu) receptors. Considering the expressions of GABA-B and III-mGlu receptors (localised in the presynaptic regions), the activation of GABA-B and III-mGlu receptors can explain the distinct therapeutic advantages of clozapine in schizophrenia or TRS associated with N-methyl-D-aspartate (NMDA) receptor disturbance compared with other atypical antipsychotics via the inhibition of the persistent tonic hyperactivation of thalamocortical glutamatergic transmission in the prefrontal cortex. L-BAIBA has also been identified as a gliotransmitter, and a detailed exploration of the function of L-BAIBA in tripartite synaptic transmission can further elucidate the pathophysiology of effectiveness for treating TRS and/or specific adverse reactions of clozapine.

Altered functional connectivity in psychotic disorder not otherwise specified.

BACKGROUND: Few studies have investigated functional connectivity (FC) in patients with psychotic disorder not otherwise specified (PNOS). We sought to identify distinct FC differentiating PNOS from schizophrenia (SZ). METHODS: In total, 49 patients with PNOS, 42 with SZ, and 55 healthy controls (HC) matched for age, sex, and education underwent functional magnetic resonance imaging (fMRI) brain scans and clinical evaluation. Using six functional networks consisting of 40 regions of interest (ROIs), we conducted ROI to ROI and intra- and inter-network FC analyses using resting-state fMRI (rs-fMRI) data. Correlations of altered FC with symptomatology were explored. RESULTS: We found common brain connectomics in PNOS and SZ including thalamo-cortical (especially superior temporal gyrus) hyperconnectivity, thalamo-cerebellar hypoconnectivity, and reduced within-thalamic connectivity compared to HC. Additionally, features differentiating the two patient groups included hyperconnectivity between the thalamic subregion and anterior cingulate cortex in PNOS compared to SZ and hyperconnectivity of the thalamic subregions with the posterior cingulate cortex and precentral gyrus in SZ compared to PNOS. CONCLUSIONS: These findings suggest that PNOS and SZ exhibit both common and differentiating changes in neuronal connectivity. Furthermore, they may support the hypothesis that PNOS should be treated as a separate clinical syndrome with distinct neural connectomics.

Altered thalamic subregion functional networks in patients with treatment-resistant schizophrenia.

BACKGROUND: The thalamus plays a key role in filtering information and has extensive interconnectivity with other brain regions. A large body of evidence points to impaired functional connectivity (FC) of the thalamocortical pathway in schizophrenia. However, the functional network of the thalamic subregions has not been investigated in patients with treatment-resistant schizophrenia (TRS). AIM: To identify the neural mechanisms underlying TRS, we investigated FC of thalamic sub-regions with cortical networks and voxels, and the associations of this FC with clinical symptoms. We hypothesized that the FC of thalamic sub-regions with cortical networks and voxels would differ between TRS patients and HCs. METHODS: In total, 50 patients with TRS and 61 healthy controls (HCs) matched for age, sex, and education underwent resting-state functional magnetic resonance imaging (rs-fMRI) and clinical evaluation. Based on the rs-fMRI data, we conducted a FC analysis between thalamic subregions and cortical functional networks and voxels, and within thalamic subregions and cortical functional networks, in the patients with TRS. A functional parcellation atlas was used to segment the thalamus into nine subregions. Correlations between altered FC and TRS symptoms were explored. RESULTS: We found differences in FC within thalamic subregions and cortical functional networks between patients with TRS and HCs. In addition, increased FC was observed between thalamic subregions and the sensorimotor cortex, frontal medial cortex, and lingual gyrus. These abnormalities were associated with the pathophysiology of TRS. CONCLUSION: Our findings suggest that disrupted FC within thalamic subregions and cortical functional networks, and within the thalamocortical pathway, has potential as a marker for TRS. Our findings also improve our understanding of the relationship between the thalamocortical pathway and TRS symptoms.

Sensing and processing whisker deflections in rodents.

The classical view of sensory information mainly flowing into barrel cortex at layer IV, moving up for complex feature processing and lateral interactions in layers II and III, then down to layers V and VI for output and corticothalamic feedback is becoming increasingly undermined by new evidence. We review the neurophysiology of sensing and processing whisker deflections, emphasizing the general processing and organisational principles present along the entire sensory pathway-from the site of physical deflection at the whiskers to the encoding of deflections in the barrel cortex. Many of these principles support the classical view. However, we also highlight the growing number of exceptions to these general principles, which complexify the system and which investigators should be mindful of when interpreting their results. We identify gaps in the literature for experimentalists and theorists to investigate, not just to better understand whisker sensation but also to better understand sensory and cortical processing.

A cerebellar-thalamocortical pathway drives behavioral context-dependent movement initiation.

Executing learned motor behaviors often requires the transformation of sensory cues into patterns of motor commands that generate appropriately timed actions. The cerebellum and thalamus are two key areas involved in shaping cortical output and movement, but the contribution of a cerebellar-thalamocortical pathway to voluntary movement initiation remains poorly understood. Here, we investigated how an auditory "go cue" transforms thalamocortical activity patterns and how these changes relate to movement initiation. Population responses in dentate/interpositus-recipient regions of motor thalamus reflect a time-locked increase in activity immediately prior to movement initiation that is temporally uncoupled from the go cue, indicative of a fixed-latency feedforward motor timing signal. Blocking cerebellar or motor thalamic output suppresses movement initiation, while stimulation triggers movements in a behavioral context-dependent manner. Our findings show how cerebellar output, via the thalamus, shapes cortical activity patterns necessary for learned context-dependent movement initiation.

Clozapine Normalizes a Glutamatergic Transmission Abnormality Induced by an Impaired NMDA Receptor in the Thalamocortical Pathway via the Activation of a Group III Metabotropic Glutamate Receptor.

Pharmacological mechanisms of gold-standard antipsychotics against treatment-refractory schizophrenia, such as clozapine (CLZ), remain unclear. We aimed to explore the mechanisms of CLZ by investigating the effects of MK801 and CLZ on tripartite synaptic transmission in the thalamocortical glutamatergic pathway using multi-probe microdialysis and primary cultured astrocytes. l-glutamate release in the medial prefrontal cortex (mPFC) was unaffected by local MK801 administration into mPFC but was enhanced in the mediodorsal thalamic nucleus (MDTN) and reticular thalamic nucleus (RTN) via GABAergic disinhibition in the RTN-MDTN pathway. The local administration of therapeutically relevant concentrations of CLZ into mPFC and MDTN increased and did not affect mPFC l-glutamate release. The local administration of the therapeutically relevant concentration of CLZ into mPFC reduced MK801-induced mPFC l-glutamate release via presynaptic group III metabotropic glutamate receptor (III-mGluR) activation. However, toxic concentrations of CLZ activated l-glutamate release associated with hemichannels. This study demonstrated that RTN is a candidate generator region in which impaired N-methyl-d-aspartate (NMDA)/glutamate receptors likely produce thalamocortical hyperglutamatergic transmission. Additionally, we identified several mechanisms of CLZ relating to its superiority in treatment-resistant schizophrenia and its severe adverse effects: (1) the prevention of thalamocortical hyperglutamatergic transmission via activation of mPFC presynaptic III-mGluR and (2) activation of astroglial l-glutamate release associated with hemichannels. These actions may contribute to the unique clinical profile of CLZ.

Corrigendum: Reconsidering Tonotopic Maps in the Auditory Cortex and Lemniscal Auditory Thalamus in Mice.

[This corrects the article on p. 14 in vol. 11, PMID: 28293178.].

Reconsidering Tonotopic Maps in the Auditory Cortex and Lemniscal Auditory Thalamus in Mice.

The auditory thalamus and auditory cortex (AC) are pivotal structures in the central auditory system. However, the thalamocortical mechanisms of processing sounds are largely unknown. Investigation of this process benefits greatly from the use of mice because the mouse is a powerful animal model in which various experimental techniques, especially genetic tools, can be applied. However, the use of mice has been limited in auditory research, and thus even basic anatomical knowledge of the mouse central auditory system has not been sufficiently collected. Recently, optical imaging combined with morphological analyses has enabled the elucidation of detailed anatomical properties of the mouse auditory system. These techniques have uncovered fine AC maps with multiple frequency-organized regions, each of which receives point-to-point thalamocortical projections from different origins inside the lemniscal auditory thalamus, the ventral division of the medial geniculate body (MGv). This precise anatomy now provides a platform for physiological research. In this mini review article, we summarize these recent achievements that will facilitate physiological investigations in the mouse auditory system.

Myelination and isochronicity in neural networks.

Our brain contains a multiplicity of neuronal networks. In many of these, information sent from presynaptic neurons travels through a variety of pathways of different distances, yet arrives at the postsynaptic cells at the same time. Such isochronicity is achieved either by changes in the conduction velocity of axons or by lengthening the axonal path to compensate for fast conduction. To regulate the conduction velocity, a change in the extent of myelination has recently been proposed in thalamocortical and other pathways. This is in addition to a change in the axonal diameter, a previously identified, more accepted mechanism. Thus, myelination is not a simple means of insulation or acceleration of impulse conduction, but it is rather an exquisite way of actively regulating the timing of communication among various neuronal connections with different length.