Intracortical inhibitory and excitatory circuits in subjects with minimal hepatic encephalopathy: a TMS study.

Minimal hepatic encephalopathy (MHE) is the earliest form of hepatic encephalopathy (HE) and affects up to 80 % of patients with liver cirrhosis. By definition, MHE is characterized by psychomotor slowing and subtle cognitive deficits,  but obvious clinical manifestations are lacking. Given its covert nature, MHE is often underdiagnosed. This study was aimed at detecting neurophysiological changes, as assessed by means of transcranial magnetic stimulation (TMS), involved in the early pathogenesis of the HE. We investigated motor cortex excitability in 15 patients with MHE and in 15 age-matched age-matched cirrhotic patients without MHE; the resting motor threshold, the short-interval intracortical inhibition (SICI) and the intracortical facilitation (ICF) were examined. Paired-pulse TMS revealed significant increased SICI and reduced ICF in the patients with MHE. These findings may reflect abnormalities in intrinsic brain activity and altered organization of functional connectivity networks. In particular, the results suggest a shift in the balance between intracortical inhibitory and excitatory mechanisms towards a net increase of inhibitory neurotransmission. Together with other neurophysiological (in particular EEG) and neuroimaging techniques, TMS may thus provide early markers of cerebral dysfunction in cirrhotic patients with MHE.

Repetitive transcranial magnetic stimulation transiently reduces punding in Parkinson's disease: a preliminary study.

Amongst the impulse-control disorders (ICDs) associated with dopamine-replacement therapy in patients with Parkinson's disease (PD) is a repetitive, complex, stereotyped behaviour called punding. Disruption of the reciprocal loops between the striatum and structures in the prefrontal cortex (PFC) following dopamine depletion may predispose patients with PD to these behavioural disorders. The purpose of the present study was to assess the effects of repetitive transcranial magnetic stimulation (rTMS) over the dorsolateral PFC (DLPFC) on punding in PD. We used low-frequency (LF) rTMS in four PD patients presenting with punding. Punding was transiently reversed by LF-rTMS over the DLPFC without enhancing motor impairment. The effect was more sustained after right DLPFC rTMS. Therefore, LF-rTMS produced a transient beneficial effect in PD patients with punding, similar to that reported in PD patients with levodopa-induced dyskinesias. rTMS might have therapeutic potential for the treatment of punding and perhaps other ICDs in PD.

Cognitive function and cholinergic transmission in patients with subcortical vascular dementia and microbleeds: a TMS study.

There has been little investigation on the association between cognitive impairment and the microbleeds (MBs) frequently seen in subcortical vascular dementia (SVaD). One possible mechanism of cognitive decline in individuals with SVaD could be disruption of cholinergic fibers by vascular lesions. Central cholinergic circuits in human brain can be tested non-invasively by means of a transcranial magnetic stimulation (TMS) protocol named short latency afferent inhibition (SAI) of motor cortex. In the present study, we used this test in SvaD patients with and without MBs. SAI was evaluated in 13 SVaD patients with MBs (MB-positive group) and the data were compared with those from a group of 15 SVaD patients without MBs (MB-negative group) and with those from 20 healthy subjects. Moreover, we studied covariation of individual SAI values with the Mini-Mental State Examination (MMSE) total score and subscores. SAI was significantly reduced in the MB-positive group when compared with the MB-negative group and the control subjects. Total MMSE score, "attention and calculation" and "orientation" subscores were significantly lower in the MB-positive group than in the MB-negative group; SAI showed a positive correlation with total MMSE score. Adjustment for age, gender, education, presence of lacunae, severe white matter hyperintensities or severe periventricular hyperintensities did not affect these findings. This study provides novel physiological evidence that MBs have an impact on central cholinergic function that is independent of the extent of associated white matter changes and ischaemic stroke. This finding shows that TMS have potential diagnostic and therapeutic implications. TMS studies may help in evaluating the causes of cognitive impairment in cerebrovascular diseases.

Cholinergic dysfunction and amnesia in patients with Wernicke-Korsakoff syndrome: a transcranial magnetic stimulation study.

The specific neurochemical substrate underlying the amnesia in patients with Wernicke-Korsakoff syndrome (WKS) is still poorly defined. Memory impairment has been linked to dysfunction of neurons in the cholinergic system. A transcranial magnetic stimulation (TMS) protocol, the short latency afferent inhibition (SAI), may give direct information about the function of some cholinergic pathways in the human motor cortex. In the present study, we measured SAI in eight alcoholics with WKS and compared the data with those from a group of age-matched healthy individuals; furthermore, we correlated the individual SAI values of the WKS patients with memory and other cognitive functions. Mean SAI was significantly reduced in WKS patients when compared with the controls. SAI was increased after administration of a single dose of donezepil in a subgroup of four patients. The low score obtained in the Rey Complex Figure delayed recall test, the Digit Span subtest of the Wechsler Adult Intelligence Scale-Revised (WAIS-R) and the Corsi's Block Span subtest of the WAIS-R documented a severe impairment in the anterograde memory and short-term memory. None of the correlations between SAI values and these neuropsychological tests reached significance. We provide physiological evidence of cholinergic involvement in WKS. However, this putative marker of central cholinergic activity did not significantly correlate with the memory deficit in our patients. These findings suggest that the cholinergic dysfunction does not account for the memory disorder and that damage to the cholinergic system is not sufficient to cause a persisting amnesic syndrome in WKS.

Functional involvement of the cerebral cortex following paramedian bithalamic infarction.

To investigate further the functional mechanisms underlying the so-called 'loss of psychic self-activation' following paramedian bithalamic lesions, we used transcranial magnetic stimulation (TMS) in a patient who presented with this clinical picture after paramedian bithalamic infarction due to arterial occlusion. The patient showed higher motor thresholds than the controls; the cortical silent period and intracortical inhibition to paired-pulse stimulation, two different forms of inhibition that are believed to reflect GABAergic mechanisms, were significantly increased; short latency afferent inhibition (SAI), a technique that may give direct information about the function of some cholinergic circuits in the human brain, was significantly reduced. This study first demonstrates that there are changes in the intracortical excitatory and inhibitory circuits in this neurobehavioral syndrome, that lead to cortical hypoexcitability. The modulation in GABAergic activity may result in excitability changes in those cholinergic cortical networks that are involved in SAI. TMS may provide important information on connections between the thalamus and cortex and may help in better understanding the role of the thalamo-cortical relationship in behavioural changes associated with thalamic stroke.

Effects of theta burst stimulation on referred phantom sensations in patients with spinal cord injury.

To further explore the mechanisms underlying cortical reorganization in patients with phantom sensations after deafferentation, a repetitive transcranial magnetic stimulation study was carried out in two patients with referred phantom sensations (RPS) after incomplete spinal cord injury at the thoracic level. We delivered continuous (inhibitory), intermittent (excitatory), and placebo theta burst stimulation to the contralateral primary motor cortex (M1), primary somatosensory cortex (S1), and secondary somatosensory cortex (S2). Perception of RPS was significantly and transiently disrupted by inhibitory theta burst stimulation applied over S1 and, to a lesser extent, S2. This study supports the hypothesis that RPS depend on remapping in the somatosensory cortex and provides further electrophysiological evidence in vivo that cortical reorganizational processes are critically modulated by GABAergic mechanisms. Enhancement of GABAergic activity may block cortical reorganization, leading to RPS in spinal cord injury patients.

Are Gibbs-Type Priors the Most Natural Generalization of the Dirichlet Process?

Discrete random probability measures and the exchangeable random partitions they induce are key tools for addressing a variety of estimation and prediction problems in Bayesian inference. Here we focus on the family of Gibbs-type priors, a recent elegant generalization of the Dirichlet and the Pitman-Yor process priors. These random probability measures share properties that are appealing both from a theoretical and an applied point of view: (i) they admit an intuitive predictive characterization justifying their use in terms of a precise assumption on the learning mechanism; (ii) they stand out in terms of mathematical tractability; (iii) they include several interesting special cases besides the Dirichlet and the Pitman-Yor processes. The goal of our paper is to provide a systematic and unified treatment of Gibbs-type priors and highlight their implications for Bayesian nonparametric inference. We deal with their distributional properties, the resulting estimators, frequentist asymptotic validation and the construction of time-dependent versions. Applications, mainly concerning mixture models and species sampling, serve to convey the main ideas. The intuition inherent to this class of priors and the neat results they lead to make one wonder whether it actually represents the most natural generalization of the Dirichlet process.

CAVEOLIN-1 expression in brain metastasis from lung cancer predicts worse outcome and radioresistance, irrespective of tumor histotype.

Brain metastases develop in one-third of patients with non-small-cell lung cancer and are associated with a dismal prognosis, irrespective of surgery or chemo-radiotherapy. Pathological markers for predicting outcomes after surgical resection and radiotherapy responsiveness are still lacking. Caveolin 1 has been associated with chemo- and radioresistance in various tumors, including non-small-cell lung cancer. Here, caveolin 1 expression was assessed in a series of 69 brain metastases from non-small-cell lung cancer and matched primary tumors to determine its role in predicting survival and radiotherapy responsiveness. Only caveolin 1 expression in brain metastasis was associated with poor prognosis and an increased risk of death (log rank test, p = 0.015). Moreover, in the younger patients (median age of <54 years), caveolin 1 expression neutralized the favorable effect of young age on survival compared with the older patients. Among the radiotherapy-treated patients, an increased risk of death was detected in the group with caveolin 1-positive brain metastasis (14 out of 22 patients, HR=6.839, 95% CI 1.849 to 25.301, Wald test p = 0.004). Overall, caveolin 1 expression in brain metastasis from non-small-cell lung cancer is independently predictive of worse outcome and radioresistance and could become an additional tool for personalized therapy in the critical subset of brain-metastatic non-small-cell lung cancer patients.

Transient beneficial effects of excitatory theta burst stimulation in a patient with phonological agraphia after left supramarginal gyrus infarction.

We report a patient showing isolated phonological agraphia after an ischemic stroke involving the left supramarginal gyrus (SMG). In this patient, we investigated the effects of focal repetitive transcranial magnetic stimulation (rTMS) given as theta burst stimulation (TBS) over the left SMG, corresponding to the Brodmann area (BA) 40. The patient and ten control subjects performed a dictational words and nonwords writing task before, and 5 and 30 min after they received excitatory intermittent TBS (iTBS) over the left BA 40, the right hemisphere homologous to BA 40, the Wernicke's area, or the primary visual cortex. ITBS over the left SMG lead to a brief facilitation of phonological non-words writing to dictation. This case study report illustrates that rTMS is able to influence, among other language functions, the phonological loading processes during the written language production in stroke patients.

Theta burst stimulation of dorsolateral prefrontal cortex modulates pathological language switching: A case report.

Although different lesion and neuroimaging studies had highlighted the importance of the dorsolateral prefrontal cortex (DLPFC) in language switching, the nature of this higher cortical disorder of communication and its neural correlates have not been clearly established. To further investigate the functional involvement of the DLPFC, we used transcranial magnetic stimulation (TMS) given as theta burst stimulation (TBS) in a bilingual patient showing pathologic language switching after an ischemic stroke involving the left frontal lobe. Inhibitory and excitatory TBS were applied to the left DLPFC, to the right DLPFC, or to an occipital cortical control site. A short-lasting interruption of the pathological language switching occurred after excitatory left DLPFC stimulation, while inhibitory left DLPFC TBS transiently increased the number of utterances produced in the unwanted second language. Effects were non-significant after right DLPFC and occipital TBS. Our findings suggest that left DLPFC is actively involved in language switching. TMS techniques may help in understanding the neural bases of bilingualism.