Usability and potential of geostatistics for spatial discrimination of multiple sclerosis lesion patterns.

BACKGROUND AND PURPOSE: In multiple sclerosis (MS) the individual disease courses are very heterogeneous among patients and biomarkers for setting the diagnosis and the estimation of the prognosis for individual patients would be very helpful. For this purpose, we are developing a multidisciplinary method and workflow for the quantitative, spatial, and spatiotemporal analysis and characterization of MS lesion patterns from MRI with geostatistics. METHODS: We worked on a small data set involving three synthetic and three real-world MS lesion patterns, covering a wide range of possible MS lesion configurations. After brain normalization, MS lesions were extracted and the resulting binary 3-dimensional models of MS lesion patterns were subject to geostatistical indicator variography in three orthogonal directions. RESULTS: By applying geostatistical indicator variography, we were able to describe the 3-dimensional spatial structure of MS lesion patterns in a standardized manner. Fitting a model function to the empirical variograms, spatial characteristics of the MS lesion patterns could be expressed and quantified by two parameters. An orthogonal plot of these parameters enabled a well-arranged comparison of the involved MS lesion patterns. CONCLUSIONS: This method in development is a promising candidate to complement standard image-based statistics by incorporating spatial quantification. The work flow is generic and not limited to analyzing MS lesion patterns. It can be completely automated for the screening of radiological archives.

Effect of transcranial brain stimulation for the treatment of Alzheimer disease: a review.

Available pharmacological treatments for Alzheimer disease (AD) have limited effectiveness, are expensive, and sometimes induce side effects. Therefore, alternative or complementary adjuvant therapeutic strategies have gained increasing attention. The development of novel noninvasive methods of brain stimulation has increased the interest in neuromodulatory techniques as potential therapeutic tool for cognitive rehabilitation in AD. In particular, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are noninvasive approaches that induce prolonged functional changes in the cerebral cortex. Several studies have begun to therapeutically use rTMS or tDCS to improve cognitive performances in patients with AD. However, most of them induced short-duration beneficial effects and were not adequately powered to establish evidence for therapeutic efficacy. Therefore, TMS and tDCS approaches, seeking to enhance cognitive function, have to be considered still very preliminary. In future studies, multiple rTMS or tDCS sessions might also interact, and metaplasticity effects could affect the outcome.

Brain activation disturbance for target detection in patients with mild cognitive impairment: an fMRI study.

Functional brain imaging in mild cognitive impairment (MCI) reveals differences in activation of task-relevant brain areas between patients and age-matched healthy controls. However, some studies reported hyperactivation and others hypoactivation in MCI compared with controls. The inconsistencies may be explained by compensatory mechanisms due to high complexity of the applied tasks. The oddball task is a simple paradigm that is known to activate a widespread network in the brain, involving attentional and monitoring mechanisms. In the present study, we examined amnestic or amnestic multidomain MCI patients (n = 12) and healthy controls (n = 13) in an auditory oddball task. Participants had to respond to infrequent targets and inhibit response to infrequent novel-nontarget stimuli. Lower stimulus related activation was found in MCI patients compared with healthy controls in parts of the middle temporal gyrus, the temporal pole, regions along the superior temporal sulcus, in the left cuneus, the left supramarginal gyrus, the anterior cingulated cortex and in the left inferior and middle frontal gyrus. Activation for oddball stimuli is assumed to reflect an automatic reflexive engagement of many brain regions in response to potentially important changes in the environment as well as cognitive control to monitor responses. The mechanisms of attention and cognitive control may be severely impaired in MCI and thus, underlie the cognitive deficits of this clinical group.

Short latency afferent inhibition differs among the subtypes of mild cognitive impairment.

Mild cognitive impairment (MCI) is considered a transitional stage between normal aging and a diagnosis of clinically probable Alzheimer disease (AD). The role of the cholinergic system in MCI is not clearly defined and needs to be further investigated. 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. We aimed to evaluate in the present study the relationship of SAI to the specific clinical subtypes of MCI. SAI was examined in 20 patients with amnestic MCI (10 SD, 10 MD), twenty patients with nonamnestic MCI (10 SD, 10 MD) and ten control subjects. Motor threshold, central motor conduction time, intracortical inhibition and facilitation to paired-TMS were also evaluated. Mean SAI was significantly reduced in amnestic MCI-MD patients when compared with the controls, while it was not significantly different in amnestic MCI-SD patients and in nonamnestic patients. SAI was increased after administration of a single dose of donepezil in a subgroup of four amnestic MCI-MD patients. The other TMS parameters did not differ significantly between the four MCI groups and the control group. We demonstrated that this putative marker of central cholinergic activity differs among MCI subtypes. The amnestic-MD type of MCI might be a phenotype of incipient AD. However, this hypothesis would be better addressed in a longitudinal study of individual patients. TMS studies may be useful in identifying MCI individuals in whom cholinergic degeneration is occurred and therefore at increased risk of conversion to AD.

Deactivation of the default mode network as a marker of impaired consciousness: an fMRI study.

Diagnosis of patients with a disorder of consciousness is very challenging. Previous studies investigating resting state networks demonstrate that 2 main features of the so-called default mode network (DMN), metabolism and functional connectivity, are impaired in patients with a disorder of consciousness. However, task-induced deactivation--a third main feature of the DMN--has not been explored in a group of patients. Deactivation of the DMN is supposed to reflect interruptions of introspective processes. Seventeen patients with unresponsive wakefulness syndrome (UWS, former vegetative state), 8 patients in minimally conscious state (MCS), and 25 healthy controls were investigated with functional magnetic resonance imaging during a passive sentence listening task. Results show that deactivation in medial regions is reduced in MCS and absent in UWS patients compared to healthy controls. Moreover, behavioral scores assessing the level of consciousness correlate with deactivation in patients. On single-subject level, all control subjects but only 2 patients in MCS and 6 with UWS exposed deactivation. Interestingly, all patients who deactivated during speech processing (except for one) showed activation in left frontal regions which are associated with conscious processing. Our results indicate that deactivation of the DMN can be associated with the level of consciousness by selecting those who are able to interrupt ongoing introspective processes. In consequence, deactivation of the DMN may function as a marker of consciousness.

Menstrual cycle variations in the BOLD-response to a number bisection task: implications for research on sex differences.

Numerical processing involves either number magnitude processing, which has been related to spatial abilities and relies on superior parietal regions, or arithmetic fact retrieval, which has been related to verbal abilities and involves the inferior parietal lobule. Since men score better in spatial and women in verbal tasks, we assume that women have advantages in fact retrieval, while men have benefits in number magnitude processing. According to findings on menstrual cycle variations in spatial and verbal abilities, fact retrieval should improve during the luteal phase and magnitude processing during the follicular phase. To dissociate sex- and menstrual cycle-dependent effects on fact retrieval and number magnitude processing, we applied a number bisection task in 15 men and 15 naturally cycling women. Multiplicative items (e.g. 12_15_18) are part of a multiplication series and can be solved by fact retrieval, while non-multiplicative items (e.g. 11_14_17) are not part of a multiplication series and require number magnitude processing. In men and women in their luteal phase, error rates were higher and deactivation of the medial prefrontal cortex and the bilateral inferior parietal lobules was stronger for non-multiplicative compared to multiplicative items (positive multiplicativity effect), while in the follicular phase women showed higher error rates and stronger deactivation in multiplicative compared to non-multiplicative items (negative multiplicativity effect). Thus, number magnitude processing improves, while arithmetic fact retrieval impairs during the follicular phase. While a female superiority in arithmetic fact retrieval could not be confirmed, we observed that sex differences are significantly modulated by menstrual cycle phase.

Posterior circulation ischemia in patients with fetal-type circle of Willis and hypoplastic vertebrobasilar system.

Little attention has been given to the fetal-type posterior circle of Willis (FTP) in the literature; also symptomatic basilar artery (BA) hypoplasia has been rarely reported. We aimed to illustrate that the association of a hypoplastic vertebrobasilar system (VBS) with the FTP may lead to posterior circulation ischemia. Magnetic resonance imaging and three-dimensional time-of-flight magnetic resonance angiography were performed in 88 consecutive patients with ischemic stroke or TIA in the VBS. Thirteen patients were identified with either stroke or TIA in the context of a hypoplastic VBS and a fetal origin of the posterior cerebral arteries. All patients had unilateral or bilateral FTP, hypoplastic BA and at least one hypoplastic vertebral artery. Transcranial color-coded duplex revealed decreased flow velocity and increased pulsatility index along the BA. A hypoplastic VBS may be accompanied by the FTP and its simultaneous occurrence can predispose to ischemic events in the posterior circulation.

Telemedicine in acute stroke care: the TESSA model.

We conducted a retrospective controlled study to assess the safety and effectiveness of intravenous thrombolysis via videoconferencing, followed by patient transport to a specialized stroke unit. Between 2006 and 2009, 47 stroke patients were treated in peripheral hospitals in the county of Salzburg in Austria by intravenous thrombolysis via telemedicine; 304 patients who were treated with intravenous thrombolysis at a stroke unit served as the control group. The mean age of the patients was 67 years in the telemedicine group and 71 years in the control group. Haemorrhagic bleeding occurred in 6.4% of the telemedicine group compared to 7.6% of the control group. The mean onset-to-needle time was 113 min in the telemedicine group and 122 min in the control group (P = 0.263). At three-month follow-up, 47% of the patients in the telemedicine group had good functional outcomes (mRS, dichotomized analysis 0-1) versus 43% in the control group (P = 0.694). The overall mortality at three-month follow-up was 19% in the telemedicine group and 13% in the control group (P = 0.248). Telemedicine can be used to support regional areas with little experience in delivering intravenous thrombolysis, thus raising the standard of stroke care and minimizing inequalities.

A review of transcranial magnetic stimulation in the in vivo functional evaluation of central cholinergic circuits in dementia.

Central cholinergic circuits of human brain can be tested non-invasively by coupling electrical peripheral stimulation with transcranial magnetic stimulation (TMS) of the motor cortex. The short-latency afferent inhibition (SAI) is reduced in cholinergic forms of dementia, such as Alzheimer disease (AD) and dementia with Lewy bodies, while it is normal in non-cholinergic forms of dementia, such as frontotemporal dementia. This finding suggests that this method can be used as a non-invasive additional tool for discriminating between cholinergic and non-cholinergic forms of dementia. Interestingly, SAI was also found to be significantly smaller in early AD patients. Identification of SAI abnormalities that occur early in the course of AD will allow earlier diagnosis and treatment with cholinergic drugs. In patients with vascular dementia, SAI responses varied widely; the number of patients with abnormal SAI conceivably reflects the percentage of subjects with a significant cholinergic dysfunction. It has recently been demonstrated that brain microbleeds have an impact on SAI that is independent of the extent of associated white matter changes and ischemic stroke. Since SAI can be increased by acetylcholinesterase inhibitors, TMS may help in identifying the patients who would be suitable for long-term treatment with cholinergic agents.

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.

Inter-individual variability of oscillatory responses to subject's own name. A single-subject analysis.

In previous studies event-related potentials and oscillations in response to subject's own name have been analyzed extensively on group-level in healthy subjects and in patients with a disorder of consciousness. Subject's own name as a deviant produces a P3. With equiprobable stimuli, non-phase-locked alpha oscillations are smaller in response to subject's own name compared to other names or subject's own name backwards. However, little is known about replicability on a single-subject level. Seventeen healthy subjects were assessed in an own-name paradigm with equiprobable stimuli of subject's own name, another name, and subject's own name backwards. Event-related potentials and non-phase locked oscillations were analyzed with single-subject, non-parametric statistics. No consistent results were found either for ERPs or for the non-phase locked changes of oscillatory activities. Only 4 subjects showed a robust effect as expected, that is, a lower activity in the alpha-beta range to subject's own name compared to other conditions. Four subjects elicited a higher activity for subject's own name. Thus, analyzing the EEG reactivity in the own-name paradigm with equiprobable stimuli on a single-subject level yields a high variance between subjects. In future research, single-subject statistics should be applied for examining the validity of physiologic measurements in other paradigms and for examining the pattern of reactivity in patients.

Preserved oscillatory response but lack of mismatch negativity in patients with disorders of consciousness.

OBJECTIVE: The diagnostic validity of non-phase-locked oscillations (NPLOs) and mismatch negativity (MMN) in an oddball task for assessing attentional reactivity in patients with disordered consciousness was examined. METHODS: Patients in a minimally conscious (MCS, n = 6) or vegetative (VS, n = 16) state and healthy controls (n = 15) were assessed. MMN and NPLOs were analyzed with single-subject, non-parametric statistics. RESULTS: In 11 healthy controls and 2 VS patients, MMN was detected. More subjects showed NPLO differences in the alpha than in the theta or beta frequency ranges. In 14 healthy controls, 4 MCS patients, and 5 VS patients, lower amplitudes after deviants were found in the alpha frequency range. One healthy subject and one VS patient showed higher amplitudes after deviants. CONCLUSIONS: Neither ERPs nor NPLOs could reliably distinguish MCS from VS patients. However, NPLOs were more sensitive than ERPs for detecting significantly different activity, and they possibly identified preserved processing better than ERPs. SIGNIFICANCE: Intact neurophysiological attentional responses observed in the NPLOs of VS patients may indicate a need for other diagnostic techniques. Inter-individual differences in the direction of the effect should be considered as normal variance.

EEG frequency analysis of responses to the own-name stimulus.

OBJECTIVE: The neuronal response to hearing a subject's own (SON) compared with other names has been examined in healthy subjects as well as in patients with disorders of consciousness. So far, on electroencephalographic data, only event-related potentials (ERPs) were considered. In this study, we examined the frequency properties of SON. METHODS: Data of 17 healthy subjects were processed for equiprobable stimuli of SON, other- and own-name backwards by calculating ERPs, evoked and induced activity for a period of 2000 ms from stimulus onset in the delta, theta, lower and upper alpha bands and averaging for four consequent temporal segments of 500 ms each. RESULTS: For SON, the N1 component's amplitude was larger, while induced activity in the alpha band decreased in the second temporal segment (of 500-1000 ms). No differences between other- and own-name backwards were found. CONCLUSIONS: The late reactivity may indicate responses to a stimulus after having recognised it. Alpha is known to play a role in attention and alertness. The results may reflect the fact that the SON stimulus enhances alertness. SIGNIFICANCE: The findings correlate previous work about alertness and alpha activity with those about attention capturing of the SON stimulus. We suggest using frequency analysis in research on disorders of consciousness.

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.

Spontaneous subdural spinal haematoma presenting as occipital headache: a case report.

Spinal subdural hematoma (SSDH) with no underlying pathology is a very rare condition and has been rarely reported. Our patient presented with severe occipital headache as isolated symptom during the first 4 days. SSDH slowly enlarges with time, and first determines tension of the pain-sensitive dural membrane, resulting in cervicogenic-like headache. Therefore, spontaneous SSDH should be considered in the differential diagnosis of recent occipital headache.

Modafinil reverses hypoexcitability of the motor cortex in narcoleptic patients: a TMS study.

OBJECTIVE: Although many animal and human studies have been performed, the exact mechanisms of action whereby modafinil promotes wakefulness are still not completely understood. We aimed to investigate the functional effects of modafinil on motor cortex excitability in patients with narcolepsy by means of transcranial magnetic stimulation (TMS) techniques. METHODS: In a double-blind and placebo-controlled design, 24 drug-naive narcoleptic patients with cataplexy and 20 control subjects were administered modafinil or placebo over a period of 4 weeks. TMS was performed twice during the awake state before and at the end of treatment; measures of cortical excitability included central motor conduction time, resting motor threshold, short latency intracortical inhibition (SICI) and intracortical facilitation to paired-TMS. TMS measures were correlated with the conventional neurophysiological method of Multiple Sleep Latency Test (MSLT) and the subjective Epworth Sleepiness Scale (ESS). RESULTS: As previously reported, motor threshold and SICI were significantly increased in patients with narcolepsy; modafinil reversed this cortical hypoexcitability, but only SICI differences reached statistical significance. The Spearman rank correlation analysis revealed the highest correlation between SICI and the MSLT; a positive correlation was also found between SICI and the ESS, as well as between RMT and both measures of daytime sleepiness. CONCLUSIONS: This represents the first report investigating effects of modafinil on cortical excitability in human narcolepsy. Since SICI is thought to be directly related to GABA(A) intracortical inhibitory activity, we demonstrated that the dose of modafinil that induces a satisfactory wakefulness-promoting response in narcoleptic patients also causes decrease in GABAergic transmission.

Subdural hematoma in a patient with spontaneous intracranial hypotension and cerebral venous thrombosis.

We report a patient with clinical and neuroimaging findings of spontaneous intracranial hypotension (SIH) who developed cerebral venous thrombosis (CVT). An association between SIH and CVT has rarely been observed. Anticoagulation therapy was administered. The clinical course was subsequently complicated by a large subdural hematoma that required neurosurgical evacuation. The present report indicates that SIH should not be always considered a benign condition, especially when associated with CVT and subdural fluid collections. Furthermore, clinicians should be aware of the potential risks of anticoagulant therapy in patients with SIH and CVT.

A common left occipito-temporal dysfunction in developmental dyslexia and acquired letter-by-letter reading?

BACKGROUND: We used fMRI to examine functional brain abnormalities of German-speaking dyslexics who suffer from slow effortful reading but not from a reading accuracy problem. Similar to acquired cases of letter-by-letter reading, the developmental cases exhibited an abnormal strong effect of length (i.e., number of letters) on response time for words and pseudowords. RESULTS: Corresponding to lesions of left occipito-temporal (OT) regions in acquired cases, we found a dysfunction of this region in our developmental cases who failed to exhibit responsiveness of left OT regions to the length of words and pseudowords. This abnormality in the left OT cortex was accompanied by absent responsiveness to increased sublexical reading demands in phonological inferior frontal gyrus (IFG) regions. Interestingly, there was no abnormality in the left superior temporal cortex which--corresponding to the onological deficit explanation--is considered to be the prime locus of the reading difficulties of developmental dyslexia cases. CONCLUSIONS: The present functional imaging results suggest that developmental dyslexia similar to acquired letter-by-letter reading is due to a primary dysfunction of left OT regions.

A dual-route perspective on poor reading in a regular orthography: an fMRI study.

This study examined functional brain abnormalities in dyslexic German readers who - due to the regularity of German in the reading direction - do not exhibit the reading accuracy problem of English dyslexic readers, but suffer primarily from a reading speed problem. The in-scanner task required phonological lexical decisions (i.e., Does xxx sound like an existing word?) and presented familiar and unfamiliar letter strings of existing phonological words (e.g., Taxi-Taksi) together with nonwords (e.g., Tazi). Dyslexic readers exhibited the same response latency pattern (words