Impaired consciousness is linked to changes in effective connectivity of the posterior cingulate cortex within the default mode network.

The intrinsic connectivity of the default mode network has been associated with the level of consciousness in patients with severe brain injury. Especially medial parietal regions are considered to be highly involved in impaired consciousness. To better understand what aspect of this intrinsic architecture is linked to consciousness, we applied spectral dynamic causal modeling to assess effective connectivity within the default mode network in patients with disorders of consciousness. We included 12 controls, 12 patients in minimally conscious state and 13 in vegetative state in this study. For each subject, we first defined the four key regions of the default mode network employing a subject-specific independent component analysis approach. The resulting regions were then included as nodes in a spectral dynamic causal modeling analysis in order to assess how the causal interactions across these regions as well as the characteristics of neuronal fluctuations change with the level of consciousness. The resulting pattern of interaction in controls identified the posterior cingulate cortex as the main driven hub with positive afferent but negative efferent connections. In patients, this pattern appears to be disrupted. Moreover, the vegetative state patients exhibit significantly reduced self-inhibition and increased oscillations in the posterior cingulate cortex compared to minimally conscious state and controls. Finally, the degree of self-inhibition and strength of oscillation in this region is correlated with the level of consciousness. These findings indicate that the equilibrium between excitatory connectivity towards posterior cingulate cortex and its feedback projections is a key aspect of the relationship between alterations in consciousness after severe brain injury and the intrinsic functional architecture of the default mode network. This impairment might be principally due to the disruption of the mechanisms underlying self-inhibition and neuronal oscillations in the posterior cingulate cortex.

Functional evaluation of central cholinergic circuits in patients with Parkinson's disease and REM sleep behavior disorder: a TMS study.

Central cholinergic dysfunction has been reported in patients with Parkinson's disease (PD) and hallucinations by evaluating short latency afferent inhibition (SAI), a transcranial magnetic stimulation protocol which gives the possibility to test an inhibitory cholinergic circuit in the human brain. REM sleep behavior disorder (RBD) was also found to be associated with cognitive impairment in PD patients. The objective of the study was to assess the cholinergic function, as measured by SAI, in PD patients with RBD (PD-RBD) and PD patients without RBD (PD-nRBD). We applied the SAI technique in 10 PD-RBD patients, in 13 PD-nRBD patients and in 15 age-matched normal controls. All PD patients and control subjects also underwent a comprehensive battery of neuropsychological tests. Mean SAI was significantly reduced in PD-RBD patients when compared with PD-nRBD patients and controls. Neuropsychological examination showed mild cognitive impairment in 9 out of the 10 PD-RBD patients, and in 5 out of the 13 PD-nRBD. SAI values correlated positively with neuropsychological tests measuring episodic verbal memory, executive functions, visuoconstructional and visuoperceptual abilities. Similar to that previously reported in the idiopathic form of RBD, SAI abnormalities suggest a cholinergic dysfunction in PD patients who develop cognitive impairment, and present findings indicate that RBD is an important determinant of MCI in PD.

Locked-in syndrome revisited.

The locked-in syndrome (LiS) is characterized by quadriplegia with preserved vertical eye and eyelid movements and retained cognitive abilities. Subcategorization, aetiologies and the anatomical foundation of LiS are discussed. The damage of different structures in the pons, mesencephalon and thalamus are attributed to symptoms of classical, complete and incomplete LiS and the locked-in plus syndrome, which is characterized by additional impairments of consciousness, making the clinical distinction to other chronic disorders of consciousness at times difficult. Other differential diagnoses are cognitive motor dissociation (CMD) and akinetic mutism. Treatment options are reviewed and an early, interdisciplinary and aggressive approach, including the provision of psychological support and coping strategies is favoured. The establishment of communication is a main goal of rehabilitation. Finally, the quality of life of LiS patients and ethical implications are considered. While patients with LiS report a high quality of life and well-being, medical professionals and caregivers have largely pessimistic perceptions. The negative view on life with LiS must be overthought and the autonomy and dignity of LiS patients prioritized. Knowledge has to be disseminated, diagnostics accelerated and technical support system development promoted. More well-designed research but also more awareness of the needs of LiS patients and their perception as individual persons is needed to enable a life with LiS that is worth living.

The vascular locked-in and locked-in-plus syndrome: A retrospective case series.

The locked-in syndrome (LiS) is defined as the loss of most voluntary muscle movements with preserved cognitive abilities due to a ventral pontine lesion. However, some patients may also have severe impairment of consciousness [locked-in plus syndrome (LiPS)]. Here we aimed to explore structural differences between LiS and LiPS patients of vascular aetiology, focusing on lesion patterns and locations to better delineate the clinical spectrum of LiS and LiPS. In this retrospective case series study, we report nine patients (two women), ages 29-74 years (median 50) with LiS and LiPS who were diagnosed between 2007 and 2021. Clinical parameters, MRI findings including the lesioned structures, and a shape feature calculation are presented for every patient. The lesioned structures were determined by a senior neuroradiologist. Two of nine patients had fully retained consciousness (LiS) and seven showed various degrees of impaired consciousness (LiPS). Lesions of LiS patients are round and confined to the pons, whereas lesions of LiPS patients are more elongated and reach neighbouring areas such as the mesencephalon, thalamus or ascending reticular activating system. Lesions involving the mesencephalon and the thalamus are strong indicators of LiPS, whereas for lesions restricted to the pons, the dorsal extension and the associated damage to the ascending reticular activating system are crucial to differentiate LiS from LiPS. Recognizing LiPS using clinical and radiological findings is important as these patients may need different therapies and care and, most importantly, should not be mistaken as unresponsive wakefulness syndrome.

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.

Narrative Review: Quantitative EEG in Disorders of Consciousness.

In this narrative review, we focus on the role of quantitative EEG technology in the diagnosis and prognosis of patients with unresponsive wakefulness syndrome and minimally conscious state. This paper is divided into two main parts, i.e., diagnosis and prognosis, each consisting of three subsections, namely, (i) resting-state EEG, including spectral power, functional connectivity, dynamic functional connectivity, graph theory, microstates and nonlinear measurements, (ii) sleep patterns, including rapid eye movement (REM) sleep, slow-wave sleep and sleep spindles and (iii) evoked potentials, including the P300, mismatch negativity, the N100, the N400 late positive component and others. Finally, we summarize our findings and conclude that QEEG is a useful tool when it comes to defining the diagnosis and prognosis of DOC patients.

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.

Altered motor cortex excitability to magnetic stimulation in alcohol withdrawal syndrome.

BACKGROUND: Alcohol addiction is a complex brain disease caused by alterations in crucial neurotransmitter systems, including gamma-aminobutyric acid (GABA) and glutamate. These disturbances could be revealed by changes in cortical excitability parameters, as assessed by transcranial magnetic stimulation (TMS). This study was aimed to further investigate the complex pathophysiology of alcohol withdrawal syndrome (AWS). METHODS: Motor cortex excitability was examined in 13 subjects with AWS in a mild predelirial state, in 12 chronic alcoholics and in 15 age-matched control subjects, using a range of TMS protocols. Central motor conduction time, resting and active motor threshold, duration of the cortical silent period, short latency intracortical inhibition (SICI), and intracortical facilitation (ICF) to paired TMS were examined. RESULTS: Intracortical facilitation was significantly increased in the AWS patients when compared with the chronic alcoholics and the control subjects. The other TMS parameters did not differ significantly from the controls. Administration of a single oral dose of the glutamatergic antagonist riluzole in a subgroup of 8 patients significantly reduced ICF; motor threshold and SICI were not affected by riluzole. CONCLUSION: Transcranial magnetic stimulation shows a selective increase in intracortical facilitation after ethanol withdrawal. Our findings support the theory that altered glutamatergic receptor function plays an important role in the pathogenesis of human alcohol withdrawal. This study provides further physiological evidence that antiglutamatergic approaches represent an efficacious alternative for treating alcohol withdrawal symptoms.

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.

Magnetic resonance imaging and motor-evoked potentials in spinal cord infarction: report of two cases.

Because in the early phases of spinal cord ischemia magnetic resonance imaging (MRI) can be normal, its clinical diagnosis is often difficult. We aimed to explore if motor-evoked potentials (MEPs) recordings may contribute to earlier diagnosis of spinal cord stroke. The clinical, MRI, and MEP findings in one case each of cervical and lumbar spinal cord infarction were reported. Spinal MRI at admission was unremarkable in both patients. At this time, MEPs were abnormal in both patients, to the upper and lower limbs in the first patient, exclusively to the lower limbs in the second. Follow-up MRI examinations documented an infarction in the territory of the anterior spinal artery and of the Adamkiewicz artery, respectively. MEP study can be useful in demonstrating spinal cord involvement also when radiological evidence for spinal cord damage is absent or equivocal. Early diagnosis may allow earlier intervention and contribute to improved patient management.

A dual-route perspective on poor reading in a regular orthography: evidence from phonological and orthographic lexical decisions.

Impairments of the lexical and the nonlexical reading route were examined for German-speaking dyslexic readers by measuring accuracy and speed of phonological and orthographic lexical decisions. Different from English-based findings, we found little difficulty with the phonological distinction between pseudohomophones and nonwords, but a major difficulty with the orthographic distinction between words and pseudohomophones. Subtyping identified pure surface dyslexia cases but no case of pure phonological dyslexia. Dyslexic speed impairments were traced to three loci in the dual-route model: an impoverished orthographic lexicon, and slow access from orthographic to phonological lexicon entries (lexical route) and from graphemes to phonemes (nonlexical route). A review of distal cognitive deficits suggested that the orthographic lexicon is affected by phonological deficits and that the slow functioning of the lexical and the nonlexical route reflects a general visual-verbal speed impairment and not a purely visual-attentional deficit.

Motor cortex excitability changes following a lesion in the posterior columns of the cervical spinal cord.

We used transcranial magnetic stimulation (TMS) to explore if an impairment of central sensory function produced by an isolated lesion in the cervical posterior white columns would change motor cortex excitability. Cortical silent period duration was prolonged when compared with the control subjects, while central motor conduction and motor thresholds were in the normal limits. We first demonstrate that the involvement of the ascending proprioceptive sensory pathways in spinal cord diseases may have direct consequences on the activity of intracortical inhibitory interneuronal circuits. These findings further elucidate the role of afferent inputs in motor cortex reorganisation.

Combining SPECT and Quantitative EEG Analysis for the Automated Differential Diagnosis of Disorders with Amnestic Symptoms.

Single photon emission computed tomography (SPECT) and Electroencephalography (EEG) have become established tools in routine diagnostics of dementia. We aimed to increase the diagnostic power by combining quantitative markers from SPECT and EEG for differential diagnosis of disorders with amnestic symptoms. We hypothesize that the combination of SPECT with measures of interaction (connectivity) in the EEG yields higher diagnostic accuracy than the single modalities. We examined 39 patients with Alzheimer's dementia (AD), 69 patients with depressive cognitive impairment (DCI), 71 patients with amnestic mild cognitive impairment (aMCI), and 41 patients with amnestic subjective cognitive complaints (aSCC). We calculated 14 measures of interaction from a standard clinical EEG-recording and derived graph-theoretic network measures. From regional brain perfusion measured by 99mTc-hexamethyl-propylene-aminoxime (HMPAO)-SPECT in 46 regions, we calculated relative cerebral perfusion in these patients. Patient groups were classified pairwise with a linear support vector machine. Classification was conducted separately for each biomarker, and then again for each EEG- biomarker combined with SPECT. Combination of SPECT with EEG-biomarkers outperformed single use of SPECT or EEG when classifying aSCC vs. AD (90%), aMCI vs. AD (70%), and AD vs. DCI (100%), while a selection of EEG measures performed best when classifying aSCC vs. aMCI (82%) and aMCI vs. DCI (90%). Only the contrast between aSCC and DCI did not result in above-chance classification accuracy (60%). In general, accuracies were higher when measures of interaction (i.e., connectivity measures) were applied directly than when graph-theoretical measures were derived. We suggest that quantitative analysis of EEG and machine-learning techniques can support differentiating AD, aMCI, aSCC, and DCC, especially when being combined with imaging methods such as SPECT. Quantitative analysis of EEG connectivity could become an integral part for early differential diagnosis of cognitive impairment.

Abnormal short-latency synaptic plasticity in the motor cortex of subjects with Becker muscular dystrophy: a rTMS study.

We used repetitive transcranial magnetic stimulation (rTMS) to further investigate motor cortex excitability in 13 patients with Becker muscular dystrophy (BMD), six of them with slight mental retardation. RTMS delivered at 5Hz frequency and suprathreshold intensity progressively increases the size of motor evoked potentials (MEPs) in healthy subjects; the rTMS-induced facilitation of MEPs was significantly reduced in the BMD patients mentally retarded or classified as borderline when compared with age-matched control subjects and the BMD patients with normal intelligence. The increase in the duration of the cortical silent period was similar in both patient groups and controls. These findings suggest an altered cortical short-term synaptic plasticity in glutamate-dependent excitatory circuits within the motor cortex in BMD patients with intellectual disabilities. RTMS studies may shed new light on the physiological mechanisms of cortical involvement in dystrophinopathies.

Cortical afferent inhibition reflects cognitive impairment in obstructive sleep apnea syndrome: a TMS study.

OBJECTIVES: Patients with obstructive sleep apnea syndrome (OSAS) show neurocognitive impairment, but the exact mechanisms that cause cognitive dysfunctions remain unknown. The cholinergic system is known to play a key role in all attentional processes and cognitive functions. A transcranial magnetic stimulation (TMS) protocol may give direct information about the function of some cholinergic circuits in the human brain; this technique relies on short latency afferent inhibition (SAI) of the motor cortex. The objective of this exploratory study was to test the hypothesis that impaired cognitive performances in OSAS patients are associated with a dysfunction of the cholinergic system, as assessed by SAI. METHODS: We applied SAI technique in a group of 13 patients with OSAS and compared the data with those from a group of 13 age-matched healthy subjects. All the patients underwent a sleep study, an extensive neuropsychological evaluation, and TMS examination. RESULTS: Mean SAI was significantly reduced in our OSAS patients when compared with controls. The neuropsychological evaluation showed impairments in most cognitive areas in the OSAS patients. SAI values were strongly correlated with the neuropsychological test scores. CONCLUSIONS: These findings suggest that the cognitive deficits in OSAS may be, at least in part, secondary to alterations in cholinergic neurotransmission, presumably caused by nocturnal hypoxemia. TMS studies may shed light on the pathophysiological mechanisms of the cognitive disturbances in OSAS patients.

When does the brain register deviances from standard word spellings?--An ERP study.

Event-related potentials (ERPs) in response to the standard form of words (e.g., taxi) were compared with ERPs in response to letter-altered (e.g., taksi) or case-altered forms (e.g., taXi). The altered forms always resulted in the same reading as the standard forms. First divergences between ERPs were found at around 160 ms. At occipital sites, the peak amplitude of the N160 was higher for standard than letter-altered strings. At frontal and central sites, the standard strings diverged from the altered strings persistently by higher positivity from about 160 ms onwards. These early ERP differences between standard and altered visual word forms speak for early contact between the letter input and stored visual-orthographic representations of words.

Inhibitory effects of first syllable-frequency in lexical decision: an event-related potential study.

Electrophysiological correlates of the behaviorally well-documented inhibitory effect of first syllable-frequency during lexical access are presented. In a lexical decision task, response times to words with high-frequency first syllables were longer than those to words with low-frequency first syllables and resulted in more negative event-related potentials (ERPs) in an early time window from 190 ms to 280 ms and in the N400 component. The onset of the observed first syllable-frequency effect was prior to the onset of the effect of lexicality (i.e., the first reliable differentiation in ERP waveforms in response to words and pseudowords, a potential marker of lexical access). The present study's results support Barber et al.'s [Neuroreport 15 (2004) 545] notion of the prelexical nature of the first syllable-frequency effect by (A) providing evidence for electrophysiological correlates of first syllable-frequency in another, non-Romance orthography (i.e., German), (B) relating the onset of the first syllable-frequency effect to the onset of the lexicality effect and (C) strengthening this pattern of results by means of a novel item-based analysis of ERP data. Implications of the prelexical nature of the inhibitory first syllable-frequency effect for computational models of reading, specifically for Ans et al.'s [Psychol. Rev. 105 (1998) 678] multiple-trace memory (MTM) model of reading are discussed.

Neural repetition suppression: evidence for perceptual expectation in object-selective regions.

It is an established finding that neuronal activity is decreased for repeated stimuli. Recent studies revealed that repetition suppression (RS) effects are altered by manipulating the probability with which stimuli are repeated. RS for faces is more pronounced when the probability of repetition is high than when it is low. This response pattern is interpreted with reference to the predictive coding (PC) account, which assumes that RS is influenced by top-down expectations. Recent findings challenge the generality of PC accounts of RS by showing repetition probability does not modulate RS for other visual stimuli than faces. However, a number of findings on visual processing are in line with PC. Thus, the influence of repetition probability on RS effects during object processing requires careful reinvestigations. In the present fMRI study, object pictures were presented in a high (75%) or low (25%) repetition probability context. We found increased RS in the high-probability context compared to the low-probability context in the left lateral occipital complex (LOC). The dorsal-caudal and the ventral-anterior subdivisions of the LOC revealed similar neuronal responses. These results indicate that repetition probability effects can be found for other visual objects than faces and provide evidence in favor of the PC account.

Connectivity biomarkers can differentiate patients with different levels of consciousness.

OBJECTIVE: In the present study, we searched for resting-EEG biomarkers that distinguish different levels of consciousness on a single subject level with an accuracy that is significantly above chance. METHODS: We assessed 44 biomarkers extracted from the resting EEG with respect to their discriminative value between groups of minimally conscious (MCS, N=22) patients, vegetative state patients (VS, N=27), and - for a proof of concept - healthy participants (N=23). We applied classification with support vector machines. RESULTS: Partial coherence, directed transfer function, and generalized partial directed coherence yielded accuracies that were significantly above chance for the group distinction of MCS vs. VS (.88, .80, and .78, respectively), as well as healthy participants vs. MCS (.96, .87, and .93, respectively) and VS (.98, .84, and .96, respectively) patients. CONCLUSIONS: The concept of connectivity is crucial for determining the level of consciousness, supporting the view that assessing brain networks in the resting state is the golden way to examine brain functions such as consciousness. SIGNIFICANCE: The present results directly show that it is possible to distinguish patients with different levels of consciousness on the basis of resting-state EEG.

Altered network properties of the fronto-parietal network and the thalamus in impaired consciousness.

Recovery of consciousness has been associated with connectivity in the frontal cortex and parietal regions modulated by the thalamus. To examine this model and to relate alterations to deficits in cognitive functioning and conscious processing, we investigated topological network properties in patients with chronic disorders of consciousness recovered from coma. Resting state fMRI data of 34 patients with unresponsive wakefulness syndrome and 25 in minimally conscious state were compared to 28 healthy controls. We investigated global and local network characteristics. Additionally, behavioral measures were correlated with the local metrics of 28 regions within the fronto-parietal network and the thalamus. In chronic disorders of consciousness, modularity at the global level was reduced suggesting a disturbance in the optimal balance between segregation and integration. Moreover, network properties were altered in several regions which are associated with conscious processing (particularly, in medial parietal, and frontal regions, as well as in the thalamus). Between minimally conscious and unconscious patients the local efficiency of medial parietal regions differed. Alterations in the thalamus were particularly evident in non-conscious patients. Most of the regions affected in patients with impaired consciousness belong to the so-called 'rich club' of highly interconnected central nodes. Disturbances in their topological characteristics have severe impact on information integration and are reflected in deficits in cognitive functioning probably leading to a total breakdown of consciousness.