Matthew D. Smyth

Electrophysiological correlates of the brain's intrinsic large-scale functional architecture

Spontaneous fluctuations in the blood-oxygen-level-dependent (BOLD) signals demonstrate consistent temporal correlations within large-scale brain networks associated with different functions. The neurophysiological correlates of this phenomenon remain elusive. Here, we show in humans that the slow cortical potentials recorded by electrocorticography demonstrate a correlation structure similar to that of spontaneous BOLD fluctuations across wakefulness, slow-wave sleep, and rapid-eye-movement sleep. Gamma frequency power also showed a similar correlation structure but only during wakefulness and rapid-eye-movement sleep. Our results provide an important bridge between the large-scale brain networks readily revealed by spontaneous BOLD signals and their underlying neurophysiology.

Two-dimensional movement control using electrocorticographic signals in humans

We show here that a brain-computer interface (BCI) using electrocorticographic activity (ECoG) and imagined or overt motor tasks enables humans to control a computer cursor in two dimensions. Over a brief training period of 12-36 min, each of five human subjects acquired substantial control of particular ECoG features recorded from several locations over the same hemisphere, and achieved average success rates of 53-73% in a two-dimensional four-target center-out task in which chance accuracy was 25%. Our results support the expectation that ECoG-based BCIs can combine high performance with technical and clinical practicality, and also indicate promising directions for further research.

Loss of Resting Interhemispheric Functional Connectivity after Complete Section of the Corpus Callosum

Slow (<0.1 Hz), spontaneous fluctuations in the functional magnetic resonance imaging blood oxygen level-dependent (BOLD) signal have been shown to exhibit phase coherence within functionally related areas of the brain. Surprisingly, this phenomenon appears to transcend levels of consciousness. The genesis of coherent BOLD fluctuations remains to be fully explained. We present a resting state functional connectivity study of a 6-year-old child with a radiologically normal brain imaged both before and after complete section of the corpus callosum for the treatment of intractable epilepsy. Postoperatively, there was a striking loss of interhemispheric BOLD correlations with preserved intrahemispheric correlations. These unique data provide important insights into the relationship between connectional anatomy and functional organization of the human brain. Such observations have the potential to increase our understanding of large-scale brain systems in health and disease as well as improve the treatment of neurologic disorders.

Preoperative Sensorimotor Mapping in Brain Tumor Patients Using Spontaneous Fluctuations in Neuronal Activity Imaged With Functional Magnetic Resonance Imaging: Initial Experience

OBJECTIVE To describe initial experience with resting-state correlation mapping as a potential aid for presurgical planning of brain tumor resection. METHODS Resting-state blood oxygenation-dependent functional magnetic resonance imaging (fMRI) scans were acquired in 17 healthy young adults and 4 patients with brain tumors invading sensorimotor cortex. Conventional fMRI motor mapping (finger-tapping protocol) was also performed in the patients. Intraoperatively, motor hand area was mapped using cortical stimulation. RESULTS Robust and consistent delineation of sensorimotor cortex was obtained using the resting-state blood oxygenation-dependent data. Resting-state functional mapping localized sensorimotor areas consistent with cortical stimulation mapping and in all patients performed as well as or better than task-based fMRI. CONCLUSION Resting-state correlation mapping is a promising tool for reliable functional localization of eloquent cortex. This method compares well with “gold standard” cortical stimulation mapping and offers several advantages compared with conventional motor mapping fMRI.

Resting-state activity in development and maintenance of normal brain function

One of the most intriguing recent discoveries concerning brain function is that intrinsic neuronal activity manifests as spontaneous fluctuations of the blood oxygen level–dependent (BOLD) functional MRI signal. These BOLD fluctuations exhibit temporal synchrony within widely distributed brain regions known as resting-state networks. Resting-state networks are present in the waking state, during sleep, and under general anesthesia, suggesting that spontaneous neuronal activity plays a fundamental role in brain function. Despite its ubiquitous presence, the physiological role of correlated, spontaneous neuronal activity remains poorly understood. One hypothesis is that this activity is critical for the development of synaptic connections and maintenance of synaptic homeostasis. We had a unique opportunity to test this hypothesis in a 5-y-old boy with severe epileptic encephalopathy. The child developed marked neurologic dysfunction in association with a seizure disorder, resulting in a 1-y period of behavioral regression and progressive loss of developmental milestones. His EEG showed a markedly abnormal pattern of high-amplitude, disorganized slow activity with frequent generalized and multifocal epileptiform discharges. Resting-state functional connectivity MRI showed reduced BOLD fluctuations and a pervasive lack of normal connectivity. The child underwent successful corpus callosotomy surgery for treatment of drop seizures. Postoperatively, the patients behavior returned to baseline, and he resumed development of new skills. The waking EEG revealed a normal background, and functional connectivity MRI demonstrated restoration of functional connectivity architecture. These results provide evidence that intrinsic, coherent neuronal signaling may be essential to the development and maintenance of the brains functional organization.

Focal Cooling Suppresses Spontaneous Epileptiform Activity without Changing the Cortical Motor Threshold

Summary:  Purpose: Focal cerebral cooling has been shown to reduce epileptiform activity in animals. There are, however, few reports of this phenomenon in humans.

Isolated sagittal and coronal craniosynostosis associated with TWIST box mutations

Craniosynostosis, the premature fusion of one or more cranial sutures, affects 1 in 2,500 live births. Isolated single‐suture fusion is most prevalent, with sagittal synostosis occurring in 1/5,000 live births. The etiology of isolated (nonsyndromic) single‐suture craniosynostosis is largely unknown. In syndromic craniosynostosis, there is a highly nonrandom pattern of causative autosomal dominant mutations involving TWIST1 and fibroblast growth factor receptors (FGFRs). Prior to our study, there were no published TWIST1 mutations in the anti‐osteogenic C‐terminus, recently coined the TWIST Box, which binds and inhibits RUNX2 transactivation. RUNX2 is the principal master switch for osteogenesis. We performed mutational analysis on 164 infants with isolated, single‐suture craniosynostosis for mutations in TWIST1, the IgIIIa exon of FGFR1, the IgIIIa and IgIIIc exons of FGFR2, and the Pro250Arg site of FGFR3. We identified two patients with novel TWIST Box mutations: one with isolated sagittal synostosis and one with isolated coronal synostosis. Kress et al. [ 2006 ] reported a TWIST Box “nondisease‐causing polymorphism” in a patient with isolated sagittal synostosis. However, compelling evidence suggests that their and our sequence alterations are pathogenic: (1) a mouse with a mutation of the same residue as our sagittal synostosis patient developed sagittal synostosis, (2) mutation of the same residue precluded TWIST1 interaction with RUNX2, (3) each mutation involved nonconservative amino acid substitutions in highly conserved residues across species, and (4) control chromosomes lacked TWIST Box sequence alterations. We suggest that genetic testing of patients with isolated sagittal or coronal synostosis should include TWIST1 mutational analysis.

The surgical treatment of spasticity

Many neurosurgical procedures have been designed for or applied to the treatment of spasticity arising from different disorders, including cerebral palsy; traumatic, ischemic, or hypoxic brain injury, multiple sclerosis, and spinal cord injury. Neurosurgical procedures are primarily aimed at reducing spasticity by interrupting the stretch reflex at various sites along the spinal reflex arc or attempting to increase the centrally mediated inhibitory influence on the pool of motor neurons in the anterior horn. Surgical interventions for spasticity can be classified into peripheral ablative procedures, such as rhizotomy or peripheral neurectomy, and central ablative procedures, such as cordectomy, myelotomy, or stereotactic procedures. Non‐ablative procedures include peripheral nerve or motor point blocks, the implantation of cerebellar or spinal stimulators, and the implantation of subdural catheters for infusion of pharmacologic agents to increase inhibitory activity. Several proposed mechanisms for spasticity are reviewed so that the rationale for the various surgical interventions for spasticity described may be better understood.

Copy number variation analysis in single-suture craniosynostosis: Multiple rare variants including RUNX2 duplication in two cousins with metopic craniosynostosis†

Little is known about genes that underlie isolated single‐suture craniosynostosis. In this study, we hypothesize that rare copy number variants (CNV) in patients with isolated single‐suture craniosynostosis contain genes important for cranial development. Using whole genome array comparative genomic hybridization (CGH), we evaluated DNA from 186 individuals with single‐suture craniosynostosis for submicroscopic deletions and duplications. We identified a 1.1 Mb duplication encompassing RUNX2 in two affected cousins with metopic synostosis and hypodontia. Given that RUNX2 is required as a master switch for osteoblast differentiation and interacts with TWIST1, mutations in which also cause craniosynostosis, we conclude that the duplication in this family is pathogenic, albeit with reduced penetrance. In addition, we find that a total of 7.5% of individuals with single‐suture synostosis in our series have at least one rare deletion or duplication that contains genes and that has not been previously reported in unaffected individuals. The genes within and disrupted by CNVs in this cohort are potential novel candidate genes for craniosynostosis.

Unique Cortical Physiology Associated With Ipsilateral Hand Movements and Neuroprosthetic Implications

Background and Purpose— Brain computer interfaces (BCIs) offer little direct benefit to patients with hemispheric stroke because current platforms rely on signals derived from the contralateral motor cortex (the same region injured by the stroke). For BCIs to assist hemiparetic patients, the implant must use unaffected cortex ipsilateral to the affected limb. This requires the identification of distinct electrophysiological features from the motor cortex associated with ipsilateral hand movements. Methods— In this study we studied 6 patients undergoing temporary placement of intracranial electrode arrays. Electrocorticographic (ECoG) signals were recorded while the subjects engaged in specific ipsilateral or contralateral hand motor tasks. Spectral changes were identified with regards to frequency, location, and timing. Results— Ipsilateral hand movements were associated with electrophysiological changes that occur in lower frequency spectra, at distinct anatomic locations, and earlier than changes associated with contralateral hand movements. In a subset of 3 patients, features specific to ipsilateral and contralateral hand movements were used to control a cursor on a screen in real time. In ipsilateral derived control this was optimal with lower frequency spectra. Conclusions— There are distinctive cortical electrophysiological features associated with ipsilateral movements which can be used for device control. These findings have implications for patients with hemispheric stroke because they offer a potential methodology for which a single hemisphere can be used to enhance the function of a stroke induced hemiparesis.