Maneesh C. Patel

White Matter Damage and Cognitive Impairment after Traumatic Brain Injury.

White matter disruption is an important determinant of cognitive impairment after brain injury, but conventional neuroimaging underestimates its extent. In contrast, diffusion tensor imaging provides a validated and sensitive way of identifying the impact of axonal injury. The relationship between cognitive impairment after traumatic brain injury and white matter damage is likely to be complex. We applied a flexible technique—tract-based spatial statistics—to explore whether damage to specific white matter tracts is associated with particular patterns of cognitive impairment. The commonly affected domains of memory, executive function and information processing speed were investigated in 28 patients in the post-acute/chronic phase following traumatic brain injury and in 26 age-matched controls. Analysis of fractional anisotropy and diffusivity maps revealed widespread differences in white matter integrity between the groups. Patients showed large areas of reduced fractional anisotropy, as well as increased mean and axial diffusivities, compared with controls, despite the small amounts of cortical and white matter damage visible on standard imaging. A stratified analysis based on the presence or absence of microbleeds (a marker of diffuse axonal injury) revealed diffusion tensor imaging to be more sensitive than gradient-echo imaging to white matter damage. The location of white matter abnormality predicted cognitive function to some extent. The structure of the fornices was correlated with associative learning and memory across both patient and control groups, whilst the structure of frontal lobe connections showed relationships with executive function that differed in the two groups. These results highlight the complexity of the relationships between white matter structure and cognition. Although widespread and, sometimes, chronic abnormalities of white matter are identifiable following traumatic brain injury, the impact of these changes on cognitive function is likely to depend on damage to key pathways that link nodes in the distributed brain networks supporting high-level cognitive functions.

Distinct frontal systems for response inhibition, attentional capture, and error processing

Stopping an action in response to an unexpected event requires both that the event is attended to, and that the action is inhibited. Previous neuroimaging investigations of stopping have failed to adequately separate these cognitive elements. Here we used a version of the widely used Stop Signal Task that controls for the attentional capture of stop signals. This allowed us to fractionate the contributions of frontal regions, including the right inferior frontal gyrus and medial frontal cortex, to attentional capture, response inhibition, and error processing. A ventral attentional system, including the right inferior frontal gyrus, has been shown to respond to unexpected stimuli. In line with this evidence, we reasoned that lateral frontal regions support attentional capture, whereas medial frontal regions, including the presupplementary motor area (pre-SMA), actually inhibit the ongoing action. We tested this hypothesis by contrasting the brain networks associated with the presentation of unexpected stimuli against those associated with outright stopping. Functional MRI images were obtained in 26 healthy volunteers. Successful stopping was associated with activation of the right inferior frontal gyrus, as well as the pre-SMA. However, only activation of the pre-SMA differentiated stopping from a high-level baseline that controlled for attentional capture. As expected, unsuccessful attempts at stopping activated the anterior cingulate cortex. In keeping with work in nonhuman primates these findings demonstrate that successful motor inhibition is specifically associated with pre-SMA activation.

Perceptual Systems Controlling Speech Production

It is proposed that the acquisition and maintenance of fluent speech depend on the rapid temporal integration of motor feedforward and polysensory (auditory and somatosensory) feedback signals. In a functional magnetic resonance imaging study on 21 healthy right-handed, English-speaking volunteers, we investigated activity within these motor and sensory pathways and their integration during speech. Four motor conditions were studied: two speech conditions (propositional and nonpropositional speech) and two silent conditions requiring repetitive movement of the principal articulators (jaw and tongue movements). The scanning technique was adapted to minimize artifact associated with overt speech production. Our result indicates that this multimodal convergence occurs within the left and right supratemporal planes (STPs), with peaks of activity at their posteromedial extents, in regions classically considered as unimodal auditory association cortex. This cortical specialization contrasted sharply with the response of somatosensory association cortex (SII), in which activity was suppressed during speech but not during the silent repetitive movement of the principal articulators. It was also clearly distinct from the response of lateral auditory association cortex, which responded to auditory feedback alone, and from that within a left lateralized ventrolateral temporal and inferior frontal system, which served lexical- and sentence-level language retrieval. This response of cortical regions related to speech production is not predicted by the classical model of hierarchical cortical processing, providing new insights into the role of the STP in polysensory integration and into the modulation of activity in SII during normal speech production. These findings have novel implications for the acquisition and maintenance of fluent speech.

Pituitary dysfunction after blast traumatic brain injury: The UK BIOSAP study.

Pituitary dysfunction is a recognized consequence of traumatic brain injury (TBI) that causes cognitive, psychological, and metabolic impairment. Hormone replacement offers a therapeutic opportunity. Blast TBI (bTBI) from improvised explosive devices is commonly seen in soldiers returning from recent conflicts. We investigated: (1) the prevalence and consequences of pituitary dysfunction following moderate to severe bTBI and (2) whether it is associated with particular patterns of brain injury.

Assessment of trace metal intake and status in a Gujerati pregnant Asian population and their influence on the outcome of pregnancy

Summary. Dietary assessments and biochemical indices including plasma zinc and copper were determined in pregnant vegetarian and non‐vegetarian Gujerati women in India at 28 weeks gestation, and the results were contrasted with those of a comparable group of Gujerati pregnant women living in Harrow. Even though the dietary intake of energy, protein and zinc was significantly lower in the Indian vegetarian Gujerati group when compared to the equivalent group in Harrow, the birthweights of the babies delivered at term were similar. The intake of zinc in the diet of the Gujerati Indian vegetarian and non‐vegetarian groups was only one quarter of the US recommended intake during pregnancy and was approximately one half in the Harrow Indian groups. Even so, the plasma concentrations of zinc were similar in all dietary groups in either India or Harrow. The albumin content in the plasma of both the Gujerati Indian vegetarian and non‐vegetarian was significantly reduced when compared to the equivalent Harrow dietary groups. The plasma concentrations of both calcium and sodium were significantly correlated with the albumin concentration but not with the plasma content of zinc. Copper levels were elevated to the normal range in both dietary groups of the Gujerati and were similar to the concentrations found in the Harrow groups.

Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson’s disease

Parkinson’s disease (PD) is associated with increased iron levels in the substantia nigra (SNc). This study evaluated whether the iron chelator, deferiprone, is well tolerated, able to chelate iron from various brain regions and improve PD symptomology. In a randomised double-blind, placebo controlled trial, 22 early onset PD patients, were administered deferiprone, 10 or 15 mg/kg BID or placebo, for 6 months. Patients were evaluated for PD severity, cognitive function, depression rating and quality of life. Iron concentrations were assessed in the substantia nigra (SNc), dentate and caudate nucleus, red nucleus, putamen and globus pallidus by T2* MRI at baseline and after 3 and 6 months of treatment. Deferiprone therapy was well tolerated and was associated with a reduced dentate and caudate nucleus iron content compared to placebo. Reductions in iron content of the SNc occurred in only 3 patients, with no changes being detected in the putamen or globus pallidus. Although 30 mg/kg deferiprone treated patients showed a trend for improvement in motor-UPDRS scores and quality of life, this did not reach significance. Cognitive function and mood were not adversely affected by deferiprone therapy. Such data supports more extensive clinical trials into the potential benefits of iron chelation in PD.

Auditory cortical function during verbal episodic memory encoding in Alzheimer's disease.

Episodic memory encoding of a verbal message depends upon initial registration, which requires sustained auditory attention followed by deep semantic processing of the message. Motivated by previous data demonstrating modulation of auditory cortical activity during sustained attention to auditory stimuli, we investigated the response of the human auditory cortex during encoding of sentences to episodic memory. Subsequently, we investigated this response in patients with mild cognitive impairment (MCI) and probable Alzheimers disease (pAD).

Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration

Head injury survivors can develop neurodegeneration associated with persistent neuroinflammation, but whether the latter is harmful or beneficial is unclear. Scott et al. report that minocycline reduces neuroinflammation months and years after injury but increases a blood marker of neurodegeneration, suggesting that persistent neuroinflammation has reparative effects long after injury.

Hypertrophic pachymeningitis with sarcoidosis: a rare cause of craniocervical compression

We describe a case of a 58-year-old woman with a suspected dural tumour. She presented with progressive pyramidal weakness. MRI confirmed compression of the medulla oblongata and spinal cord at the level of C1–3. The localised dural mass lesion homogenously enhanced on T1 MRI and was considered most likely to be a meningioma. Incidentally, CT scan of the chest revealed peribronchial soft tissue thickening, suggestive of pulmonary sarcoidosis. Owing to the progressive nature of her weakness, she had a posterior occipitocervical decompression with a C1–3 laminectomy and resection of the thickened dura. Histology showed densely collagenous tissue with scanty psammoma bodies and multinucleate giant cells, consistent with hypertrophic pachymeningitis (HP)—a rare, chronic inflammatory condition, characterised by thickening and fibrosis of the dura. This case demonstrates that masses in the craniocervical junction can be varied in pathology and when there is evidence of systemic inflammation, HP should be considered.

Extracranial-intracranial bypass of the bilateral anterior cerebral circulation using a thoracodorsal axis artery-graft

Bilateral extracranial-intracranial (EC-IC) bypass-grafting of the cerebral circulation is uncommon. We report a case of anterior cerebral artery EC-IC bypass using the thoracodorsal axis artery-graft. The bifurcation of the thoracodorsal axis allows bypass of both anterior hemispheres, while matching appropriate small-vessel dimensions.