Noninvasive Brain Stimulation in the Investigation and Treatment of Neglect

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Noninvasive Brain Stimulation in the
Investigation and Treatment of Neglect
Roy Hamilton, MD, MSLaboratory for Cognition and
Neural Stimulation University of Pennsylvania
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Topics

• Challenges in investigating and treating neglect
• Induction of neglect-like effects with brain
  stimulation
• Interhemispheric interactions in neglect
• Therapy with brain stimulation

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Clinical impact of neglect

• Failure to report, respond, or orient to
  meaningful or novel stimuli on the contralesional
  side of space.
• Up to 2/3 of right hemisphere stroke patients
  acutely.
• Poor prognostic indicator
• More limited mobility
• Longer hospitalizations
• Increased long-term functional disability
• Increased family burden

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Challenges of treating chronic neglect

• No established treatment
• Sensory stimulation techniques (e.g. caloric,
  vestibular, mechanical, or electrical
  stimulation, prisms) have drawbacks.
• Short duration of benefit
• Many techniques are uncomfortable

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Challenges of treating chronic neglect

• Some paradigms show specific behavioral
  improvements, but dont generalize to everyday
  settings.
• Effective approaches grounded in the neural basis
  of neglect are lacking.

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Challenges of investigating neglect

• Practical problems
• Varied phenomenology
• Distribution, means of eliciting, input/output
  demands
• Symptoms vary over time (Hamilton et al., 2008)
• Large lesions/imprecise localization
• Frequently short-lived symptoms

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Challenges of investigating neglect

• What would be helpful?
• Experimental models that accurately replicate
  symptoms
• Approaches with anatomic specificity
• Safe, effective, noninvasive interventions

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Noninvasive brain stimulation as a model of
neglect

• By inducing lateralized deficits of attention or
  action in healthy individuals, noninvasive brain
  stimulation can be used to further elucidate the
  neural mechanism of neglect.

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rTMS induces neglect symptoms in animals
Valero-Cabre et al., 2006
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tDCS induces neglect symptoms in animals
Schweid et al., 2008
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Right parietal TMS disrupts visuospatial
perception
Fierro et al., 2001

• 9 healthy subjects
• Forced-choice estimation of bisected
  line-segments
• Right parietal (P6) and frontal (F4) single-pulse
  TMS at 115 MT
• Rightward bias only with parietal TMS 150 ms
  after stimulus presentation

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TMS studies further implicate the right parietal
cortex

• Inhibition of left target detection
• Muggleton et al., 2006
• Inhibition of visual exploration
• Nyffeler et al., 2008
• Right temporoparietal junction TMS induces
  hemiextinction
• Meister et al., 2006

Muggleton et al., 2006
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TMS studies further implicate the right parietal
cortex

• Inhibition of left target detection
• Muggleton et al., 2006
• Inhibition of visual exploration
• Nyffeler et al., 2008
• Right temporoparietal junction TMS induces
  hemiextinction
• Meister et al., 2006

Nyffeler et al., 2008
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TMS studies further implicate the right parietal
cortex

• Inhibition of left target detection
• Muggleton et al., 2006
• Inhibition of visual exploration
• Nyffeler et al., 2008
• Right temporoparietal junction TMS induces
  hemiextinction
• Meister et al., 2006

Meister et al., 2006
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Subsets of neglect symptoms maybe dissociable
using TMS

• Input vs. Output Demands

Attentional
Intentional
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Substrates of neglect symptoms can be dissociated
using TMS
Ghacibeh et al., 2007
TMS
Apparatus

• F4 (middle frontal gyrus) P6 (interparietal
  sulcus)
• Brief trains (5-sec at 5 Hz) MT 15
• Simultaneous with stimulus presentation

Predictions

• Parietal TMS Attentional
• Screen Normal Skew right
• Screen Reversed Skew left
• Frontal TMS Intentional
• Screen Normal Skew right
• Screen Reversed Skew right

Adapted from Na et al., 2007
Stimuli
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Substrates of neglect symptoms can be dissociated
using TMS
Ghacibeh et al., 2007
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Interhemispheric inhibition and neglect

• Interhemispheric interactions likely play an
  important role in the phenomenology and treatment
  of neglect.

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Interhemispheric inhibition and neglect

• Transcallosal inhibitory connections may subserve
  rival networks between the two hemispheres, the
  dynamic balance of which permits normal
  redirection of attention.
• (Kinsbourne, 1977)

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Interhemispheric inhibition and neglect

• Two-lesion case studies
• Sprague (1966) Neglect from cortical lesion can
  be reversed by contralateral superior colliculus
  lesion.
• Vuilleumier et al. (1996) In humans with one
  lesion, a contralateral second lesion may
  attenuate neglect.

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Manipulation of interhemispheric imbalance
affects visuospatial attention

• Unilateral parietal single-pulse TMS impairs
  contralateral target detection.
• Biparietal TMS induced no change.
• Analogous to two-lesion studies.

Dambeck et al., 2006
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Therapeutic modulation of interhemispheric
connections
Fregni Pascual-Leone (2007)
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Contralesional TMS attenuates neglect

• 5 subjects with neglect (3 right brain injury 2
  left brain injury)
• Stimulation over right and left parietal cortex
• 10 pulses of TMS at 25 Hz, synchronous with
  stimuli

Oliveri et al., 2001
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Extended rTMS may lead to sustained improvement
Brighina et al., 2003

• 3 patients right brain injury with neglect
• rTMS to left parietal cortex
• 900 Pulses
• 1 Hz (inhibitory)
• Every other day x 2 weeks
• Improvement persisted 15 days after completing
  TMS

Pre-rTMS
Post-rTMS
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Extended rTMS may lead to sustained improvement
Song et al., 2009

• 14 Patients 7 treatment, 7 control
• 0.5 Hz, 90 MT, 15 min, twice daily x 2 weeks
• Left P3 stimulated
• Testing 2 weeks prior, start of treatment, end of
  treatment, and two weeks later
• No control site, task, or sham

Line Cancellation
Line Bisection
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Extended rTMS may lead to sustained improvement
Subject 1
Subject 2

• Two chronic neglect patients
• Six rTMS sessions over two weeks
• 900 pulses to P5 per session
• 0.9 Hz, 95 MT
• Behavioral Inattention Test (BIT) administered at
  baseline, 2, 4, and 6 weeks.

Shindo et al., 2006
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Reduction of parietal hyperexcitability
correlates with behavioral benefit

• Twin-coil TMS test of PPC-M1 influences.
• 12 RH patients with neglect, 10 without, 8
  healthy controls
• MEP amplitude after conditioning pulse correlated
  with neglect severity.

Koch et al., 2008
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Reduction of parietal hyperexcitability
correlates with behavioral benefit

• MEP amplitude in neglect patients reduced after
  600 pulses of 1 Hz TMS (90 MT)
• Stimulation of right PPC also temporarily
  improved neglect symptoms of visual chimeric test
  (Sarri et al., 2006)

Koch et al., 2008
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Improved visual scanning after parietal tDCS
Ko et al., 2008

• 15 patients with subacute neglect
• Anodal stimulation 2.0 mA x 20 minutes sham
  controlled
• Right posterior parietal cortex stimulated

Shape-unstructured cancellation
Letter-structured cancellation
Line-Bisection
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Improved visual scanning after parietal tDCS
Fregni Pascual-Leone (2007)
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Improved visual scanning after parietal tDCS
Ko et al., 2008

• 15 patients with subacute neglect
• Anodal stimulation 2.0 mA x 20 minutes sham
  controlled
• Right posterior parietal cortex stimulated

Shape-unstructured cancellation
Letter-structured cancellation
Line-Bisection
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Future directions?

• Focal stimulation to achieve improvement of
  specific neglect symptoms
• Combining stimulation with therapy

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Summary

• Neglect, a condition affecting many patients with
  right hemisphere stroke, is associated with poor
  outcomes and is frequently resistant to
  currently-used treatments.
• Interhemispheric interactions may play a key role
  in both the emergence of neglect after stroke and
  the potential to treat it by manipulation of
  contralesional cortical activity.
• Administration of low-frequency rTMS to the left
  parietal cortex and anodal tDCS to the right
  parietal cortex have been associated with
  improvement in neglect symptoms.