Deep brain stimulation method

The present subject matter is directed to a method for treating a conscious. The method includes selecting a conscious patient having impaired cognitive function and applying electrical stimulation to at least a portion of the patient's intralaminar nuclei under conditions effective to relieve the patient's impaired cognitive function. A method for improving coordination of function across a patient's cortical regions is also described. The method includes applying electrical stimulation to two or more subdivisions of the patient's intralaminar nuclei. The two or more subdivisions of the patient's intralaminar nuclei modulate separate cortical regions. Using the methods of the present invention, patients suffering from impaired cognitive function can have at least a portion of the function restored, thus improving their quality of life and reducing societal costs.

FIELD OF THE INVENTION 
The present invention relates generally to deep brain electrical 
stimulation methods and, more particularly, methods for treating conscious 
patients having impaired cognitive function. 
BACKGROUND OF THE INVENTION 
Brain injuries which lead to impaired cognitive function remain the least 
explored area for active neurological intervention. Several clinical 
observations suggest that mechanisms of plasticity are available to the 
brain that might be harnessed for therapeutic advantage for treating 
cognitive disorders. A significant percentage, roughly 20%, of patients 
who suffer severe brain damage remain conscious with preserved capacity 
for memory, attention, intention, and awareness. In many cases these 
patients fluctuate dramatically (e.g., the well-known case of Gary 
Dockery, the brain-injured police officer who "woke up" and interacted 
with his family for nearly twenty-four hours after seven years of minimal 
responsiveness--Chicago Tribune Jan. 29, 1997 "After miracle coma patient 
has way to go"). 
At present, however, there is a striking lack of therapeutic options for 
these patients, despite evidence of their capacity to further optimize 
their brain function; this capacity is evident in the spontaneous 
fluctuations of functional level in many patients and the induced 
functional changes in some patients following sensory stimulation or 
patient initiated behaviors. The significance of developing a therapeutic 
intervention for patients having impaired cognitive function, especially 
those who remain conscious with preserved capacity for memory, attention, 
intention, and awareness lies in both the devastating reduction in quality 
of life they suffer and the economic burden these patients place on the 
health care system. These costs include full-time care in nursing and 
chronic rehabilitation facilities. Moreover, head trauma accounts for the 
largest percentage of these patients and most patients having impaired 
function caused by head trauma are under 40 years of age. These patients 
represent a disproportionate economic cost in terms of both the loss of 
their expected productivity and the attendant costs of very long-term 
full-time care based on their young age. 
Thus, a need exists for methods for treating patients suffering from 
impaired cognitive function. The present invention is directed toward 
meeting this need. 
SUMMARY OF THE INVENTION 
The present invention relates to a method for treating a conscious patient 
having impaired cognitive function. The method includes selecting a 
conscious patient having impaired cognitive function. Electrical 
stimulation is then applied to at least a portion of the patient's 
intralaminar nuclei under conditions effective to relieve the patient's 
impaired cognitive function. 
The present invention also relates to a method for improving coordination 
of function across cortical regions in a patient. The method includes 
applying electrical stimulation to two or more subdivisions of the 
patient's intralaminar nuclei. The two or more subdivisions of the 
patient's intralaminar nuclei modulate separate cortical regions. 
Using the methods of the present invention, patients suffering from 
impaired cognitive function can have at least a portion of the function 
restored, thus improving their quality of life and reducing societal costs 
.

DETAILED DESCRIPTION OF THE INVENTION 
The present invention relates to a method for treating a conscious patient 
having impaired cognitive function. The method includes selecting a 
conscious patient having impaired cognitive function. Electrical 
stimulation is then applied to at least a portion of the patient's 
intralaminar nuclei under conditions effective to relieve the patient's 
impaired cognitive function. 
As used herein, cognitive function means the information processing 
capacities of the brain, including all semantic information processing, 
including interpretation of external and internal sensory signals and 
integration of those signals to support behavior. Perceptual awareness, as 
used herein, is a subset of cognitive function and is meant to include the 
mechanisms of selecting, organizing, and classifying internally or 
externally generated brain signals. A variety of methods can be used to 
assess a patient's cognitive function and to detect deficits in perceptual 
awareness. These include clinical neurological and neuropsychological 
evaluation and administration of detailed neuropsychological test 
batteries. 
The patient with impaired cognitive function may have that condition alone, 
or, alternatively, the patient may suffer from a variety of other ailments 
in addition to impaired cognitive function. Such other ailments may 
include chronic pain or generalized seizures, each of which conditions may 
be present without the other. Alternatively, patients with impaired 
cognitive function may additionally suffer from both chronic pain and 
generalized seizures. Patients with impaired cognitive function alone, 
patients with impaired cognitive function accompanied by either chronic 
pain or generalized seizures, and patients with impaired cognitive 
function accompanied by both chronic pain and generalized seizures can all 
benefit from the practice of the present invention. As used herein, 
chronic pain means a syndrome of protracted pain, typically resulting from 
a persistent activation of central pain mechanisms (i.e., in the brain 
(commonly referred to as "neuropathic pain") as opposed to pain which 
results primarily from activation of pain mechanisms in the peripheral 
nervous system. As used herein, generalized seizures is meant to include 
epileptic seizures, such as those experienced by severe medication 
resistant refractory epileptics (i.e., patients who have been treated with 
multiple antiepileptic medications at near toxic doses and failed this 
therapy as evidenced by their continuing to have multiple seizures daily 
despite such medication). 
The method of the present invention can be practiced on patients whose 
cognitive dysfunction (e.g., impaired perceptual awareness) is, for 
example, produced, at least in part, by brain injuries, including those 
produced, at least in part, by stroke, head trauma (e.g., blunt head 
trauma or missile penetration), toxicological agents (e.g., carbon 
monoxide, arsenic, or thallium), anoxia (e.g., reduced oxygen levels in 
the blood), ischemia (e.g., reduced blood flow), nutritional deficiencies, 
developmental diseases, infectious diseases, neoplastic diseases, 
degenerative diseases, complications thereof, or other structural lesions. 
These brain injuries frequently manifest themselves in combined deficits of 
attention, intention, working memory, and/or awareness. As used herein, 
attention refers to the cognitive function that provides the capacities 
for selection of internal or external stimuli and thoughts, supports the 
preparation of intended behaviors (e.g., speeds perceptual judgements and 
reaction times), and supports the maintenance of sustained cognition or 
motor behaviors (e.g., the focusing of attention). Intention, as used 
herein, refers to the mechanism of response failures (i.e., lack of 
behavioral interaction) which is not due to a perceptual loss (i.e., 
intention is the cognitive drive linking sensory-motor integration to 
behavior). Intention deficits include failure to move a body part despite 
intact motor pathways, awareness, and sensory processing as demonstrated 
by neurophysiological and neuropsychological evaluation. Another example 
of a patient's intention deficit is a failure to initiate action of any 
kind despite evidence of awareness or action produced by stimulation. Loss 
of intention is a disorder of cognitive function, as defined herein, and 
is a major division of the neuropsychological disorder of neglect, which 
may be present in many patients with cognitive loss following brain 
injury. Working memory, as used herein, refers to the fast memory process 
required for on-line storage and retrieval of information, including 
processes of holding incoming information in short-term memory before it 
can be converted into long-term memory and processes which support the 
retrieval of established long-term (episodic) memories. Deficits in 
awareness relate to impaired perceptual awareness, as described above. 
Clinical signs of these brain injuries also include profound hemispatial 
neglect, disorders of motor intention, disorders of impaired awareness of 
behavioral control, or apathy and cognitive slowing. 
A patient's attention, intention, working memory, and/or awareness function 
can be evaluated using standard tests. Most of these test batteries 
encompass the different types of basic cognitive functions and are used to 
initially screen a patient for a pattern of deficits. More specific tests 
can be employed and individualized to a patient's neuropsychological 
profile. In practice, the choice of particular neuropsychological test 
batteries depends on the experience of the tester and the normative data 
available for the test. This changes as new studies are done and as new 
testing materials are tried out and compared. For example, suitable 
comprehensive tests include the Mental Status Exam ("MSE") (set forth, for 
example, in Strub et al., The Mental Status Exam in Neurology, 3rd ed., 
Philadelphia:Davis (1993), which is hereby incorporated by reference) as 
well as broad neuropsychological test batteries, like the Halstead-Reitan 
Neuropsychological Test Battery (which encompasses memory, attention, 
intention, and perception/awareness). In order to delineate more narrowly 
specific deficits of working memory, attention, perception, etc., more 
individualized tests can be chosen. For example, a `Shipley-Hartford 
scale` test may be employed to assess cognitive slowing (intelligence); a 
`Bender-Gestalt` test can be used to assess spatial relations and 
constructions; Aphasia screening tests, such as the Boston Diagnostic 
Aphasia Examination or the Western Aphasia Battery, can detect language 
dysfunction; and Trials A/B or Memory Assessment Scales ("MAS") test can 
be used to assess working memory. Further details with regard to these and 
other tests for assessing a patient's attention, intention, working 
memory, and/or awareness function can be found in, for example, Berg, 
"Screening Tests in Clinical Neuropsychology," Chapter 10, pp. 331-363, in 
Horton et al., eds., The Neuropsychology Handbook, Vol. 1, Foundations and 
Assessment, 2nd ed., New York:Springer Publishing Company (1997), which is 
hereby incorporated by reference. 
Clinical guidelines for patient selection are based on the patient's 
functional disturbance. For example, the patient's cognitive impairment 
may be slowing (or, in a severe case, dementia), as manifested in the 
patient's decreased attention, impaired intention, and decreased working 
memory Alternatively, the patient may exhibit primary failure to initiate 
action despite interaction when stimulated. Patient selection in the 
clinical setting would also depend, in part, on prognostic signs, such as 
the presence of spontaneous fluctuations in functional level, modulation 
of functional level by external stimulation, or reliably produced 
modulation by internally generated stimulation. 
As indicated above, the present invention relates to a method of treating a 
conscious patient having impaired cognitive function. Conscious, as used 
herein, has the conventional meaning, as set forth in Plum, et al., The 
Diagnosis of Stupor and Coma, CNS Series, Philadelphia:Davis (1982), which 
is hereby incorporated by reference. Conscious patients include those who 
have a capacity for reliable, reproducible, interactive behavior 
evidencing awareness of self or the environment. Conscious patients 
include patients who recover consciousness with less severe brain injury 
but who, because of their impaired cognitive function, do not reach 
independent living and remain in nursing facilities. Conscious patients do 
not include those who exhibit wakefulness but lack interaction (e.g., 
those deemed to be in a persistent vegetative state) A significant 
percentage, roughly 20% of patients who suffer severe brain damage remain 
conscious with preserved capacity for memory, attention, intention, and 
awareness. This is in contrast to patients who suffer from states of 
global unconsciousness, as indicated by conditions such as coma, 
persistent vegetative states, apallic state, coma vigil, and severe 
dementia. 
Since adult patients in their twenties to forties have the most to gain 
from treatment and represent the greatest cost to society if left 
untreated, they would be preferred candidates for the intervention of the 
present invention. However, patients younger or older than those in the 
above age range would also benefit from the practice of the present 
invention. Although, in the early stages of clinical application, the 
method of the present invention will likely target more seriously 
compromised patients, it is believed that, ultimately, the method will 
have wider application to patients with mild to moderate cognitive 
impairment following brain injury as well. Patients suffering from post 
encephalitic parkinsonism or other disease processes which include 
oculogyric crises as a symptom are envisioned as being one class of 
patients who can be treated using the method of the present invention. 
Once the conscious patient having impaired cognitive function is selected, 
electrical stimulation is applied to at least a portion of the patient's 
intralaminar nuclei under conditions effective to relieve the patient's 
impaired cognitive function. 
Generally, stimulation of the patient's intralaminar nuclei involves 
contacting the intralaminar nuclei with an electrode capable of delivering 
an electrical signal to the patient's intralaminar nuclei. A variety of 
electrodes can be employed for delivering the stimulation. For example, 
suitable electrodes include the deep brain stimulation electrodes used in 
Katayama, "Characterization and Modification of Brain Activity with Deep 
Brain Stimulation in Patients in a Persistent Vegetative State: 
Pain-Related Late Positive Component of Cerebral Evoked Potential," Pace, 
14:116-121 (1991), which is hereby incorporated by reference, and the 
Medtronic DBS 3280 (available from Medtronic, Minneapolis, Minn.), which 
has a flexible TEFLON-SILASTIC.TM. coated, platinum iridium electrodes 
with 4 contacts, 4 mm tips, 2 mm, mean tip separation, and an impedance of 
5-7 k.OMEGA. within the brain, described in Velasco et al., 
"Electrocortical and Behavioral Responses Produced By Acute Electrical 
Stimulation of the Human Centromedian Thalamic Nucleus," 
Electroencephalography and Clinical Neurophysiolocy, 102:461-471 (1997) 
("Velasco"), which is hereby incorporated by reference. Preferably the 
electrode is an implantable multipolar electrode with either an 
implantable pulse generator that can be under patient control or a 
radiofrequency controlled device operated by an external transmitter. 
Preferably, the multipolar electrode contacts should allow for adjustment 
of frequency (or "rate"), amplitude, and pulse width within at least the 
following respective ranges: about 2-200 Hz, about 0.1-10 Volts, and about 
50-500 microseconds. More preferably, the multipolar electrode contacts 
allow for adjustment in a broader range than those recited above, 
particularly toward higher intensities. Such preferred electrodes include 
a Medtronic 3387 electrode (available from Medtronic, Minneapolis, Minn.) 
and are described, for example, in Benabid et al., "Chronic Electrical 
Stimulation of the Ventralis Intermedius Nucleus of the Thalamus As a 
Treatment of Movement Disorders," J. Neurosurgery, 84:203-214 (1996), 
which is hereby incorporated by reference. In some situations, it may be 
desirable to use an electrode capable of delivering pharmacological agents 
to the patient's intralaminar nuclei. Such electrodes include electrodes 
with microcannulae and are described in, for example, Hikosaka et al., 
"Modification of Saccadic Eye Movements by GABA-related Substances. I. 
Effect of Muscimol and Bicuculline in Monkey Superior Colliculus. J. 
Neurophysiology, 53:266-291 (1985), which is hereby incorporated by 
reference. Examples of suitable pharmaceutical agents which can be used in 
conjunction with the electrical stimulation methods of the present 
invention include known excitatory and inhibitory transmitters that 
influence intralaminar nuclei function. Excitatory transmitters would 
preferably include acetylcholine ("Ach"), noradrenaline ("NE"), and/or 
serotonin ("5-HT") or analogues thereof. Inhibitory transmitters would 
include primary gamma-aminobutyric acid ("GABA") or analogs thereof. Other 
amino acid transmitters know to affect the intralaminar nuclei, such as 
adenosine or glutamate, can also be used. 
The electrode can be contacted with the patient's intralaminar nuclei by 
the methods conventionally employed for embedding or emplacing electrodes 
for deep brain electrical stimulation in other thalamic nuclei. Such 
methods are described in Tasker et al., "The Role of the Thalamus in 
Functional Neurosurgery," Neurosurgery Clinics of North America, 
6(1):73-104 (1995) ("Tasker"), which is hereby incorporated by reference. 
Briefly, the multi-polar electrode or electrodes are introduced via burr 
holes in the skull. The burr holes are placed based on the particular 
region of the intralaminar nuclei to be contacted. Preferably, prior to 
the introduction of the implantable multi-polar electrode(s), a detailed 
mapping with microelectrode and microstimulation following standard 
methods is carried out as described in Tasker, which is hereby 
incorporated by reference. Briefly, for each subdivision of the 
intralaminar nuclei, a preferred trajectory of approach optimizing the 
safety of entry point and maximal number of identifiable physiological 
landmarks in the responses of cell groups encountered along the trajectory 
into the desired region or regions of the intralaminar nuclei can be 
identified by one skilled in the art. This can be done, for example, by 
following the methods and catalogued physiological responses of different 
human thalamic cell groups described in Tasker, which is hereby 
incorporated by reference. Initial mapping of the path for the stimulating 
electrode(s) can, therefore, be carried out via a combination of detailed 
single-unit recording of receptive field ("RF") properties of the cells 
encountered along the trajectory, projective fields ("PF") mapped by 
microstimulation of the same cell groups, and comparison with known RF and 
PF responses in the human thalamus. Similarly, evoked potentials can be 
recorded and, for the intralaminar nuclei, have several characteristic 
signatures identifiable from scalp surface recording as discussed in 
Velasco and Tasker, which are hereby incorporated by reference. For this 
mapping, microstimulation, using tungsten microelectrodes with impedances 
of roughly 1.5 megaohms, every 1 mm at threshold of up to 100 microamperes 
with short trains of 300 Hz pulses of 0.2 millisecond pulse width are 
employed as described in Tasker, which is hereby incorporated by 
reference. Typically, an on-line data base of RF and PF information along 
the trajectory and stereotactic coordinates derived, for example, from 
Schaltenbrand et al., Introduction to Stereotaxis with an Atlas of the 
Human Brain, Stuttgart:Thieme (1977), which is hereby incorporated by 
reference, or by computed mapping techniques, such as those described in 
Tasker et al., "Computer Mapping of Brainstem Sensory Centres in Man," J. 
Neurosurg., 44:458-464 (1976), which is hereby incorporated by reference, 
can be used, either with or without a magnetic resonance imaging ("MRI") 
based stereotactic apparatus. To carry out the above methods a patient 
would typically remain conscious with application of local anesthesia or 
mild sedation. However, in cases where a patient is not sufficiently 
cooperative to remain conscious during the procedure, the above-described 
approach can be modified to allow the operation to be completed under 
general anesthesia. 
The electrical stimulation can be continuous, intermittent, or periodic. 
The range of stimulation frequencies and intensity of stimulation will 
depend on several factors: impedance of the electrode once in the brain, 
excitation properties of cells which may differ within subdivisions of the 
intralaminar nuclei, the type of induced physiologic responses sought for 
a particular patient, and interindividual variation. While higher 
frequency ranges are thought to be preferred, lower frequencies will also 
be employed. Suitable stimulation frequencies range from about 1 Hz to 1 
kHz; preferably, from about 10 Hz to about 500 Hz; and, more preferably, 
from about 50 Hz to about 250 Hz. 
Typically, the electrode is connected to an insulated conductor which leads 
to an external connector plug which is removably connected to a mating 
plug which is, in turn, connected to a voltage control and pulse 
generator. The pulse generator produces a selected pulse train, and the 
voltage control provides a selected current amplitude or voltage to the 
waves of the pulse train. Preferably, both the voltage control and pulse 
generator are under control of a computer microprocessor. The signal pulse 
generator should preferably be capable of generating voltage wave trains 
of any desired form (sine, square wave, spike, rectangular, triangular, 
ramp, etc.) in a selectable voltage amplitude in the range from about 0.1 
volts to about 10 volts and at selectable frequencies as set forth above. 
In practice, the pulse train and voltage amplitudes employed will be 
selected on a trial and error basis by evaluating a patient's response to 
various types and amplitudes of electrical stimulation over a time course 
of from about 1 to about 12 months. For example, after implanting the 
electrode in the patient's intralaminar nuclei, stimulation with a voltage 
within the range of from about 0.1 to about 10 volts or higher, a rate 
within the range of from about 50 to about 250 Hz, and a pulse width 
within the range of from about 50 to about 500 microseconds is applied for 
from about 8 to about 12 hours a day. During and after the implantation of 
the electrode, the parameters of the stimulation (voltage, pulse width, 
and frequency) are adjusted to optimize the patient's interactive 
behavior. The stimulation parameters can be further optimized by 
monitoring the patient clinically, anatomically, physiologically, or 
metabolically to assess his or her response to the stimulation. For 
example, the patient can be physiologically examined using 
electroencephalogram ("EEG"), magnetoencephalogram ("MEG"), or functional 
magnetic resonance imaging ("fMRI"). Metabolic evaluation can be carried 
out, for example, using quantitative fluorodeoxy-glucose positron emission 
tomography ("FDG-PET"). In addition, correlation of induced changes in 
surface electrical brain activity (as measured, for example, by EEG or 
MEG) can be correlated with improved function and increased resting 
metabolism of a damaged brain regions as identified by FDG-PET. Careful 
evaluation of these different indices of brain function in conjunction 
with standard neurological and neuropsychological tests can thus be used 
to optimize the beneficial effect of the stimulation method of the present 
invention. 
Intralaminar nuclei are a small set of nuclei located in the paramedian 
thalamus. The intralaminar nuclei can be divided into an anterior group 
and a posterior group. FIG. 1 illustrates the anatomical connections of 
the intralaminar nuclei with distributed circuits underlying arousal, 
attention, intention, working memory, and gaze and motor control. The 
anterior group projects widely throughout the neocortex to primary sensory 
and motor areas and association cortices, while the posterior group 
projects mainly to sensory-motor and premotor areas and striatal targets. 
The anterior IL group includes the central lateral nucleus ("CL"), which 
projects to the frontal eye field ("FEF"), motor cortex, and, more 
heavily, to the posterior parietal cortex ("PPC"). The paracentralis 
("Pc") nucleus projects to the prefrontal cortex (with heavier projection 
than CL) and very strongly to the inferior parietal lobe and visual 
association cortices. The central medial ("CeM") nucleus, which also 
projects to the prefrontal and visual association cortices, also projects 
to the cingulate cortex and pregenual areas and to the medial cortical 
surface and orbitofrontal cortex. Included within the meaning of 
intralaminar nuclei, as used herein, is the Paraventricular nucleus 
("Pv"), which is strongly associated with the limbic system, and midline 
thalamic nuclei. Projections to prefrontal cortex ("IPFC") and anterior 
cingulate cortex arise, as well, from the anterior intralaminar group. The 
CL is also known to project to the primary visual cortex in the cat and 
monkey. The posterior group is dominated by the 
centromedian-parafasicularis complex ("Cm-Pf"), which strongly projects to 
areas 6 and 4. In primates, the CmPf undergoes a notable expansion, and 
the CL also expands and develops further subdivisions. This system 
projects strongly to the caudate (from Pf), putamen (from Cm nuclei of the 
basal ganglia), and prefrontal and parietal association cortices. A small 
projection (Pf) also goes to the FEF. The intralaminar nuclei projections 
to the striatum per se are considered the principle efferent connections 
of the intralaminar nuclei and include anterior group projections to the 
caudate, as well. Thus the intralaminar nuclei (including the midline 
nuclei) are believed to be in a preferred position to modulate the large 
thalamo-cortical-basal ganglia loops, especially to synchronize their 
function (Groenewegen et al., "The Specificity of the `Nonspecific` 
Midline and Intralaminar Thalamic Nuclei," Trends in Neuroscience 17:52-66 
(1994), which is hereby incorporated by reference. 
The intralaminar nuclei receive ascending inputs from several components of 
the ascending reticular arousal system, including the pedunculopontine 
cholinergic group (lateral dorsal tegmentum), mesencephalic reticular 
formation, locus ceruleus, and dorsal raphe. Thus, the intralaminar nuclei 
are targets of modulation by a wide variety of neurotransmitter agents, 
including acetylcholine (pendunculopontine, lateral dorsal tegmentum, and 
mesencephalic reticular formation neurons), noradrenaline (locus ceruleus) 
serotonin (raphe nuclei), and histamine (hypothalamus). Also received by 
the intralaminar nuclei are nociceptive, cerebellar, tectal, pretectal, 
and rhinencephalic inputs. Descending inputs reciprocally relate 
components of the intralaminar nuclei with their cortical projections. 
Although each cell group within the intralaminar nuclei projects to many 
separate cortical targets, each neuron of the intralaminar nuclei has a 
narrowly elaborated projection and receives its cortical feedback from the 
same restricted area. The reciprocal projections between the intralaminar 
nuclei and cortex have a distinctive laminar pattern that differs from the 
more well-known pattern of the reciprocal projections of the relay nuclei. 
The intralaminar nuclei neurons synapse in Layer I on the terminal 
dendritic tufts of layers III and V pyramidal cells and in layers V and 
VI, whereas neurons of the relay nuclei terminate primarily in cortical 
layers III and IV. Feedback to intralaminar nuclei neurons originates in 
Layer V, but feedback to the relay nuclei originates in Layer VI. In the 
cat, the dominant corticothalamic input to the CL originates in the PFC, 
whereas the visual areas, including area 17, also project directly to the 
CL. 
As used herein, intralaminar nuclei also include paralamellar regions, such 
as parts of the medial dorsal ("MD") nucleus and the midline nuclei (which 
are sometimes distinguished from the intralaminar nuclei but, for purposes 
of the present application, are not). 
FIGS. 2A-2E illustrate intralaminar nuclei subdivisions suitable for 
stimulation in accordance with the practice of the present invention. 
Table 1 sets forth the meanings of the abbreviations used in FIGS. 2A-2E 
(See Buren et al., Variations and Connections of the Human Thalamus, New 
York: Springer-Verlag (1972), which is hereby incorporated by reference). 
TABLE 1 
__________________________________________________________________________ 
Term Sagittal 
Horizontal 
Transverse 
__________________________________________________________________________ 
A -- N. amygdalae 
S -- L 12.0-22.0 
T -- A 20.3 (PC)-10.9 (PC) 
Ad -- N. anterodorsalis 
S -- L 3.0 
H -- S 13.2 
T -- A 20.3 (PC)-14.1 (PC) 
A pr -- N. anteroprincipalis 
S -- L 3.0-9.0 
H -- S 13.2-6.3 
T -- A 23.4 (PC)-10.9 (PC), 
4.7 (PC) 
B -- N. basalis S -- L 6.0-22.0 
H -- I 4.5-8.1 
T -- A 23.4 (PC)-10.9 (PC) 
B cj -- Brachium conjunctivum 
H -- I 8.1 
B co i 
-- Brachium colliculi inferioris 
S -- L 9.0 
H -- I 4.5 
T -- A 1.6 (PC), 4.7 (PC) 
B co s 
-- Brachium colliculi superioris 
S -- L 9.0 
H -- I 4.5 
C cl s 
-- Corporis callosi splenium 
S -- L 2.0-3.0 
Cd -- N. caudatus 
S -- L 6.0, 
H -- S 17.0-13.2 
T -- A 23.4 (PC)-P 4.7 (PC) 
12.0-25.0 
Ce mc 
-- N. centralis magnocellularis 
S -- L 9.0 
H -- S 2.7 
T -- A 7.8 (PC)-1.6 (PC) 
Ce pc 
-- N. centralis parvocellularis 
S -- L 9.0-12.0 
H -- S 6.3-I 0.9 
T -- A 7.8 (PC)-1.6 (PC) 
Cl -- Claustrum H -- S 17.0, 9.7 
T -- A 23.4 (PC) 
C m -- Corpus mammillare 
S -- L 2.0, 2.5 T -- 14.1 (PC) 
Cm a -- Commissura anterior 
S -- L 2.0, 6.0, 
H -- S 2.7-18.1 
T -- A 23.4 (PC) 17.2 (PC) 
12.0-25.0 
Cm p -- Commissura posterior 
S -- L 2.0, 3.0 
H -- S 2.7, I 0.9 
T -- P 1.6 (PC) 
Cn A -- Cornu Ammonis 
S -- L 19.0-25.0 
H -- I 0.9, 18.1 
T -- A 7.8 (PC)-1.6 (PC) 
Co -- N. commissuralis 
S -- L 2.0-2.5 
H -- S 2.7 
T -- A 20.3 (PC)-10.9 (PC) 
Co s -- Colliculus superior 
S -- L 2.0-6.0 
H -- I 0.9, 4.5 
T -- P 4.7 (PC) 
D c -- N. dorsocaudalis 
S -- L 12.0-19.0 
H -- S 13.2, 9.7 
T -- A 7.8 (PC)-1.6 (PC) 
D o -- N. dorsooralis 
S -- L 9.0-19.0 
H -- S 17.0-9.7 
T -- A 17.2 (PC)-7.8 (PC) 
D sf -- N. dorsalis superficialis 
S -- L 6.0-12.0 
H -- S 17.0, 13.2 
T -- A 10.9 (PC)-4.7 (PC) 
Edy -- N. endymalis 
S -- L 2.0, 2.5 
H -- I 0.9 
T -- A 17.2 (PC)-10.9 (PC), 
4.7 (PC) 
F -- Fornix S -- L 2.0-3.0 
H -- S 17.0-I 8.1 
T -- A 23.4 (PC)-14.1 (PC), 
P 1.6 (PC), 4.7 (PC) 
Fa -- N. fasciculosus 
S -- L 3.0, 6.0 
H -- S 2.7-I 0.9 
T -- A 23.4 (PC)-17.2 (PC) 
G l mc 
-- Corpus geniculatum laterale, 
S -- L 19.0-25.0 
H -- I 4.5, 8.1 
T -- A 1.6 (PC), P 1.6 (PC) 
magnocellularis 
G l pc 
-- Corpus geniculatum laterale, 
S -- L 19.0-25.0 
H -- I 4.5, 8.1 
T -- A 1.6 (PC), P 1.6 (PC) 
parvocellularis 
G m mc 
-- Corpus geniculatum mediale, 
S -- L 12.0 
H -- I 4.5 
T -- P 1.6 (PC) 
magnocellularis 
G m pc 
-- Corpus geniculatum mediale, 
S -- L 12.0, 16.0 
H -- I 0.9, 4.5 
T -- A 1.6 (PC), P 1.6 (PC) 
parvocellularis 
Gr ce me 
-- Grisea centralis mesencephali 
S -- L 2.0-3.0 
H -- I 4.5, 8.1 
T -- A 1.6 (PC), 4.7 (PC) 
cf H.sub.1 
-- Campus Forelii H.sub.1 
S -- L 6.0, 9.0 
H -- I 4.5 
T -- A 10.9 (PC) 
cf H.sub.1 
-- Campus Forelii H.sub.2 
S -- L 6.0, 9.0 
H -- I 4.5 
T -- A 10.9 (PC) 
H l -- N. habenularis lateralis 
S -- L 3.0 
H -- S 6.3, 2.7 
T -- A 1.6 (PC) 
H m -- N. habenularis medialis 
S -- L 2.0-3.0 
H -- S 6.3, 2.7 
T -- A 1.6 (PC) 
Hpth -- Hypothalamus 
S -- L 2.0-6.0 
H -- I 0.9-8.1 
T -- A 23.4 (PC)-10.9 (PC) 
iLa -- N. intralamellaris 
S -- L 2.0-12.0 
H -- S 13.2-2.7 
T -- A 17.2 (PC)-1.6 (PC) 
I s -- N. interstitialis (Cajal) T -- A 1.6 (PC), P 4.7 (PC) 
Li -- N. limitans 
S -- L 6.0-12.0 
H -- I 0.9 
T -- A 1.6 (PC) 
L l -- Lemniscus lateralis T -- A 1.6 (PC), 4.7 (PC) 
L m -- Lemniscus medialis H -- I 4.5, 8.1 
L po -- N. lateropolaris 
S -- L 6.0-16.0 
H -- S 13.2-I 0.9 
T -- A 23.4 (PC)-14.1 (PC) 
M -- N. medialis 
S -- L 2.0-9.0 
H -- S 13.2-2.7 
T -- A 17.2 (PC)-1.6 (PC) 
N III 
-- N. oculomotorius 
S -- L 2.0 T -- A 1.6 (PC)-P 4.7 (PC) 
N V me 
-- N. nervi trigemini T -- P 4.7 (PC) 
mesencephalicus 
N EW -- N. Edinger Westphal 
S -- L 2.0 T -- A 4.7 (PC)-P 4.7 (PC) 
Pf -- N. parafascicularis 
S -- L 6.0 
H -- I 0.9 
T -- A 7.8 (PC)-1.6 (PC) 
Pi -- Pineal S -- L 2.0-3.0 T -- A 4.7 (PC) 
P l -- Pallidum laterale 
S -- L 9.0-22.0 
H -- S 6.3-I 4.5 
T -- A 23.4 (PC)-7.8 (PC) 
P m -- Pallidum mediale 
S -- L 9.0-19.0 
H -- S 2.7-I 4.5 
T -- A 23.4 (PC)-10.9 (PC) 
Pm a -- N. paramedianus anterior 
S -- L 2.0-2.5 
H -- S 2.7 
T -- A 20.3 (PC)-10.9 (PC) 
Pm p -- N. paramedianus posterior 
S -- L 2.0-2.5 
H -- S 2.7 
T -- A 7.8 (PC)-1.6 (PC) 
P pd -- N. peripeduncularis 
S -- L 12.0 
H -- I 4.5, 8.1 
T -- A 1.6 (PC) 
Pret -- Area pretectalis 
S -- L 6.0 
H -- I 0.9, 4.5 
T -- A 1.6 (PC) 
Pr G -- N. praegeniculatus 
S -- L 19.0-22.0 
H -- I 4.5, 8.1 
T -- A 1.6 (PC) 
Pt -- N. parataenialis 
S -- L 2.0-3.0 
H -- S 9.7-2.7 
T -- A 20.3 (PC)-7.8 (PC) 
Pu i -- N. pulvinaris intergeniculatus 
S -- L 12.0 
H -- I 4.5 
T -- A 1.6 (PC) 
Pu l -- N. pulvinaris lateralis 
S -- L 16.0-22.0 
H -- S 13.2-I 0.9 
T -- A 1.6 (PC)-P 4.7 (PC) 
Pu m -- N. pulvinaris medialis 
S -- L 6.0-16.0 
H -- S 13.2-I 0.9 
T -- A 1.6 (PC)-P 4.7 (PC) 
Pu o -- N. pulvinaris oralis 
S -- L 12.0 
H -- S 6.3, 2.7 
T -- A 1.6 (PC) 
Put -- Putamen S -- L 19.0-25.0 
H -- S 13.2-I 8.1 
T -- A 23.4 (PC)-7.8 (PC) 
Pv -- N. paraventricularis 
S -- L 2.5, 3.0 
H -- I 0.9-8.1 
T -- A 23.4 (PC), 20.3 (PC) 
hypothalami 
R -- N. reticularis 
S -- L 6.0-25.0 
H -- S 17.0-I 0.9 
T -- A 23.4 (PC)-4.7 (PC), 
P 1.6 (PC), 4.7 (PC) 
Ru -- N. ruber S -- L 2.0-6.0 
H -- I 4.5-8.1 
T -- A 7.8 (PC)-1.6 (PC) 
S m th 
-- Stria medullaris thalami 
S -- L 2.0-3.0 
H -- S 9.7, 6.3 
T -- A 23.4 (PC)-1.6 (PC) 
Sn -- Substantia nigra 
S -- L 6.0-12.0 
H -- I 8.1 
T -- A 14.1 (PC)-1.6 (PC) 
So -- N. supraopticus hypothalami 
S -- L 3.0-6.0, T -- A 23.4 (PC), 20.3 (PC) 
12.0 
Sth -- N. subthalamicus 
S -- L 6.0-12.0 
H -- I 4.5, 8.1 
T -- A 14.1 (PC)-7.8 (PC) 
T l -- Nucleus tuberis lateralis 
S -- L 6.0 
T M -- Tractus Menerti 
S -- L 2.0-6.0 
H -- S 2.7-8.1 
T -- A 7.8 (PC)-1.6 (PC) 
T m th 
-- Tractus mammillothalamicus 
S -- L 2.5-6.0 
H -- S 6.3-I 8.1 
T -- A 17.2 (PC), 14.1 (PC) 
T O -- Tractus opticus 
S -- L 2.5-22.0 T -- A 20.3 (PC)-4.7 (PC) 
V c e 
-- N. ventrocaudalis externus 
S -- L 16.0-19.0 
H -- S 9.7-I 0.9 
T -- A 7.8 (PC)-1.6 (PC) 
V c i 
-- N. ventrocaudalis internus 
S -- L 12.0-16.0 
H -- S 6.3-I 0.9 
T -- A 7.8 (PC)-1.6 (PC) 
V c pc 
-- N. ventrocaudalis 
S -- L 9.0-12.0 
H -- I 0.9 
T -- A 7.8 (PC), 4.7 (PC) 
parvocellularis 
V c v 
-- N. ventrocaudalis ventralis 
S -- L 16.0 
H -- I 4.5 
T -- A 7.8 (PC)-1.6 (PC) 
V im -- N. ventrointermedius 
S -- L 9.0-19.0 
H -- S 6.3-I 0.9 
T -- A 10.9 (PC)-4.7 (PC) 
V o e 
-- N. ventrooralis externus 
S -- L 9.0-16.0 
H -- S 13.2-I 0.9 
T -- A 17.2 (PC)-7.8 (PC) 
V o i 
-- N. yentrooraiis internus 
S -- L 6.0 
H -- S 9.7-I 0.9 
T -- A 14.1 (PC)-10.9 (PC) 
Zi -- Zona incerta 
S -- L 6.0-16.0 
H -- I 4.5 
T -- A 17.2 (PC)-4.7 
__________________________________________________________________________ 
(PC) 
For example, the stimulated intralaminar nuclei subdivisions can include 
the centromedian-parafasicularis or the central lateral or both. 
Alternatively, the stimulated portion of the patient's intralaminar nuclei 
can be selected so that it does not include the 
centromedian-parafasicularis, the central lateral, or either the 
centromedian-parafasicularis or the central lateral nuclei. 
The electrical stimulation can be applied to the patient's entire 
intralaminar nuclei or to one or more portions of the patient's 
intralaminar nuclei. In addition to being applied to the patient's 
intralaminar nuclei or portion thereof, the electrical stimulation can 
also extend to other regions of the brain. Preferably, the electrical 
stimulation is applied only to the patient's intralaminar nuclei or 
portion thereof without stimulating other regions of the patient's brain. 
For example, the electrical stimulation can be applied to all portions of 
the patient's intralaminar nuclei except the centromedian-parafasicularis, 
except the central lateral, or except both the central lateral and 
centromedian-parafasicularis. 
The method of the present invention can further comprise selecting one or 
more subdivisions of the patient's intralaminar nuclei for stimulation. In 
particular, the subdivision to be stimulated can be one which modulates 
the specific cognitive function which is impaired in the patient. For 
example, Table 2 sets forth various subdivisions of the intralaminar 
nuclei and the specific cognitive function with which each is associated. 
TABLE 2 
______________________________________ 
Specific ILN Subdivision 
Cognitive Function Impairment 
______________________________________ 
centromedian-parafasicularis 
attention deficits, 
anosognosia, working memory 
deficits, intentional deficits, 
nonsensory neglect, akinesia, 
frontal lobe damage 
central lateral perceptual impairment, sensory 
neglect, visuomotor impairment, 
working memory deficits, 
attentional deficits, 
anosognosia 
paracentralis working memory deficits, 
apathy, emotional dyscontrol 
paraventricularis loss of awareness of 
emotional/limbic signals 
central medial apathy, emotional dyscontrol, 
intentional deficits 
______________________________________ 
Further details regarding the identification of intralaminar nuclei 
subdivisions which modulate specific cognitive function can be found in, 
for example, Macchi et al., "The Thalamic Intralaminar Nuclei and the 
Cerebral Cortex," pp. 355-389, in Jones et al., eds., Cerebral Cortex, 
Vol. 5, New York:Plenum Press (1986), Castaigne et al., "Paramedian 
Thalamic and Midbrain Infarcts: Clinical and Neuropathological Study," 
Ann. Neurol., 10:127-148 (1980), and Purpura et al., "The Thalamic 
Intralaminar Nuclei: A Role in Visual Awareness," The Neuroscientist, 
3:8-15 (1997) ("Purpura"), which are hereby incorporated by reference. 
Thus, by knowing the specific cognitive function or functions impaired in a 
particular patient, the preferred subdivision of the particular patient's 
intralaminar nuclei to receive electrical stimulation can be determined. 
In cases where the patient suffers from post-encephalitic parkinsonism or 
other disease processes which include oculogyric crises as a symptom, it 
is believed that the preferred intralaminar nuclei subdivision is the 
centromedian. 
Once the particular subdivision to be stimulated is selected, that 
subdivision and, optionally, others are stimulated as described above. 
That is, electrical stimulation can be applied to the selected subdivision 
only, or, alternatively, electrical stimulation can be applied to the 
selected subdivision as well as other subdivisions of the patient's 
intralaminar nuclei. Stimulation can be applied to the selected 
subdivision and optional other subdivisions of the intralaminar nuclei in 
either or both brain hemispheres. 
Preferably, the intralaminar nuclei subdivision which is to receive 
electrical stimulation is one which projects to an area of the brain which 
has reduced baseline function but which also exhibits increased function 
during periods of external stimulation or internally generated 
stimulation, such as patient's self-generated activity (e.g., head 
turning). 
In many cases, patients with cognitive impairments following brain injury 
can have their cognitive function modulated by various forms of external 
stimulation. For example, in some patients, stimulation of the brainstem 
vestibular system with cold water caloric stimulation of the external ear 
canal, such as described in Gainotti, "The Role of Spontaneous Eye 
Movements in Orienting Attention and in Unilateral Neglect," pp. 107-113, 
in Robertson et al., eds., Unilateral Neglect: Clinical and Experimental 
Studies, Hove, United Kingdom:Lawrence Erlbaum Associates, Publishers 
(1993) and Vallar et al., "Modulation of the Neglect Syndrome by Sensory 
Stimulation," pp. 555-578, in Thier et al., eds., Parietal Lobe 
Contributions to Orientation in 3D Space, Heidelberg, 
Germany:SpringerVerlag (1997), which are hereby incorporated by reference, 
generates transient but profound recovery of multiple cognitive functions 
including self-awareness, intention, and perceptual awareness. Other 
external stimulation that may modulate cognitive function, would include 
alteration of trunk, head, or limb position signals, such as a vibrational 
stimulation of the sternocleidomastoid muscle. 
Similarly, some patients with less severe global impairments of 
consciousness discover strategies to self-generate behaviors that assist 
in supporting their cognitive or perceptual function. For example, some 
patients with visual agnosias who have visual perceptual problems discover 
that self-generated rhythmic head movements or hand tracing movements 
improve their visual awareness and cognitive skills in identifying 
figures. These self-generated rhythmic head and hand movements are 
described in Farah, Visual Agnosia, Cambridge, Mass.:MIT Press (1990), 
which is hereby incorporated by reference. 
It is believed that the capacity to modulate cognitive function by external 
or internal stimulation in these patients demonstrates that certain brain 
activations can optimize their function. In the case of vestibular 
stimulation, it is believed that the intralaminar nuclei are directly 
implicated by their strong inputs from the vestibular nuclei. Although the 
present invention is not intended to be limited by the mechanism by which 
it operates, it is believed that the intralaminar nuclei's role in 
supporting these function relates to the generation of event-holding 
functions that may promote interaction across the cortex, possibly by 
enhancing synchronization, as described in Purpura. One theory of the 
present invention is that similar event-holding functions tied to head, 
hand, trunk or other bodily coordinates are generated by intralaminar 
nuclei stimulation and account for the improved cognitive function seen in 
patients who are externally or internally stimulated. Whether or not such 
other modulations are directly tied to intralaminar nuclei stimulation, 
functional studies in an individual patient, such as those carried out in 
Bottini et al, "Modulation od Conscious Experience by Peripheral Sensory 
Stimuli," Nature, 376:778-781 (1995), which is hereby incorporated by 
reference, can be used to identify specific cortical regions that are 
modulated as an initial step in applying the method of the present 
invention. 
Although the above described method for selecting a subdivision of the 
patient's intralaminar nuclei to which to apply electrical stimulation in 
accordance with the present invention is acceptable, in many cases, it is 
preferred to determine, on a individual basis, which areas of the brain 
have reduced baseline function, and then to correlate the area of the 
brain having reduced baseline function with an intralaminar nuclei 
subdivision which projects thereto. As one skilled in the art would 
recognize, determining areas of the brain which have reduced baseline 
function can be carried out advantageously using quantitative metabolic 
information obtained from a FDG-PET study of resting brain metabolism; 
using electromagnetic indicators of regional functional activity; 
anatomically, physiologically, or metabolically; or using combinations of 
these methods. As used herein, baseline brain function is defined within 
the patient and across a database of normal values for resting cerebral 
metabolism and is typically measured in terms of glucose uptake and 
utilization. One particularly useful gauge of baseline brain function is 
the regional cerebral metabolic rate as measured using fluorodeoxyglucose 
("rCMRgluc"). This is quantitated by fluorodeoxyglucose-PET measurements 
and compared across brain structures within the patient's brain and 
against normative values for particular brain regions. Further details 
regarding assessing baseline brain function are described in, for example, 
Mazziota, ed., Clinical Brain Imaging, CNS Series, Philadelphia:Davis 
(1992), which is hereby incorporated by reference Once the portion of the 
brain having reduced baseline function is identified, the portion can be 
correlated with the intralaminar nuclei ("ILN") subdivision which projects 
to this region, for example, by using Table 3. 
TABLE 3 
______________________________________ 
Specific ILN Subdivision 
Primary Cortical Targets 
______________________________________ 
centromedian-parafasicularis 
prefrontal cortex, premotor 
cortex, parietal cortex 
central lateral prefrontal cortex, parietal 
cortex, visual association 
cortex, motor cortex 
paracentralis prefrontal cortex, 
orbitofrontal cortex 
paraventricularis amydala, limbic system 
central medial orbitofrontal cortex 
paralam MD prefrontal cortex 
midline nuclei hippocampus, limbic system 
______________________________________ 
Further details regarding the correlation of areas of the brain to the 
intralaminar nuclei subdivisions which project thereto can be found in, 
for example, Jones et al., eds., The Thalamus, Amsterdam:Elsevier (1995), 
which is hereby incorporated by reference. When a subdivision is selected 
in this manner, electrical stimulation can be applied to the selected 
subdivision only, or, alternatively, it can be applied to the selected 
subdivision and, in addition, to other subdivisions of the patient's 
intralaminar nuclei. 
As indicated above, electrical stimulation can be applied to the entire 
group of intralaminar nuclei or to one, two, or more specific subdivisions 
thereof. Stimulation can be applied to the one, two, or more specific 
subdivisions in either or both brain hemispheres. In some cases, it can be 
advantageous to apply electrical stimulation to two or more subdivisions 
of the intralaminar nuclei which modulate separate cortical regions. As 
used herein, cortical regions are considered to be separate when they are 
not contiguous on the cortical mantle or they are considered separate in 
function based on known anatomical or physiological characteristics of 
cells within their borders. For example, the patient's central medial and 
centromedian-parafasicularis intralaminar nuclei subdivisions, which 
respectively project strongly to the orbitofrontal and premotor regions of 
the cortex, can be stimulated. Where two or more subdivisions of the 
intralaminar nuclei are stimulated, both can lie in the same thalamus. 
Alternatively, at least one of the two or more subdivisions of the 
intralaminar nuclei can lie in the left thalamus while at least one of the 
two or more subdivisions of the intralaminar nuclei lies in the right 
thalamus. Preferably, at least one of the two or more subdivisions and, 
more preferably, at least two of the two or more subdivisions of the 
intralaminar nuclei to which electrical stimulation is applied modulates 
the specific cognitive function which is impaired in the patient. 
Where two or more subdivisions of the patient's intralaminar nuclei are 
electrically stimulated periodically and at the same frequency, such 
stimulation can be completely in phase, partially in phase and partially 
out of phase, or completely out of phase. When such stimulation is 
substantially entirely in phase, it is said to be synchronized. In a 
preferred embodiment of the present invention, the electrical stimulation 
applied to two or more subdivisions of the patient's intralaminar nuclei 
is synchronized. It is believed that activation of separate cortical 
regions by common intralaminar nuclei inputs promotes coordinated 
processing in these separated cortical regions because of the strong 
capacity of these intralaminar inputs to generate depolarization of 
neurons in the supragranular layers (upper) of the cerebral cortex. It is 
believed that such strong depolarization generates improved 
synchronization of neuronal activity across cortical regions. This 
improved synchronization may result from high frequency oscillations 
excited by these inputs or sustained enhancement of neural activity seen 
in the form of broadband activity or increased average power across a 
cortical region. More particularly, the method of the present invention 
can be optimized by monitoring regional and intrahemispheric changes in 
brain waves (e.g., changes in absolute power, relative power, and/or 
intra- and/or inter-regional coherence) as measured by using conventional 
techniques (e.g., EEG or MEG techniques) or by monitoring regional and 
intrahemispheric changes in metabolic activity. As indicated above, 
metabolic activity can be assessed using conventional methods (e.g., 
positron emission tomography ("PET") or FDG-PET). 
The result of intralaminar nuclei stimulation under one aspect of the 
present invention is that correction of functional disconnections of brain 
regions by release of inhibition of remaining cortical or subcortical 
regions may be achieved by stimulation of the appropriately connected 
intralaminar nuclei; such release of inhibition may increase metabolic 
activity in suppressed areas. Alternatively, such stimulation may result 
in an alteration of population activity of many neurons in a local 
cortical area that improves information transfer or processing capacities 
of the neurons in that region (for example, by sharpening their receptive 
fields). Under another aspect of the present invention, synchronization of 
stimulated areas may facilitate a broader integration of cortical 
processing via synchronization of activity within the intralaminar nuclei 
of each thalamus and promote a global integrative process at the level of 
the cortex. Similarly, intralaminar nuclei connected to cortical areas 
known to be important for specific cognitive functions independent of a 
patient's particular injury, but selected by the patient's behaviorally 
evidenced impairment, may be selected for stimulation. 
Selection of a particular strategy of intralaminar nuclei stimulation for a 
given patient will depend on several features including the specific 
cortical regions a given subdivision of the intralaminar nuclei projects 
to, particular stimulation parameters, evidence of modulation of cognitive 
function by external stimulation, internally generated stimulation (e.g., 
head turning), or spontaneously, and the patient's underlying brain damage 
and/or behavioral dysfunction Optimization of the preferred method of the 
present invention involves promoting coordinated information processing or 
enhanced participation in integrated brain function of cortical regions 
innervated by intralaminar nuclei. If possible, this optimization can be 
based on evidence of improved function with reliable external (or 
internal) stimulation procedures or indexed by strong clinical inferences 
and functional anatomic information based on areas of identified 
hypometabolism or anatomical disconnection. 
As one skilled in the art will recognize, optimization of the method of the 
present invention can be achieved by varying specific stimulation 
parameters (such as intensity, frequency, pulse width, on time and off 
time, and duty cycle) while monitoring cognitive function as assessed by 
standard neuropsychologic instruments of working memory, attention, and/or 
intention. Optimization can also be effected by monitoring specific 
regional and intrahemispheric changes in distribution of signal power and 
coherence within the frequency spectrum. 
It is believed that the mechanism which permits treatment of patients 
having impaired cognitive function with electrical stimulation of his or 
her intralaminar nuclei is based, in part, on applicant's newly theorized 
role for the intralaminar nuclei in cognitive operations, which is set 
forth in Purpura, which is hereby incorporated by reference. Although the 
present invention is not meant in any way to be limited by the mechanism 
in which it operates, for example, as set forth in Purpura, it is believed 
that the proposed mechanism may assist in optimizing the method of the 
present invention. 
In another aspect of the present invention, coordination of function across 
cortical regions in a patient is improved by applying electrical 
stimulation to two or more subdivisions of the patient's intralaminar 
nuclei. Improved coordination of function across cortical regions, as used 
herein, is meant to include improved functional interactions of specific 
cortical regions within and across left and right hemispheres, such as 
those discussed above in regard to the effects of vestibular stimulation. 
In this method, the two or more subdivisions of the patient's intralaminar 
nuclei modulate separate cortical regions. Preferably, the electrical 
stimulation applied to the two or more subdivisions of the intralaminar 
nuclei is synchronized or periodic, more preferably, synchronized and 
periodic. Suitable frequencies for use in the method of this aspect of the 
present invention range from about 1 Hz to 1 kHz; preferably, from about 
10 Hz to about 500 Hz; and, more preferably, from about 50 Hz to about 250 
Hz. 
Several possible mechanisms may explain the improved coordination of 
function across cortical regions which is believed to result from 
application of electrical stimulation to two or more subdivisions of the 
patient's intralaminar nuclei. These include changes in global dynamics of 
a distributed neural network, changes in inhibition or excitation at one 
or more points in large loops of circuits activated by ILN inputs, and 
increases in metabolic rates that change the firing rates or other 
cellular processes. Also, increases in synchrony may promote increased 
firing rate and increased metabolism or vice versa. 
Applicant's copending U.S. Provisional Patent Application Serial No. 
60/062,728, filed Oct. 22, 1997, is hereby incorporated by reference. 
The present invention is further illustrated by the following examples. 
EXAMPLES 
Example 1 
Clinical History 
A 28 year old man with no past medical history suffers coup and contre coup 
head injuries in a motor vehicle accident. MRI imaging reveals a large 
hemorrhage of the right parietal cortex, left prefrontal, and bilateral 
(left greater than right) orbitofrontal white matter. These changes are 
consistent with contre coup injury. In addition, the patient has small 
petechial areas of blood in the corpus callosum consistent with shear 
force injury. The patient is comatose initially for 2 weeks and gradually 
recovers consciousness over a 4-8 week period, achieving a new baseline 
which stabilizes at 3 months. Over the next six months the patient is 
noted to demonstrate fluctuations of interactive behavior. At baseline, 
the patient neglects the left side of his body which typically exhibits no 
spontaneous movement. At other times the patient will spontaneously 
interact, speak and follow commands. He remains usually stimulus-bound 
(i.e., he is dependent on prompting by those around him and exhibits a 
paucity of spontaneous behavior). His "good" times last for weeks, as do 
his "bad" times where he is awake but minimally interactive. Although, at 
times, he is nearly able to feed himself and/or perform other basic 
activities of daily living, on average, his fluctuations and profound 
short-term memory impairments require that he remain in a full-time 
nursing facility despite his family's strong desire to care for him at 
home. 
Example 2 
Intervention 
Because, at his best, the patient in Example 1 is close to a level where 
part-time care at home would be possible (e.g., within 10 points on a 
Karnofsky scale of function), he is evaluated for deep brain stimulation 
to optimize his brain function. In the course of evaluation, several 
important observations are made. First, the patient's left-sided neglect, 
attributable to the right parietal hemorrhage, is markedly improved upon 
irrigation of the left external ear canal. In addition, irrigation of the 
left external ear canal produces spontaneous movements of the left arm. 
Second, FDG-PET reveals depressed right parietal, left prefrontal, and 
left greater than right orbitofrontal metabolism compared against other 
regions within the patient's brain that are within normal ranges and 
against normative values for these brain areas. Third, there is MEG 
evidence of decreased high frequency activity over the right parietal 
cortex and left prefrontal cortex. This correlates with the FDG-PET 
evaluation. Based on these observations, the patient is chosen for the 
deep brain stimulation method of the present invention. 
Using the clinical, MRI, PET, and MEG data, the following intralaminar 
nuclei subdivisions are chosen for stimulation. The rationale for choosing 
these sites is explained below. The patient's spontaneous fluctuations 
support the interference that several different dynamic patterns may 
organize this patient's brain function at any one time, with some patterns 
more optimal than others. The injuries to the right parietal cortex (the 
dominant cortical area for attention) and the left prefrontal and 
orbitofrontal (important for working memory, motor planning, and 
intention) suggest the cortical areas where intervention may push the 
brain toward the more optimal pattern. The presence of metabolic and 
physiologic activity depressed below normal levels indicates both that 
some function remains in these areas but that this function is abnormal. 
Intralaminar nuclei subdivisions are chosen to modulate these cortical 
areas. 
The right centromedian-parafasicularis ("Cm-Pf") nucleus is chosen for 
several reasons, including its strong projections to the parietal and 
premotor cortices in the right hemisphere, which cortices modulate the 
motor neglect and attentional impairments evident in this patient. In 
addition, the evidence of shear injury on the MRI and history of coma 
suggest damage to ascending arousal inputs to the cortex which could be 
supported by increased activation of the Cm-Pf nucleus which is most 
strongly innervated by the arousal systems. Placement of such Cm-Pf 
electrodes is well-known in the art. 
The left paracentralis ("Pc"), central lateral ("CL"), and paralamellar MD 
regions of the intralaminar nuclei are also chose as targets. Since these 
are small and closely spaced, the multipolar electrode is likely to 
activate at least one or two of these targets with each contact when 
optimally placed. Placement of this electrode is guided by the activation 
of widespread but specific cortical areas by stimulation of the lateral 
aspect of CL along its anterior-posterior extent (See, for example, 
Tasker, which is hereby incorporated by reference). These areas are chosen 
because of their strong inputs to prefrontal cortex (Pc, paralamellar 
MD&gt;CL) and, in the case of paralamellar MD, known influence on working 
memory. An alternative site for this electrode would pass into CeM to 
modulate orbitofrontal cortical activations. The approach could be 
optimized based on other considerations, such as safety of entry point. 
After placement of the electrode(s) in the operating room, activation of 
the right Cm-Pf stimulator elicits spontaneous left arm movements. While 
no similarly dramatic behavioral change is noted with the left 
Pc/CL/paralamellar MD stimulator, scalp EEG electrodes monitored by a 
digital-EEG with spectral displays show increased high frequency activity 
over the left prefrontal cortex. The stimulators are left in place and the 
patient is brought to rehabilitation. It is predicted, based on increased 
attentional and working memory capacity along with improved spontaneous 
movement and left-sided motor control, that the patient will demonstrate 
increased capacity to perform activities of daily living. 
Although the invention has been described in detail for the purpose of 
illustration, it is understood that such detail is solely for that 
purpose, and variations can be made therein by those skilled in the art 
without departing from the spirit and scope of the invention which is 
defined by the following claims.